bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological Modulation of the Gating Properties of Small Conductance Ca2+-Activated K+ Channels Alters the Firing Pattern of Dopamine Neurons In Vivo
Authors: Herrik Kjartan F. , Christophersen Palle , Shepard Paul D.
Published: July 2010

Dopamine (DA) neurons are autonomous pacemakers that occasionally fire bursts of action potentials, discharge patterns thought to reflect tonic and phasic DA signaling, respectively. Pacemaker activity depends on the concerted and cyclic interplay between intrinsic ion channels with small conductance Ca2+-activated K+ (SK) channels playing an important role. Bursting activity is synaptically initiated but neither the transmitters nor the specific ion conductances involved have been definitively identified. Physiological and pharmacological regulation of SK channel Ca2+ sensitivity has recently been demonstrated and could represent a powerful means of modulating the expression of tonic/phasic signaling in DA neurons in vivo. To test this premise, we characterized the effects of intravenous administration of the novel positive and negative SK channel modulators NS309 and NS8593, respectively, on the spontaneous activity of substantia nigra pars compacta DA neurons in anesthetized C57BL/6 mice. NS309, dose-dependently decreased DA cell firing rate, increased the proportion of regular firing cells, and eventually stopped spontaneous firing. By contrast, systemic administration of the negative SK channel modulator NS8593 increased firing rate and shifted the pattern toward increased irregularity/bursting; an effect similar to local application of the pore blocking peptide apamin. The altered firing patterns resulting from inhibiting SK currents persisted independently of changes in firing rates induced by administration of DA autoreceptor agonists/antagonists. We conclude that pharmacological modulation of SK channel Ca2+-sensitivity represents a powerful mechanism for switching DA neuron firing activity between tonic and phasic signaling modalities in vivo.
Yield of Smear Microscopy and Radiological Findings of Male and Female Patients with Tuberculosis in Abuja, Nigeria
Authors: Lawson Lovett , Yassin Mohammed A. , Onuoha Alex N. , Ramsay Andrew , Anderson de Cuevas Rachel R. M. , Theobald Sally , Davies Peter D. O. , Cuevas Luis E.
Published: July 2010

Objective. To describe the yield of smear-microscopy and radiological findings by male and female patients with symptoms of tuberculosis in Abuja, Nigeria.Methods. Patients ≥15 years old with cough for >3 weeks submitted 3 sputum samples for smear microscopy. One specimen was cultured using MGIT-960. All patients had lung X-rays and screened for HIV.Results. were more likely to be smear-positive than females (262/774 [34%] and 137/547 [25%],P<.01), but similar proportions of males and females were culture-positive (437/691 [63%] and 294/495 [59%],P=.09). 317/626 (50.6%) males and 249/419 (59.4%) females were HIV-positive (P<.005). Among culture-positives patients, HIV-infected males were less likely to have positive smears than HIV-negative males (49.2% versus 66%,P=.001). Among females, smear positivity did not vary with HIV (46.4% for HIV-positive and 52.9% for HIV-negative,P=.38). Of 274 culture-confirmed TB cases, 226 (82.5%) had cavities, and 271 (99%) had ≥1 lung areas affected. HIV-positive males were more likely to have lung cavities than HIV-positive females (85% versus 69%,P<.04) and to have ≥3 lung areas affected (P=.03).Conclusion. Differences in the yield of smear-microscopy, culture and X-rays on presentation are due to several factors including HIV coinfection and gender.
Responses of Ammonia-Oxidising Bacterial Communities to Nitrogen, Lime, and Plant Species in Upland Grassland Soil
Authors: Rooney Deirdre C. , Kennedy Nabla M. , Gleeson Deirdre B. , Clipson Nicholas J. W.
Published: July 2010

