bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing non-response rates for the National Child Safety Seat Survey in Canada
Authors: Yi Wen Tang , Snowdon Anne W , Hussein Abdulkadir , Ahmed S Ejaz
Published: November 2010

Background

Canada has a Road Safety Vision of having the safest roads in the world, yet vehicle crashes have remained the leading cause of death of Canadian children for a number of years.

Objectives

Determine the influence of high rates of non-participation on the estimates for correct use of safety seats for child occupants in vehicles. Examine the impact of three different criteria for determining correct safety seat use on the estimates of correct use of safety seats for children in Canada.

Methods

A national child seat safety survey was conducted in 200 randomly selected sites across Canada that included both naturalistic observation of child seat safety use at intersections and a detailed vehicle inspection in nearby parking lots. Non-participation in the detailed parking lot study was high. This study reports on statistical methods for managing high rates of non-response and compared estimates of correct use using three different criteria.

Results and conclusions

Results revealed that high non-participation rates introduced bias into the raw estimates of correct safety seat use. Correct use estimates also varied substantially depending on which criterion (more stringent or less stringent) for correct use was applied in the analysis. When child age was the only criterion for correct use, estimates were higher than when more stringent criteria of child height and weight were applied to estimate rates of correct use. This study identifies the importance of managing high rates of non-response in safety seat observation studies using statistical techniques. Stringent criteria for correct use may provide more accurate estimates of the correct use of safety seats. Studies of child seat use in vehicles (using voluntary participation) may benefit from the use of naturalistic observation to capture non-participants' use of child occupant restraints, as it may more accurately estimate the rates of correct use in populations.
Fine needle aspiration cytology is a valuable adjunct to axillary ultrasound in the preoperative staging of breast cancer
Authors: MacNeill Morna , Arnott Isobel , Thomas Jeremy
Published: November 2010

Aims

To compare the predictive values of axillary ultrasound (US) combined with fine needle aspiration (FNA) cytology with tumour size (T stage) and grade in the preoperative staging of breast cancer. More precise definition of axillary FNA reporting nomenclature is also presented.

Patients and Methods

314 patients: 119 patients had suspicious US investigated by FNA, 195 patients had normal US not investigated further preoperatively. This study examined the node-positive and node-negative cases in these two groups, calculating predictive values for cytology, US, T stage and tumour grade, and tested comparisons for significance.

Results

Axillary FNA has a positive predictive value of 84.8% compared with US (66.7%). The difference is significant (p=0.008). Negative US has a negative predictive value of 81.0% compared with a negative predictive value for cytology of 66.7%, but the difference is not significant (p=0.08). 43% of patients with unsatisfactory cytology were node positive. Of 195 patients with negative axillary US, 37 (19%) had metastatic nodal disease. Fewer than 20% of these patients had micrometastases alone. Tumour size and grade influenced node status in US-suspicious cases only.

Conclusion

Axillary FNA adds significantly to the positive predictive value provided by US. US gives false-negative results in 19% of cases and only a small proportion of these can be explained by micrometastases. Unsatisfactory cytology needs to be repeated because of a high rate of positive nodes in this group.
The dorsal root ganglion under attack: the acquired sensory ganglionopathies
Authors: Sheikh Sarah I , Amato Anthony A
Published: November 2010

Acquired sensory ganglionopathies—or sensory neuronopathies—are a rare type of peripheral neuropathy characterised by damage to the sensory nerve cell bodies in the dorsal root ganglia. Subacute or chronic in onset, sensory ganglionopathies typically present with a non-length dependent pattern of large fibre sensory loss. The causes of this distinct clinical picture include paraneoplastic syndromes, immune mediated diseases, infections, as well as drug, toxin and excess vitamin exposure. Here we discuss the clinical and pathological features of acquired sensory ganglionopathies and focus on a practical approach to their diagnosis and management.
Reversible heart failure: the role of inflammatory activation
Authors: Robinson Tim , Smith Alyson , Channer Kevin S
Published: November 2010

Heart failure is increasingly common in western populations and is an inevitable consequence of the improved survival after myocardial infarction, and of an ageing population. Heart failure is usually relentlessly progressive as the maladaptive processes triggered by the physiological changes of the condition lead to further deterioration. However, in certain circumstances, heart failure is transient or potentially reversible when it occurs as part of intense systemic inflammatory activation. This review considers the role of inflammation in the aetiology of heart failure, and illustrates the strategies which have been used to modify the inflammatory response with anonymised clinical case reports.
Spatial and temporal heterogeneities are localized to the right ventricular outflow tract in a heterozygotic Scn5a mouse model
Authors: Martin Claire A. , Grace Andrew A. , Huang Christopher L.-H.
Published: November 2010