Agricultural improvement of seminatural grasslands has been shown to result in changes to plant and microbial diversity, with consequences for ecosystem functioning. A microcosm approach was used to elucidate the effects of two key components of agricultural improvement (nitrogen addition and liming) on ammonia-oxidising bacterial (AOB) communities in an upland grassland soil. Plant species characteristic of unimproved and improved pastures (A. capillarisandL. perenne) were planted in microcosms, and lime, nitrogen (NH4NO3), or lime plus nitrogen added. The AOB community was profiled using terminal restriction fragment length polymorphism (TRFLP) of theamoAgene. AOB community structure was largely altered byNH4NO3addition, rather than liming, although interactions between nitrogen addition and plant species were also evident. Results indicate that nitrogen addition drives shifts in the structure of key microbial communities in upland grassland soils, and that plant species may play a significant role in determining AOB community structure.
A Semianalytical Method for Nonlinear Vibration of Euler‐Bernoulli Beams with General Boundary Conditions
Authors: Peng Jian-She , Liu Yan , Yang Jie
Published: July 2010

This paper presents a new semianalytical approach for geometrically nonlinear vibration analysis of Euler‐Bernoulli beams with different boundary conditions. The method makes use of Linstedt‐Poincaré perturbation technique to transform the nonlinear governing equations into a linear differential equation system, whose solutions are then sought through the use of differential quadrature approximation in space domain and an analytical series expansion in time domain. Validation of the present method is conducted in numerical examples through direct comparisons with existing solutions, showing that the proposed semianalytical method has excellent convergence and can give very accurate results at a long time interval.
Performance Evaluation of a Topology Control Algorithm for Wireless Sensor Networks
Authors: Ababneh Nedal
Published: July 2010

A main design challenge in the area of sensor networks is energy efficiency to prolong the network operable lifetime. Since most of the energy is spent for radio communication, an effective approach for energy conservation is scheduling sleep intervals for extraneous nodes, while the remaining nodes stay active to provide continuous service. Assuming that node position information is unavailable, we present a topology control algorithm, termed OTC, for sensor networks. It uses two-hop neighborhood information to select a subset of nodes to be active among all nodes in the neighborhood. Each node in the network selects its own set of active neighbors from among its one-hop neighbors. This set is determined such that it covers all two-hop neighbors. OTC does not assume the network graph to be a Unit Disk Graph; OTC also works well on general weighted network graphs. OTC is evaluated against two well-known algorithms from the literature, namely, Span and GAF through realistic simulations using TOSSIM. In terms of operational lifetime, load balancing and Spanner property OTC shows promising results. Apart from being symmetric and connected, the resulting graph when employing OTC shows good spanner properties.
Existence, Uniqueness and Ergodicity of Positive Solution of Mutualism System with Stochastic Perturbation
Authors: Ji Chunyan , Jiang Daqing , Liu Hong , Yang Qingshan
Published: July 2010

We discuss a two‐species Lotka‐Volterra mutualism system with stochastic perturbation. We show that there is a unique nonnegative solution of this system. Furthermore, we investigate that there exists a stationary distribution for this system, and it has ergodic property.
Modelling Nonstationary Gene Regulatory Processes
Authors: Grzegorcyzk Marco , Husmeier Dirk , Rahnenführer Jörg
Published: July 2010

An important objective in systems biology is to infer gene regulatory networks from postgenomic data, and dynamic Bayesian networks have been widely applied as a popular tool to this end. The standard approach for nondiscretised data is restricted to a linear model and a homogeneous Markov chain. Recently, various generalisations based on changepoint processes and free allocation mixture models have been proposed. The former aim to relax the homogeneity assumption, whereas the latter are more flexible and, in principle, more adequate for modelling nonlinear processes. In our paper, we compare both paradigms and discuss theoretical shortcomings of the latter approach. We show that a model based on the changepoint process yields systematically better results than the free allocation model when inferring nonstationary gene regulatory processes from simulated gene expression time series. We further cross-compare the performance of both models on three biological systems: macrophages challenged with viral infection, circadian regulation in Arabidopsis thaliana, and morphogenesis in Drosophila melanogaster.
The Khovanov‐Lauda 2‐Category and Categorifications of a Level Two Quantum SL(N) Representation
Authors: Hill David , Sussan Joshua
Published: July 2010

We construct 2‐functors from a 2‐category categorifying quantum sl(n) to 2‐categories categorifying the irreducible representation of highest weight 2ωk.
Mitochondrial Chaperone Trap1 and the Calcium Binding Protein Sorcin Interact and Protect Cells against Apoptosis Induced by Antiblastic Agents
Authors: Landriscina Matteo , Laudiero Gabriella , Maddalena Francesca , Amoroso Maria Rosaria , Piscazzi Annamaria , Cozzolino Flora , Monti Maria , Garbi Corrado , Fersini Alberto , Pucci Piero , Esposito Franca
Published: July 2010

TRAP1, a mitochondrial chaperone (Hsp75) with antioxidant and antiapoptotic functions, is involved in multidrug resistance in human colorectal carcinoma cells. Through a proteomic analysis of TRAP1 coimmunoprecipitation complexes, the Ca2+-binding protein Sorcin was identified as a new TRAP1 interactor. This result prompted us to investigate the presence and role of Sorcin in mitochondria from human colon carcinoma cells. Using fluorescence microscopy and Western blot analysis of purified mitochondria and submitochondrial fractions, we showed the mitochondrial localization of an isoform of Sorcin with an electrophoretic motility lower than 20 kDa that specifically interacts with TRAP1. Furthermore, the effects of overexpressing or downregulating Sorcin and/or TRAP1 allowed us to demonstrate a reciprocal regulation between these two proteins and to show that their interaction is required for Sorcin mitochondrial localization and TRAP1 stability. Indeed, the depletion of TRAP1 by short hairpin RNA in colorectal carcinoma cells lowered Sorcin levels in mitochondria, whereas the depletion of Sorcin by small interfering RNA increased TRAP1 degradation. We also report several lines of evidence suggesting that intramitochondrial Sorcin plays a role in TRAP1 cytoprotection. Finally, preliminary evidence that TRAP1 and Sorcin are both implicated in multidrug resistance and are coupregulated in human colorectal carcinomas is provided. These novel findings highlight a new role for Sorcin, suggesting that some of its previously reported cytoprotective functions may be explained by involvement in mitochondrial metabolism through the TRAP1 pathway. Cancer Res; 70(16); 6577–86. ©2010 AACR.
Low-Field Magnetic Resonance Imaging to Visualize Chronic and Cycling Hypoxia in Tumor-Bearing Mice
Authors: Yasui Hironobu , Matsumoto Shingo , Devasahayam Nallathamby , Munasinghe Jeeva P. , Choudhuri Rajani , Saito Keita , Subramanian Sankaran , Mitchell James B. , Krishna Murali C.
Published: July 2010

Tumors exhibit fluctuations in blood flow that influence oxygen concentrations and therapeutic resistance. To assist therapeutic planning and improve prognosis, noninvasive dynamic imaging of spatial and temporal variations in oxygen partial pressure (pO2) would be useful. Here, we illustrate the use of pulsed electron paramagnetic resonance imaging (EPRI) as a novel imaging method to directly monitor fluctuations in oxygen concentrations in mouse models. A common resonator platform for both EPRI and magnetic resonance imaging (MRI) provided pO2 maps with anatomic guidance and microvessel density. Oxygen images acquired every 3 minutes for a total of 30 minutes in two different tumor types revealed that fluctuation patterns in pO2 are dependent on tumor size and tumor type. The magnitude of fluctuations in pO2 in SCCVII tumors ranged between 2- to 18-fold, whereas the fluctuations in HT29 xenografts were of lower magnitude. Alternating breathing cycles with air or carbogen (95% O2 plus 5% CO2) distinguished higher and lower sensitivity regions, which responded to carbogen, corresponding to cycling hypoxia and chronic hypoxia, respectively. Immunohistochemical analysis suggests that the fluctuation in pO2 correlated with pericyte density rather than vascular density in the tumor. This EPRI technique, combined with MRI, may offer a powerful clinical tool to noninvasively detect variable oxygenation in tumors. Cancer Res; 70(16); 6427–36. ©2010 AACR.
New Strategies in Pancreatic Cancer: Emerging Epidemiologic and Therapeutic Concepts
Authors: Li Donghui , Abbruzzese James L.
Published: July 2010