Ventricular tachycardia (VT) in Brugada Syndrome patients often originates in the right ventricular outflow tract (RVOT). We explore the physiological basis for this observation using murine whole heart preparations. Ventricular bipolar electrograms and monophasic action potentials were recorded from seven epicardial positions in Langendorff-perfused wild-type and Scn5a+/− hearts. VT first appeared in the RVOT, implicating it as an arrhythmogenic focus in Scn5a+/− hearts. RVOTs showed the greatest heterogeneity in refractory periods, response latencies, and action potential durations, and the most fractionated electrograms. However, incidences of concordant alternans in dynamic pacing protocol recordings were unaffected by the Scn5a+/− mutation or pharmacological intervention. Conversely, particularly at the RVOT, Scn5a+/− hearts showed earlier and more frequent transitions into discordant alternans. This was accentuated by flecainide, but reduced by quinidine, in parallel with their respective pro- and anti-arrhythmic effects. Discordant alternans preceded all episodes of VT. The RVOT of Scn5a+/− hearts also showed steeper restitution curves, with the diastolic interval at which the gradient equaled one strongly correlating with the diastolic interval at which discordant alternans commenced. We attribute the arrhythmic tendency within the RVOT to the greater spatial heterogeneities in baseline electrophysiological properties. These, in turn, give rise to a tendency to drive concordant alternans phenomena into an arrhythmogenic discordant alternans. Our findings may contribute to future work investigating possible pharmacological treatments for a disease in which the current mainstay of treatment is implantable cardioverter defibrillator implantation.
Slow and incomplete sympathetic reinnervation of rat tail artery restores the amplitude of nerve-evoked contractions provided a perivascular plexus is present
Authors: Tripovic Diana , Pianova Svetlana , McLachlan Elspeth M. , Brock James A.
Published: November 2010

We have investigated the recovery of sympathetic control following reinnervation of denervated rat tail arteries by relating the reappearance of noradrenergic terminals to the amplitude of nerve-evoked contractions of isometrically mounted artery segments in vitro. We have also assessed reactivity to vasoconstrictor agonists. Freezing the collector nerves near the base of the tail in adult rats denervated the artery from ∼40 mm along the tail. Restoration of the perivascular plexus declined along the length of the tail, remaining incomplete for >6 mo. After 4 mo, nerve-evoked contractions were prolonged but of comparable amplitude to control at ∼60 mm along the tail; they were smaller at ∼110 mm. At ∼60 mm, facilitation of contractions to short trains of stimuli by the norepinephrine transporter blocker, desmethylimipramine, and by the α2-adrenoceptor antagonist, idazoxan, was reduced in reinnervated arteries. Blockade of nerve-evoked contractions by the α1-adrenoceptor antagonist, prazosin, was less and by idazoxan greater than control after 8 wk but similar to control after 16 wk. Sensitivity of reinnervated arteries to the α1-adrenoceptor agonist, phenylephrine, was raised in the absence but not in the presence of desmethylimipramine. Sensitivity to the α2-adrenoceptor agonist, clonidine, was maintained in 16-wk reinnervated arteries when it had declined in controls. Thus regenerating sympathetic axons have a limited capacity to reinnervate the rat tail artery, but nerve-evoked contractions match control once a relatively sparse perivascular plexus is reestablished. Functional recovery involves prolongation of contractions and deficits in both clearance of released norepinephrine and autoinhibition of norepinephrine release.
Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2in Pseudomonas aeruginosa-infected epithelial cells
Authors: Hurley Bryan P. , Pirzai Waheed , Mumy Karen L. , Gronert Karsten , McCormick Beth A.
Published: November 2010

Airway neutrophil infiltration is a pathological hallmark observed in multiple lung diseases including pneumonia and cystic fibrosis. Bacterial pathogens such as Pseudomonas aeruginosa instigate neutrophil recruitment to the air space. Excessive accumulation of neutrophils in the lung often contributes to tissue destruction. Previous studies have unveiled hepoxilin A3as the key molecular signal driving neutrophils across epithelial barriers. The eicosanoid hepoxilin A3is a potent neutrophil chemoattractant produced by epithelial cells in response to infection with P. aeruginosa . The enzyme phospholipase A2liberates arachidonic acid from membrane phospholipids, the rate-limiting step in the synthesis of all eicosanoids, including hepoxilin A3. Once generated, aracidonic acid is acted upon by multiple cyclooxygenases and lipoxygenases producing an array of functionally diverse eicosanoids. Although there are numerous phospholipase A2isoforms capable of generating arachidonic acid, the isoform most often associated with eicosanoid generation is cytoplasmic phospholipase A2α. In the current study, we observed that the cytoplasmic phospholipase A2α isoform is required for mediating P. aeruginosa -induced production of certain eicosanoids such as prostaglandin E2. However, we found that neutrophil transepithelial migration induced by P. aeruginosa does not require cytoplasmic phospholipase A2α. Furthermore, P. aeruginosa -induced hepoxilin A3production persists despite cytoplasmic phospholipase A2α suppression and generation of the 12-lipoxygenase metabolite 12-HETE is actually enhanced in this context. These results suggest that alterative phospholipase A2isoforms are utilized to synthesize 12-lipoxygenase metabolites. The therapeutic implications of these findings are significant when considering anti-inflammatory therapies based on targeting eicosanoid synthesis pathways.
Dermatophagoides pteronyssinus 2regulates nerve growth factor release to induce airway inflammation via a reactive oxygen species-dependent pathway
Authors: Ye Yi-Ling , Wu Hung-Tsung , Lin Chiou-Feng , Hsieh Chia-Yuan , Wang Jiu-Yao , Liu Fu-Hua , Ma Ching-Ting , Bei Chia-Hao , Cheng Yu-Lun , Chen Ching-Chun , Chiang Bor-Luen , Tsao Chiung-Wen
Published: November 2010