Pancreatic cancer (PC) is a highly lethal disease with complex etiology involving both environmental and genetic factors. Although cigarette smoking is known to explain 25% of cases, data from recent studies suggest that obesity and long-term type II diabetes are two major modifiable risk factors for PC. Furthermore, obesity and diabetes seem to affect the clinical outcome of patients with PC. Understanding the mechanistic effects of obesity and diabetes on the pancreas may identify new strategies for prevention or therapy. Experimental and epidemiologic evidence suggests that the antidiabetic drug metformin has protective antitumor activity in PC. In addition to insulin resistance and inflammation as mechanisms of carcinogenesis, obesity and diabetes are linked to impairments in endothelial function and coagulation status, which increase the risks of thrombosis and angiogenesis and, in turn, the risk of PC development and progression. The associations of the ABO blood group gene and NR5A2 gene variants with PC discovered by recent genome-wide association studies may link insulin resistance, inflammation, and thrombosis to pancreatic carcinogenesis. These exciting findings open new avenues for understanding the etiology of PC and provide opportunities for developing novel strategies for prevention and treatment of this disease. Clin Cancer Res; 16(17); 4313–8. ©2010 AACR.
Targeting Cell Division Cycle 7 Kinase: A New Approach for Cancer Therapy
Authors: Montagnoli Alessia , Moll Jürgen , Colotta Francesco
Published: July 2010

The cell division cycle 7 (Cdc7) is a serine-threonine kinase, originally discovered in budding yeast, required to initiate DNA replication. Human Cdc7 phosphorylates the minichromosome maintenance protein 2 (Mcm2), a component of the DNA replicative helicase needed for genome duplication. Inhibition of Cdc7 in cancer cells impairs progression through S phase, inducing a p53-independent apoptotic cell death, whereas in normal cells, it does not affect cell viability. Small molecule compounds able to interfere with Cdc7 activity have been identified and shown to be effective in controlling tumor growth in animal models. Two Cdc7 inhibitors are currently in phase I clinical development. Inhibition of Cdc7 kinase activity in cancer cells restricts DNA replication and induces apoptotic cell death by an unprecedented molecular mechanism of action. Clin Cancer Res; 16(18); 4503–8. ©2010 AACR.
Immunologic Response to Xenogeneic gp100 DNA in Melanoma Patients: Comparison of Particle-Mediated Epidermal Delivery with Intramuscular Injection
Authors: Ginsberg Brian A. , Gallardo Humilidad F. , Rasalan Teresa S. , Adamow Matthew , Mu Zhenyu , Tandon Sapna , Bewkes Barrett B. , Roman Ruth-Ann , Chapman Paul B. , Schwartz Gary K. , Carvajal Richard D. , Panageas Katherine S. , Terzulli Stephanie L. , Houghton Alan N. , Yuan Jianda D. , Wolchok Jedd D.
Published: July 2010

Purpose: Prior studies show that i.m. injection of xenogeneic orthologues of melanosomal antigens (tyrosinase, gp100) induces CD8+ T-cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a pilot clinical trial comparing i.m. injection with particle-mediated epidermal delivery (PMED).

Experimental Design: Human leukocyte antigen (HLA)-A*0201+ disease–free melanoma patients were randomized to the PMED or i.m. arm, receiving eight vaccinations over 4 months. Patients received 4 μg or 2,000 μg per injection, respectively, of mouse gp100 DNA. Peripheral blood mononuclear cells were collected, cultured with gp100 peptides, and analyzed by tetramer and intracellular cytokine staining for responses to HLA-A*0201–restricted gp100 epitopes [gp100209-217 (ITDQVPFSV) and gp100280-288 (YLEPGPVTA)].

Results: Twenty-seven patients with stage IIB-IV melanoma were analyzable for immune response. The only common toxicity was grade 1 injection site reaction in nine patients with no intergroup difference, and one dose-limiting toxicity of acute hypersensitivity occurred in a PMED patient with undiagnosed gold allergy. Four of 27 patients produced gp100 tetramer+CD8+ T cells, all carrying the CCR7loCD45RAlo effector-memory phenotype. Five of 27 patients generated IFN-γ+CD8+ T cells, one who was also tetramer-positive. Overall, vaccination induced a response in 30% of patients, which was not significantly associated with study arm or clinical outcome. However, the PMED group showed a trend toward increased IFN-γ+CD8+ T-cell generation (P = 0.07).