Group 2 allergen of Dermatophagoides pteronyssinus 2 (Der p2) induces airway inflammation without protease activity, and elevated nerve growth factor (NGF) levels are also found in this inflammation. How the allergen Der p2 regulates NGF release via reactive oxygen species (ROS) to induce inflammation remains unclear. In the present study, intratracheal administration of Der p2 to mice led to inflammatory cell infiltration, mucus gland hyperplasia, and NGF upregulation in the bronchial epithelium, as well as elevated ROS and NGF production in bronchoalveolar lavage fluids. In addition, Der p2 caused fibrocyte accumulation and mild fibrosis. p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) inhibitors inhibited Der p2-induced NGF release in LA4 lung epithelial cells and MLg lung fibroblasts. Pretreatment with an antioxidant, tiron, reduced the Der p2-induced ROS production, NGF expression and release, p38 MAPK or JNK phosphorylation, and airway inflammation. These results suggest that Der p2 allergen-induced airway inflammation and elevated NGF release were through increasing ROS production and a MAPK-dependent pathway. The use of an antioxidant, tiron, may provide a new therapeutic modality for the treatment of allergic asthma.
Caveolin-1: a critical regulator of lung injury
Authors: Jin Yang , Lee Seon-Jin , Minshall Richard D. , Choi Augustine M. K.
Published: November 2010

Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. Cav-1 regulates critical cell functions including proliferation, apoptosis, cell differentiation, and transcytosis via diverse signaling pathways. Abundant in almost every cell type in the lung, including type I epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, macrophages, and neutrophils, cav-1 plays a crucial role in the pathogenesis of acute lung injury (ALI). ALI and its severe form, acute respiratory distress syndrome (ARDS), are responsible for significant morbidity and mortality in intensive care units, despite improvement in ventilation strategies. The pathogenesis of ARDS is still poorly understood, and therapeutic options remain limited. In this article, we summarize recent data regarding the regulation and function of cav-1 in lung biology and pathology, in particular as it relates to ALI. We further discuss the potential molecular and cellular mechanisms by which cav-1 expression contributes to ALI. Investigating the cellular functions of cav-1 may provide new insights for understanding the pathogenesis of ALI and provide novel targets for therapeutic interventions in the future.
TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness
Authors: Gilliam Laura A. A. , Moylan Jennifer S. , Ferreira Leonardo F. , Reid Michael B.
Published: November 2010

Doxorubicin, a common chemotherapeutic agent, causes respiratory muscle weakness in both patients and rodents. Tumor necrosis factor-α (TNF), a proinflammatory cytokine that depresses diaphragm force, is elevated following doxorubicin chemotherapy. TNF-induced diaphragm weakness is mediated through TNF type 1 receptor (TNFR1). These findings lead us to hypothesize that TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm muscle weakness. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via intravenous injection. Three days later, we measured contractile properties of muscle fiber bundles isolated from the diaphragm. We tested the involvement of TNF/TNFR1 signaling using pharmaceutical and genetic interventions. Etanercept, a soluble TNF receptor, and TNFR1 deficiency protected against the depression in diaphragm-specific force caused by doxorubicin. Doxorubicin stimulated an increase in TNFR1 mRNA and protein ( P < 0.05) in the diaphragm, along with colocalization of TNFR1 to the plasma membrane. These results suggest that doxorubicin increases diaphragm sensitivity to TNF by upregulating TNFR1, thereby causing respiratory muscle weakness.
MCP-1/CCR2B-dependent loop upregulates MUC5AC and MUC5B in human airway epithelium
Authors: Monzon Maria E. , Forteza Rosanna Malbrán , Casalino-Matsuda S. Marina
Published: November 2010

Cigarette smoke represents a major risk factor for the development of chronic obstructive pulmonary disease (COPD), a respiratory condition associated with airflow obstruction, mucus hypersecretion, chronic inflammation, and upregulation of inflammatory mediators such as the monocyte chemotactic protein-1 (MCP-1). MCP-1 through its receptor CCR2 induces chemotaxis and activates44/42MAPK, a kinase known to play a key role in mucin regulation in bronchial epithelium. In the present study we used differentiated primary cultures of normal human bronchial epithelial (NHBE) cells to test whether MCP-1 through its receptor CCR2 induces mucin upregulation. We have provided evidence that NHBE cells release MCP-1 to the epithelial surface and express the CCR2B isoform of the receptor mainly at the apical pole. In addition, we found that MCP-1 has a novel function in airway epithelium, increasing the two major airway mucins MUC5AC and MUC5B, an effect mediated, at least in part, by a cascade of events initiated by interaction of its receptor CCR2B with Gqsubunits in caveolae, followed by PLCβ, PKC, and44/42MAPK activation. We also have shown that MCP-1 is able to induce its own expression using the same receptor but through a different pathway that involves RhoA GTPase. Furthermore, we found that a single exposure to MCP-1 is enough to induce MCP-1 secretion and sustained mucin upregulation up to 7 days after initial exposure, an effect mediated by CCR2B as confirmed using short hairpin RNA. These results agree with our data in smoker's airway epithelium, where CCR2B is present in MUC5AC- and MUC5B-expressing cells and augmented MCP-1 expression is associated with increased MUC5AC and MUC5B immunolabeling, suggesting that the mechanisms described in primary cell cultures in the present study are operative in vivo. Therefore, therapeutic approaches targeting MCP-1/CCR2B may be useful in preventing not only influx of inflammatory cells to the airways but also mucus hypersecretion and goblet cell hyperplasia.
PDGFR Signaling Blockade in Marrow Stroma Impairs Lung Cancer Bone Metastasis
Authors: Catena Raúl , Luis-Ravelo Diego , Antón Iker , Zandueta Carolina , Salazar-Colocho Pablo , Larzábal Leyre , Calvo Alfonso , Lecanda Fernando
Published: November 2010

Bone microenvironment and cell–cell interactions are crucial for the initiation and development of metastasis. By means of a pharmacologic approach, using the multitargeted tyrosine kinase inhibitor sunitinib, we tested the relevance of the platelet-derived growth factor receptor (PDGFR) axis in the bone marrow (BM) stromal compartment for the initiation and development of lung cancer metastasis to bone. PDGFRβ was found to be the main tyrosine kinase target of sunitinib expressed in BM stromal ST-2 and MC3T3-E1 preosteoblastic cells. In contrast, no expression of sunitinib-targeted receptors was found in A549M1 and low levels in H460M5 lung cancer metastatic cells. Incubation of ST-2 and human BM endothelial cells with sunitinib led to potent cell growth inhibition and induction of apoptosis in a dose-dependent manner. Similarly, sunitinib induced a robust proapoptotic effect in vivo on BM stromal PDGFRβ+ cells and produced extensive disruption of tissue architecture and vessel leakage in the BM cavity. Pretreatment of ST-2 cells with sunitinib also hindered heterotypic adhesion to lung cancer cell lines. These effects were correlated with changes in cell–cell and cell–matrix molecules in both stromal and tumor cells. Pretreatment of mice with sunitinib before intracardiac inoculation of A549M1 or H460M5 cells caused marked inhibition of tumor cells homing to bone, whereas no effect was found when tumor cells were pretreated before inoculation. Treatment with sunitinib dramatically increased overall survival and prevented tumor colonization but not bone lesions, whereas combination with zoledronic acid resulted in marked reduction of osteolytic lesions and osseous tumor burden. Thus, disruption of the PDGFR axis in the BM stroma alters heterotypic tumor–stromal and tumor–matrix interactions, thereby preventing efficient engagement required for bone homing and osseous colonization. These results support the notion that concomitant targeting of the tumor and stromal compartment is a more effective approach for blocking bone metastasis. Cancer Res; 71(1); 164–74. ©2010 AACR.
Genetic and Structural Variation in the Gastric Cancer Kinome Revealed through Targeted Deep Sequencing
Authors: Zang Zhi Jiang , Ong Choon Kiat , Cutcutache Ioana , Yu Willie , Zhang Shen Li , Huang Dachuan , Ler Lian Dee , Dykema Karl , Gan Anna , Tao Jiong , Lim Siyu , Liu Yujing , Futreal P. Andrew , Grabsch Heike , Furge Kyle A. , Goh Liang Kee , Rozen Steve , Teh Bin Tean , Tan Patrick
Published: November 2010

Genetic alterations in kinases have been linked to multiple human pathologies. To explore the landscape of kinase genetic variation in gastric cancer (GC), we used targeted, paired-end deep sequencing to analyze 532 protein and phosphoinositide kinases in 14 GC cell lines. We identified 10,604 single-nucleotide variants (SNV) in kinase exons including greater than 300 novel nonsynonymous SNVs. Family-wise analysis of the nonsynonymous SNVs revealed a significant enrichment in mitogen-activated protein kinase (MAPK)-related genes (P < 0.01), suggesting a preferential involvement of this kinase family in GC. A potential antioncogenic role for MAP2K4, a gene exhibiting recurrent alterations in 2 lines, was functionally supported by siRNA knockdown and overexpression studies in wild-type and MAP2K4 variant lines. The deep sequencing data also revealed novel, large-scale structural rearrangement events involving kinases including gene fusions involving CDK12 and the ERBB2 receptor tyrosine kinase in MKN7 cells. Integrating SNVs and copy number alterations, we identified Hs746T as a cell line exhibiting both splice-site mutations and genomic amplification of MET, resulting in MET protein overexpression. When applied to primary GCs, we identified somatic mutations in 8 kinases, 4 of which were recurrently altered in both primary tumors and cell lines (MAP3K6, STK31, FER, and CDKL5). These results demonstrate that how targeted deep sequencing approaches can deliver unprecedented multilevel characterization of a medically and pharmacologically relevant gene family. The catalog of kinome genetic variants assembled here may broaden our knowledge on kinases and provide useful information on genetic alterations in GC. Cancer Res; 71(1); 29–39. ©2011 AACR.
Tumor Growth Inhibition by Olaparib in BRCA2 Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts
Authors: Kortmann Ursula , McAlpine Jessica N. , Xue Hui , Guan Jun , Ha Gavin , Tully Sophie , Shafait Sharaz , Lau Alan , Cranston Aaron N. , O'Connor Mark J. , Huntsman David G. , Wang Yuzhuo , Gilks C. Blake
Published: November 2010

Purpose: Most patients with ovarian carcinomas succumb to their disease and there is a critical need for improved therapeutic approaches. Carcinomas arising in BRCA mutation carriers display defective DNA double-strand break repair that can be therapeutically exploited by inhibition of PARP-1, a key enzyme in the repair of DNA single-strand breaks, creating synthetic lethality in tumor cells.