Conclusion: A comparable efficacy and safety profile was shown between the i.m. and PMED arms, despite a significantly decreased dose of DNA used for PMED injection. Clin Cancer Res; 16(15); 4057–65. ©2010 AACR.
Systemic Administration of Polymeric Nanoparticle-Encapsulated Curcumin (NanoCurc) Blocks Tumor Growth and Metastases in Preclinical Models of Pancreatic Cancer
Authors: Bisht Savita , Mizuma Masamichi , Feldmann Georg , Ottenhof Niki A. , Hong Seung-Mo , Pramanik Dipankar , Chenna Venugopal , Karikari Collins , Sharma Rajni , Goggins Michael G. , Rudek Michelle A. , Ravi Rajani , Maitra Amarnath , Maitra Anirban
Published: July 2010

Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-κB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy. Mol Cancer Ther; 9(8); 2255–64. ©2010 AACR.
A Review of Trabectedin (ET-743): A Unique Mechanism of Action
Authors: D'Incalci Maurizio , Galmarini Carlos M.
Published: July 2010

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. Two of these rings (subunits A and B) provide the framework for covalent interaction with the minor groove of the DNA double helix, whereas the third ring (subunit C) protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins. The compound's chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways, likely to be different from other DNA-interacting agents. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment. The promising data on the combination of trabectedin with other anticancer agents, observed in preclinical systems, have prompted several clinical studies that are currently ongoing. One of these combinations (trabectedin-pegylated liposomal doxorubicin) was recently authorized by the European Commission for the treatment of patients with relapsed platinum-sensitive ovarian cancer. Mol Cancer Ther; 9(8); 2157–63. ©2010 AACR.
Deletion at Fragile Sites Is a Common and Early Event in Barrett's Esophagus
Authors: Lai Lisa A. , Kostadinov Rumen , Barrett Michael T. , Peiffer Daniel A. , Pokholok Dimitry , Odze Robert , Sanchez Carissa A. , Maley Carlo C. , Reid Brian J. , Gunderson Kevin L. , Rabinovitch Peter S.
Published: July 2010

Barrett's esophagus (BE) is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for BE by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity at 56 fragile sites in 20 patients with premalignant BE. Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement or loss in many human cancers. Seventy-eight percent of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%), and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR, which detected the loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients, respectively. Loss of heterozygosity in these cases was confirmed through pyrosequencing at FRA3B and FRA16D (75% and 70%, respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk. Mol Cancer Res; 8(8); 1084–94. ©2010 AACR.
Proteomic Profiling of Potential Molecular Targets of Methyl-Selenium Compounds in the Transgenic Adenocarcinoma of Mouse Prostate Model
Authors: Zhang Jinhui , Wang Lei , Anderson Lorraine B. , Witthuhn Bruce , Xu Yanji , Lü Junxuan
Published: July 2010

Because the Selenium (Se) and Vitamin E Cancer Prevention Trial (SELECT) failed to show the efficacy of selenomethionine for prostate cancer prevention, there is a critical need to identify safe and efficacious Se forms for future trials. We have recently shown significant preventive benefit of methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in the transgenic adenocarcinoma mouse prostate (TRAMP) model by oral administration. The present work applied iTRAQ proteomic approach to profile protein changes of the TRAMP prostate and to characterize their modulation by MSeA and MSeC to identify their potential molecular targets. Dorsolateral prostates from wild-type mice at 18 weeks of age and TRAMP mice treated with water (control), MSeA, or MSeC (3 mg Se/kg) from 8 to 18 weeks of age were pooled (9-10 mice per group) and subjected to protein extraction, followed by protein denaturation, reduction, and alkylation. After tryptic digestion, the peptides were labeled with iTRAQ reagents, mixed together, and analyzed by two-dimensional liquid chromatography/tandem mass spectrometry. Of 342 proteins identified with >95% confidence, the expression of 75 proteins was significantly different between TRAMP and wild-type mice. MSeA mainly affected proteins related to prostate functional differentiation, androgen receptor signaling, protein (mis)folding, and endoplasmic reticulum–stress responses, whereas MSeC affected proteins involved in phase II detoxification or cytoprotection, and in stromal cells. Although MSeA and MSeC are presumed precursors of methylselenol and were equally effective against the TRAMP model, their distinct affected protein profiles suggest biological differences in their molecular targets outweigh similarities. Cancer Prev Res; 3(8); 994–1006. ©2010 AACR.
Vascular Endothelial Growth Factor Receptor 2–Targeted Chemoprevention of Murine Lung Tumors
Authors: Karoor Vijaya , Le Mysan , Merrick Daniel , Dempsey Edward C. , Miller York E.
Published: July 2010