Experimental Design: To investigate synthetic lethality in vivo, we established a BRCA2 germline-mutated xenograft model that was developed directly from human ovarian cancer tissue, treated with the PARP inhibitor olaparib (AZD2281) alone and in combination with carboplatin.

Results: We show that olaparib alone and in combination with carboplatin greatly inhibit growth in BRCA2-mutated ovarian serous carcinoma. This effect was not observed in a serous carcinoma with normal BRCA function, showing a specific antitumor effect of olaparib in mutation carriers. Immunohistochemistry (cleaved caspase-3 and Ki-67 stains) of remnant tissue after olaparib treatment revealed significantly decreased proliferation and increased apoptotic indices in these tumors compared with untreated controls. Furthermore, olaparib-treated tumors showed highly reduced PARP-1 activity that correlated with olaparib levels.

Conclusions: We established a BRCA2-mutated human ovarian cancer xenograft model suitable for experimental drug testing. The demonstrated in vivo efficacy of olaparib extends on the preclinical rationale for further clinical trials targeting ovarian cancer patients with BRCA mutations. Clin Cancer Res; 17(4); 783–91. ©2010 AACR.
Genetic Polymorphisms Associated with a Prolonged Progression-Free Survival in Patients with Metastatic Renal Cell Cancer Treated with Sunitinib
Authors: van der Veldt Astrid A.M. , Eechoute Karel , Gelderblom Hans , Gietema Jourik , Guchelaar Henk-Jan , van Erp Nielka P. , van den Eertwegh Alfons J.M. , Haanen John B. , Mathijssen Ron H.J. , Wessels Judith A.M.
Published: November 2010

Purpose: The objective of this study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a prolonged progression-free survival (PFS) and/or overall survival (OS) in patients with clear-cell metastatic renal cell cancer (mRCC) treated with sunitinib.

Experimental design: A retrospective multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 30 polymorphisms in 11 candidate genes, together with clinical characteristics were tested univariately for association with PFS as primary and OS as secondary outcome. Candidate variables with P < 0.1 were analyzed in a multivariate Cox regression model.

Results: Multivariate analysis showed that PFS was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P = 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; HR, 1.76; P = 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P = 0.033). Carriers with a favorable genetic profile (n = 95) had an improved PFS and OS as compared with noncarriers (median PFS and OS: 13.1 versus 7.5 months and 19.9 versus 12.3 months). Next to the genetic variants, the Memorial Sloan-Kettering Cancer Center prognostic criteria were associated with PFS and OS (HR, 1.99 and 2.27; P < 0.001).

Conclusions: This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in mRCC patients treated with this drug. These findings advocate prospective validation and further elucidation of these genetic determinants in relation to sunitinib exposure and efficacy. Clin Cancer Res; 17(3); 620–9. ©2010 AACR.
Extent and Patterns ofMGMTPromoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres
Authors: Sciuscio Davide , Diserens Annie-Claire , van Dommelen Kristof , Martinet Danielle , Jones Greg , Janzer Robert-Charles , Pollo Claudio , Hamou Marie-France , Kaina Bernd , Stupp Roger , Levivier Marc , Hegi Monika E.
Published: November 2010

Purpose: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma.

Experimental Design: Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity.

Results: In glioblastoma, MGMT-methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception (<50%). The CpG methylation patterns were characteristic for each glioblastoma exhibiting 25% to 90% methylated CpGs of 28 sites interrogated. Furthermore, MGMT promoter methylation was associated with a nonpermissive chromatin status in accordance with very low MGMT transcript levels and undetectable MGMT activity.

Conclusions: In MGMT-methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy. Clin Cancer Res; 17(2); 255–66. ©2010 AACR.
High Impact of Oatp1a/1b Transporters on In Vivo Disposition of the Hydrophobic Anticancer Drug Paclitaxel
Authors: van de Steeg Evita , van Esch Anita , Wagenaar Els , van der Kruijssen Cornelia M.M. , van Tellingen Olaf , Kenworthy Kathryn E. , Schinkel Alfred H.
Published: November 2010

Purpose: Organic anion-transporting polypeptides (OATP) mediate the cellular uptake of a broad range of drugs. The hydrophobic anticancer drug, paclitaxel (PTX), was recently identified as a substrate for OATP1B3 in vitro. We investigated the role of Oatp1a/1b transporters in the pharmacokinetics of PTX in vivo, as well as their impact at different dose levels of PTX and methotrexate (MTX).

Experimental Design: Recently generated Slco1a/1b−/− (lacking all Oatp1a/1b transporters) and wild-type mice were intravenously dosed with 2, 10, or 50 mg/kg of PTX, or with 10, 50, or 500 mg/kg of MTX, and plasma and tissue drug concentrations were measured.

Results: In spite of its hydrophobicity, PTX systemic exposure (at 10 mg/kg) was increased by greater than 2-fold in Slco1a/1b−/− mice compared with wild-type, whereas PTX liver uptake was reduced by about 2-fold. Oatp1a/1b transporters displayed a high impact on PTX and MTX pharmacokinetics over a broad dose range. For MTX, even at 500 mg/kg, saturation of Oatp1a/1b was not observed, with a 3.4-fold increase in plasma and 30-fold decrease in liver levels in Slco1a/1b−/− mice compared with wild-type. Although beginning saturation of Oatp1a/1b was observed at the highest dose of PTX, plasma levels in Slco1a/1b−/− mice were still 1.7-fold increased and liver levels 1.5-fold decreased compared with wild-type.

Conclusion: Oatp1a/1b transporters play a pronounced role in determining plasma levels and tissue distribution of MTX and PTX, thus affecting even highly hydrophobic drugs. Variation in OATP1A/1B transporter activity, due to genetic variation, inhibition, and/or tumor expression might affect toxicity and therapeutic efficacy of these anticancer drugs. Clin Cancer Res; 17(2); 294–301. ©2010 AACR. Clin Cancer Res; 17(2); 294–301. ©2010 AACR.
NSAID Inhibition of Prostate Cancer Cell Migration Is Mediated by Nag-1 Induction via the p38 MAPK-p75NTR Pathway
Authors: Wynne Shehla , Djakiew Daniel
Published: November 2010

The nonsteroidal anti-inflammatory drugs (NSAID) R-flurbiprofen and ibuprofen have been shown to induce expression of p75NTR (neurotrophin receptor) in prostate cancer cell lines. p75NTR, a tumor necrosis factor receptor superfamily member, is a proapoptotic protein that functions as a tumor suppressor in the human prostate. Expression of p75NTR is lost as prostate cancer progresses and is minimal in several metastatic prostate cancer cell lines. NSAIDs induce p75NTR through activation of the p38 mitogen-activated protein kinase (MAPK) pathway, with a concomitant decrease in cell survival. Here, we show that treatment with R-flurbiprofen and ibuprofen induces expression of the NSAID-activated gene-1 (Nag-1) protein, a divergent member of the TGF beta (TGF-β) family, in PC-3 cells. Using the selective pharmacologic inhibitor of p38 MAPK, SB202190, and p38 MAPK-specific siRNA (small interfering RNA), we show that Nag-1 induction following NSAID treatment is mediated by the p38 MAPK pathway. p75NTR-specific siRNA pretreatment shows that Nag-1 induction by NSAIDs is downstream of p75NTR induction. Decreased survival of NSAID-treated cells is rescued by p75NTR-specific siRNA but not by Nag-1 siRNA. Transwell chamber and in vitro wound healing assays demonstrate decreased cell migration upon NSAID treatment. Pretreatment of PC-3 cells with p75NTR and Nag-1–specific siRNA shows that NSAID inhibition of cell migration is mediated by Nag-1 and p75NTR. These results demonstrate a role for Nag-1 in NSAID inhibition of cell migration, but not survival. Mol Cancer Res; 8(12); 1656–64. ©2010 AACR.
Cannabinoid Receptors, CB1 and CB2, as Novel Targets for Inhibition of Non–Small Cell Lung Cancer Growth and Metastasis
Authors: Preet Anju , Qamri Zahida , Nasser Mohd W , Prasad Anil , Shilo Konstantin , Zou Xianghong , Groopman Jerome E. , Ganju Ramesh K.
Published: November 2010

Non–small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC. We observed expression of CB1 (24%) and CB2 (55%) in NSCLC patients. Furthermore, we have shown that the treatment of NSCLC cell lines (A549 and SW-1573) with CB1/CB2- and CB2-specific agonists Win55,212-2 and JWH-015, respectively, significantly attenuated random as well as growth factor-directed in vitro chemotaxis and chemoinvasion in these cells. We also observed significant reduction in focal adhesion complex, which plays an important role in migration, upon treatment with both JWH-015 and Win55,212-2. In addition, pretreatment with CB1/CB2 selective antagonists, AM251 and AM630, prior to JWH-015 and Win55,212-2 treatments, attenuated the agonist-mediated inhibition of in vitro chemotaxis and chemoinvasion. In addition, both CB1 and CB2 agonists Win55,212-2 and JWH-133, respectively, significantly inhibited in vivo tumor growth and lung metastasis (∼50%). These effects were receptor mediated, as pretreatment with CB1/CB2 antagonists abrogated CB1/CB2 agonist–mediated effects on tumor growth and metastasis. Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2. Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC. Cancer Prev Res; 4(1); 65–75. ©2010 AACR.
Chronic Electrical Stimulation of the Carotid Sinus Baroreflex Improves Left Ventricular Function and Promotes Reversal of Ventricular Remodeling in Dogs With Advanced Heart Failure
Authors: Sabbah Hani N. , Gupta Ramesh C. , Imai Makoto , Irwin Eric D. , Rastogi Sharad , Rossing Martin A. , Kieval Robert S.
Published: November 2010

Background—

Autonomic abnormalities exist in heart failure and contribute to disease progression. Activation of the carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electric activation of the CSB improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic heart failure.