No clinically effective chemoprevention for lung cancer has been found. Angiogenesis is an early feature of both adenocarcinoma and squamous cell lung cancer. We investigated the effects of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) inhibition on lung carcinogenesis in a murine model of adenocarcinoma. The VEGFR-2 tyrosine kinase inhibitor, vandetanib, was given to FVB/N mice in chow for 7 days at varying doses to show pharmacologic activity by inhibition of VEGF-mediated VEFGR-2 and ERK phosphorylation. Plasma levels corroborated adequate dosage. For chemoprevention experiments, mice were injected i.p. with 1 mg/g of urethane, a carcinogen found in tobacco smoke. Chow containing vandetanib, 75 mg/kg/d, or control chow was given to mice, starting 7 days after urethane administration. Sixteen weeks after urethane injection, mice were sacrificed, tumors enumerated and measured. Vandetanib resulted in reductions in tumor multiplicity (6.5 ± 0.86 versus 1.0 ± 0.30, P = 0.001) and average tumor volume (0.85 ± 0.10 versus 0.15 ± 0.09 mm3, P = 0.001), but not incidence (71% versus 100%, P = ns), compared with control. As vandetanib has other activities besides VEGFR-2 tyrosine kinase inhibition, we gave the anti–VEGFR-2 monoclonal antibody, DC101, for weeks 11 to 15 of a urethane carcinogenesis protocol with an arrest in tumor volume increase, but no change in multiplicity or incidence. Further investigation of the chemopreventive effect of vandetanib and other VEGF signaling inhibitors is needed. Cancer Prev Res; 3(9); 1141–7. ©2010 AACR.
Etiopathology of Arnold-Chiari Malformation: A Fetal Rat Model of Dysraphism
Authors: Corti G. , Manzur T. , Nagle C. , Martinez-Ferro M.
Published: July 2010

Objectives: We report an experimental fetal rat model with the aim of comparing two surgical methods used to check Arnold-Chiari Malformation (ACM) by dysraphism. We also wanted to (1) determine which type(s) of ACM akin to human anatomical findings were generated with the model and (2) study whether a cerebrospinal fluid pressure gradient could be responsible for ACM’s etiopathology. Materials and Methods: At E20, a mean of two fetuses per pregnant rat underwent an incision at the 2–3 lumbar level, deep into the medulla oblongata central canal, by two different surgical methods. Cesarian section was performed at E22. Dysraphic fetuses were examined clinically. Those born alive and controls without lesions were anatomically and histologically studied. Results: Method 2 was better than method 1 at reproducing the model. 100% of operated fetuses showed no spontaneous motility or sensibility to pressure on the posterior limbs in addition to anatomopathological evidence of type II ACM. Conclusions: A high rate of ACM could be checked by dysraphism with both methods. The opening of the central canal was demonstrated to generate a cerebrospinal fluid pressure gradient responsible for the herniation of encephalic structures comparable with human ACM. We believe this model may be useful for evaluating further strategies for prenatal treatment.
Efficacy and Safety of Micafungin as an Empirical Antifungal Agent for Febrile Neutropenic Patients with Hematological Diseases
Authors: Park Joon Seong , Kim Dong Hwan , Choi Chul Won , Jeong Seong Hyun , Choi Jin-Hyuk , Kim Kihyun , Kim Seok Jin , Jung Chul Won , Yang Deok-Hwan , Jang Jun Ho
Published: July 2010