Methods and Results—

Studies were performed in 14 dogs with coronary microembolization-induced heart failure (LV ejection fraction ≈25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos System (CVRx Inc, Minneapolis, Minn) and 6 were not and served as controls. All dogs were followed for 3 months, and none received other background therapy. During follow-up, treatment with CSB increased LV ejection fraction 4.0±2.4% compared with a reduction in control dogs of −2.8±1.0% (
P
<0.05). Similarly, treatment with CSB decreased LV end-systolic volume −2.5±2.7 mL compared with an increase in control dogs of 6.7±2.9 mL (
P
<0.05). Compared with control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac β
1
-adrenergic receptors, β-adrenergic receptor kinase, and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy.

Conclusions—

In dogs with advanced heart failure, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.
Myocardial Parvovirus B19 Persistence
Authors: Stewart Garrick C. , Lopez-Molina Javier , Gottumukkala Raju V.S.R.K. , Rosner Gregg F. , Anello Mary S. , Hecht Jonathan L. , Winters Gayle L. , Padera Robert F. , Baughman Kenneth L. , Lipes Myra A.
Published: November 2010

Background—

Multiple viruses have been isolated from the heart, but their significance remains controversial. We sought to determine the prevalence of cardiotropic viruses in endomyocardial biopsy (EMB) samples from adult patients with heart failure (HF) and to define the clinicopathologic profile of patients exhibiting viral positivity.

Methods and Results—

EMB from 100 patients (median ejection fraction, 30%; interquartile range [IQR], 20% to 45%) presenting for cardiomyopathy evaluation (median symptom duration, 5 months; IQR, 1 to 13 months) were analyzed by polymerase chain reaction for adenovirus, cytomegalovirus, enteroviruses, Epstein-Barr virus, and parvovirus B19. Each isolate was sequenced, and viral load was determined. Parvovirus B19 was the only virus detected in EMB samples (12% of subjects). No patient had antiparvovirus IgM antibodies, but all had IgG antibodies, suggesting viral persistence. The clinical presentation of parvovirus-positive patients was markedly heterogeneous with both acute and chronic HF, variable ventricular function, and ischemic cardiomyopathy. No patient met Dallas histopathologic criteria for active or borderline myocarditis. Two patients with a positive cardiac MRI and presumed “parvomyocarditis” had similar viral loads to autopsy controls without heart disease. The oldest parvovirus-positive patients were positive for genotype 2, suggesting lifelong persistence in the myocardium.

Conclusions—

Parvovirus B19 was the only virus isolated from EMB samples in this series of adult patients with HF from the United States. Positivity was associated with a wide array of clinical presentations and HF phenotypes. Our studies do not support a causative role for parvovirus B19 persistence in HF and, therefore, advocate against the use of antiviral therapy for these patients.
How Are the Form and Magnitude of DIF Effects in Multiple-Choice Items Determined by Distractor-Level Invariance Effects?
Authors: Penfield Randall D.
Published: November 2010

This article explores how the magnitude and form of differential item functioning (DIF) effects in multiple-choice items are determined by the underlying differential distractor functioning (DDF) effects, as modeled under the nominal response model. The results of a numerical investigation indicated that (a) the presence of one or more nonzero DDF effects implies a nonzero DIF effect; (b) the magnitude of the DDF effects creates an upper bound to the magnitude of the resulting DIF effect; (c) the presence of a large DDF effect does not necessarily imply a large DIF effect; (d) under the condition of constant DDF effects the resulting DIF effect is independent of other item properties (i.e., location and discrimination parameters), but under the condition of varying DDF effects the resulting DIF effect magnitude is dependent on other item properties; and (e) although crossing DIF can only exist with divergent (varying in sign) DDF effects, divergent DDF effects do not always yield crossing DIF. Implications of these findings for evaluating DIF effects and interpreting the causes of DIF effects are discussed.
Bullying Behavior, Parents’ Work Hours and Early Adolescents’ Perceptions of Time Spent With Parents
Authors: Christie-Mizell C. André , Keil Jacqueline M. , Laske Mary Therese , Stewart Jennifer
Published: November 2010

This research investigates the relationships among bullying behavior, mother’s and father’s work hours, and early adolescents’ perceptions of whether they spend sufficient time with their parents. In cross-sectional models, we find maternal work hours are modestly associated with increases in bullying behavior. However, in more rigorous change models, our findings indicate that over time maternal work hours bear no direct relationship to bullying behavior. Moreover, in our final models, an interaction between father’s work hours and perceptions of time spent with him has one of the most robust associations with bullying for adolescents. When paternal employment is full- or overtime and youth perceive they do not spend enough with their fathers, bullying behavior increases. Other important factors that shape bullying behavior are the quality of the home environment and the adolescent’s school performance.
Factors Predicting Homeowners’ Attitudes toward Tourism
Authors: Hao Huili , Long Patrick , Kleckley James
Published: November 2010

This study assessed factors predicting local resident and second home property owners’ attitudes toward tourism development and its impacts in a second home–intensive coastal county. A total of 860 respondents (468 permanent residents and 392 second home property owners) contributed information about their perceptions of the impacts of tourism and second home development on various dimensions of community life. Factor analysis was used to identify the primary attitude dimensions. Factors that predicted local resident property owners’ attitudes toward tourism include length of residence, land use, and quality of life, while only the land use factor predicted second home property owners’ attitudes toward tourism.
Development of a Scale to Measure Memorable Tourism Experiences
Authors: Kim Jong-Hyeong , Ritchie J. R. Brent , McCormick Bryan
Published: November 2010

The quality experiences provided to customers, which are indeed memorable, directly determine a business’s ability to generate revenue (Pine and Gilmore 1999). However, the extant tourism literature has provided limited explanation of the factors that characterize memorable tourism experiences. Thus, the goal of the present study was to develop a valid and reliable measurement scale that will assist in understanding the concept and in improving the effective management of the memorable experience. Following Churchill’s (1979) recommended process, we developed a 24-item memorable tourism experience scale that we believe is applicable to most destination areas. The scale comprises seven domains: hedonism, refreshment, local culture, meaningfulness, knowledge, involvement, and novelty. The data support this dimensional structure of the memorable tourism experience as well as its internal consistency and validity (i.e., content, construct, convergent, and discriminant validity). Theoretical and managerial implications of the study results are discussed in detail.
Contemporary Peace Support Operations
Authors: Michael Kobi , Ben-Ari Eyal
Published: November 2010

In this article the authors examine two set of issues that constrain contemporary peace support operations (PSOs): one centered on the kinds of knowledge prevalent in PSOs and the second involving the organizational structures that characterize them. The authors' aim is to show the deep discursive and structural limitations and contradictions that continue to characterize the actions of armed forces and the dominance of militaristic thinking within PSOs. This article centers on multidimensional peacekeeping marked by emphasizing two main points in regard to the complex nature of such peacekeeping. First, Western military thinking is still dominant in the professional discourse of peacekeeping despite the fact that in many cases it is less relevant to the arenas where it is applied (in weakened or failed states). Second, forces in second-generation peacekeeping missions are by definition a form of hybrid organizations, and therefore conceptual changes in regard to PSOs not only involve the realm of knowledge but also entail practical consequences for the very organizational means used to achieve their aims. The authors' analysis demonstrates the blending, hybridization, and linkages that are an essential part of PSOs as processes that carry both advantages and disadvantages for organizational action.
Creating a Culture of Clinical Excellence in Critical Care Nutrition
Authors: Heyland Daren K. , Heyland Richard D. , Cahill Naomi E. , Dhaliwal Rupinder , Day Andrew G. , Jiang Xuran , Morrison Siouxzy , Davies Andrew R.
Published: November 2010

Objective: To develop, validate, and implement a system to reward top performers in critical care nutrition practice and to illuminate characteristics of top‐performing intensive care units (ICUs). Design: An international, prospective, observational, cohort study conducted in May 2008. Setting: 179 ICUs from 18 countries. Patients: 2956 consecutively enrolled mechanically ventilated adult patients who stayed in the ICU for at least 72 hours. Interventions: To qualify for the “Best of the Best” (BOB) award, sites had to have implemented a nutrition protocol and contributed complete data on a minimum of 20 patients. Measurements and Main Results: Data on nutrition practices were collected from ICU admission to ICU discharge for a maximum of 12 days. Eligible sites were ranked based on their performance on the following 5 criteria: adequacy of provision of energy, use of enteral nutrition (EN), early initiation of EN, use of promotility drugs and small bowel feeding tubes, and adequate glycemic control. Of the 179 participating ICUs, 81 qualified for the BOB award. Overall, the average nutrition adequacy across sites was 56.2% (site range, 20.3%‐90.1%). The top 10 performers were identified and publicly recognized. Regression analysis suggested that the presence of a dietitian in the ICU was associated with a high BOB award ranking, whereas being located in the United States or China, relative to other participating countries, was associated with worst performance. Conclusions: There is variable performance with respect to critical care nutrition practices across the world.
Understanding Adherence to Guidelines in the Intensive Care Unit
Authors: Cahill Naomi E. , Suurdt Jeanette , Ouellette‐Kuntz Hélène , Heyland Daren K.
Published: November 2010

Background: Clinical practice guidelines (CPGs) have been hailed as a useful method of translating evidence into practice. Several CPGs have been published that provide recommendations for feeding patients in the intensive care unit (ICU). Despite a rigorous development process and active dissemination of these guidelines, their impact on nutrition practice has been modest. The purpose of this study was to develop a comprehensive framework for understanding adherence to nutrition CPGs in the critical care setting. Methods: Multiple case studies were completed at 4 Canadian ICUs. Semistructured interviews were conducted with 7 key informants at each ICU site who were asked about their perceptions and attitudes toward guidelines in general and the Canadian Critical Care Nutrition CPGs specifically. Interview transcripts and related documents were analyzed qualitatively using a framework approach. Results: The 5 key components of the developed framework were characteristics of the CPGs, the implementation process, institutional factors, provider intent, and the clinical condition of the patient. These key themes encapsulate numerous itemized factors that contribute to guideline adherence either as barriers or enablers. Conclusions: Adherence to nutrition CPGs is determined by a complex interaction of multiple factors that act as barriers or enablers. The comprehensive framework for adherence to CPGs in the ICU attempts to elucidate this process and provides a useful template for future research. Future quality improvement initiatives should assess local barriers to change and design interventions to overcome these barriers.