Background: This observational study was conducted to document the efficacy and safety of the use of micafungin (Mycamine) as an empirical antifungal agent in febrile neutropenic patients. Methods: Micafungin was administered for sustained fever (>38.4°C) on days 3–5 following the initiation of empirical antibiotic therapy. The overall success rate and side effects were evaluated. Results: A total of 47 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome and lymphoma were enrolled in the study. The overall success rate of micafungin was 61.7% (29/47). A total of 3 patients (6.4%) experienced grade 3/4 elevations in their aspartate aminotransferase levels, and 10 patients (21%) experienced grade 3/4 hyperbilirubinemia, 9 of which resolved. Four patients died of septic shock. Younger patients (<50 years) and patients with acute lymphoblastic leukemia exhibited a better response to micafungin than other patients. Patients that were less profoundly neutropenic (≧0.05 × 109/l) also had a better response to micafungin, as did the patients who recovered from their fever or neutropenia. Conclusion: Micafungin has an excellent efficacy (61.7%) and safety profile when used as an empirical antifungal agent in febrile neutropenic patients with hematological disorders.
Treatment of Lupus Nephritis by Mycophenolate Mofetil
Authors: Rabrenović Violeta , Poskurica Mileta , Kovačević Zoran , Nešić Vidosava , Savin Marina , Mitić Branka , Dimković Nada , Čučković Čedomir , Vujić Danica , Plješa Steva , Peruničić-Peković Gordana , Čurić Slobodan , Mitić Igor , Ratković Marina , Marinković Jelena , Jovanović Dragan
Published: July 2010

Background/Aims: Mycophenolate mofetil (MMF) has been increasingly used for the treatment of lupus nephritis (LN). The aim of this study was to examine the efficacy and safety of MMF used with low doses of corticosteroids as maintenance therapy in patients with LN. Methods: The study covered 35 patients, most of them with proliferative types of LN (5 WHO class III, 26 class IV), while 1 had class V and 3 class VI nephritis. MMF was administered in the dose of 1.5–2 g/24 h and prednisone at 10–20 mg/day. The treatment effects were followed over a 12-month period. Results: After 3 months of therapy significant reduction in proteinuria was achieved (2.1 ± 2.4 g/24 h vs. 1.0 ± 1.0 g/24 h, p < 0.01) and maintained to the end of the study. In parallel, a significant rise in serum albumin, a fall of cholesterol and a significant increase in mean glomerular filtration rate were noted. Complete remission was achieved in 16 patients (45.7%), including all patients in class III and V plus 10 patients in class IV. Not a single adverse effect was observed. Conclusion: MMF combined with low doses of steroids is an effective and safe treatment for the maintenance of stable remission of LN.
Predicting Atelectasis by Assessment of Collateral Ventilation prior to Endobronchial Lung Volume Reduction: A Feasibility Study
Authors: Gompelmann D. , Eberhardt R. , Michaud G. , Ernst A. , Herth F.J.F.
Published: July 2010

Background: The advent of endoscopic lung volume reduction (ELVR), especially relying on valve technology to achieve atelectasis, has aroused new interest in the assessment of collateral ventilation, which has been implicated in ELVR failures. We are reporting on the use of a catheter-based device that measures airway pressures and flows, and calculates airway resistance in vivo. Objectives: To assess the safety of this catheter-based system and the feasibility of obtaining measurements predictive of atelectasis after ELVR. Methods: Patients undergoing ELVR were prospectively included in this double-blind cohort study. Each lobe targeted for ELVR was blocked with a catheter system (Chartis® System; Pulmonx, Inc., Redwood, Calif., USA); pressures and flows were assessed continuously. The primary endpoints were to evaluate the safety and feasibility; the secondary endpoint was to assess whether there was a relationship between the measurements and the incidence of atelectasis following ELVR. Results: From June 2008 to November 2008, 25 patients were included in the study. All procedures could be performed without any complications. Due to pneumothorax in 1 case and inability to assess the catheter-based measurements in 4 cases, the final analysis included 20 patients. Atelectasis occurred in 8 out of 20 cases following implantation. In 18 patients (90%), the resistance measurements correlated with the postimplantation atelectasis visualized on a chest X-ray; in 2 patients (10%), a mismatch was detected. Conclusions: Resistance measurements were safely and successfully achieved. In 90% of the analyzable cases, the resistance measurements correlated with the occurrence of atelectasis after ELVR. The clinical impact of these findings will need to be evaluated in subsequent trials.
Head-Out Spirometry Accurately Monitors the Course of Pseudomonas aeruginosa Lung Infection in Mice
Authors: Wölbeling Florian , Munder Antje , Stanke Frauke , Tümmler Burkhard , Baumann Ulrich
Published: July 2010

Background: Classic infection models in rodents use lethal doses of bacteria as inocula, thus creating models which are rarely comparable to the clinical situation. Moreover, single time-point evaluation requires killing of the animals, necessitating large numbers of animals. Longitudinal parameters such as temperature appear to have a relatively low accuracy. Spirometry might be an accurate method to assess the course of a bacterial lung infection without the necessity to sacrifice the animals. Objectives: We measured lung function in C57BL/6JZtm mice following intratracheal infection with Pseudomonas aeruginosa and compared it to physiological parameters and lung histology. Methods: Head-out spirometry measuring 14 parameters was performed on C57BL6/J mice for eight days following a P. aeruginosa lung infection. Additionally rectal temperature, body weight and condition were assessed together with histological data and bacteriological clearance. Results: Several spirometric parameters were significantly altered for more than 72 h after inoculation, which was four times longer than observed alterations in physiological parameters such as temperature. Volume (amount of air inspired) decreased more than seven-fold within 6 h after inoculation and required 72 h to recover, rendering it the most sensitive spirometric parameter investigated. Spirometric and histological data correlated well. Conclusions: Our findings suggest that non-invasive head-out spirometry is a reliable and highly sensitive method to longitudinally assess the course of bacterial lung infections.
A randomised determination of the Effect of Fluvastatin and Atorvastatin on top of dual antiplatelet treatment on platelet aggregation after implantation of coronary drug-eluting stents
Authors: Abrecht Linda , Zwahlen Marcel , Schmidlin Kurt , Windecker Stephan , Meier Bernhard , Haeberli Andre , Hess Otto , Wenaweser Peter , Eshtehardi Parham
Published: July 2010

Drug-drug interaction between statins metabolised by cytochrome P450 3A4 and clopidogrel have been claimed to attenuate the inhibitory effect of clopidogrel. However, published data regarding this drug-drug interaction are controversial. We aimed to determine the effect of fluvastatin and atorvastatin on the inhibitory effect of dual anti-platelet therapy with acetylsalicylic acid (ASA) and clopidogrel. One hundred one patients with symptomatic stable coronary artery disease undergoing percutaneous coronary intervention and drug-eluting stent implantation were enrolled in this prospective randomised study. After an interval of two weeks under dual antiplatelet therapy with ASA and clopidogrel, without any lipid-lowering drug, 87 patients were randomised to receive a treatment with either fluvastatin 80 mg daily or atorvastatin 40 mg daily in addition to the dual antiplatelet therapy for one month. Platelet aggregation was assessed using light transmission aggregometry and whole blood impedance platelet aggregometry prior to randomisation and after one month of receiving assigned statin and dual antiplatelet treatment. Platelet function assessment after one month of statin and dual antiplatelet therapy did not show a significant change in platelet aggregation from 1st to 2nd assessment for either statin group. There was also no difference between atorvastatin and fluvastatin treatment arms. In conclusion, neither atorvastatin 40 mg daily nor fluvastatin 80 mg daily administered in combination with standard dual antiplatelet therapy following coronary drug-eluting stent implantation significantly interfere with the antiaggregatory effect of ASA and clopidogrel.
Risk of drug-eluting stent thrombosis in patients receiving proton pump inhibitors
Authors: Sibbing Dirk , Sonntag Ulrich , Ellert Julia , Schulz Stefanie , Byrne Robert , Mehilli Julinda , Schömig Albert , Kastrati Adnan , Sarafoff Nikolaus
Published: July 2010

Clopidogrel is a prodrug that is converted via the hepatic cytochrome P450 system into its active thiol metabolite. Evidence is accumulating that proton pump inhibitors (PPIs) inhibit this enzymatic pathway and may therefore attenuate the antiplatelet effect of clopidogrel. The objective of this study was to investigate whether patients on clopidogrel therapy after drug-eluting stent (DES) placement who also receive a PPI are at higher risk of stent thrombosis (ST). This is a retrospective analysis of patients who received dual antiplatelet treatment including clopidogrel after DES placement. Outcomes were compared according to PPI therapy. The primary endpoint was the incidence of definite ST at 30 days. Secondary endpoints were death, combined death or ST and myocardial infarction (MI). The study population included 3,338 patients and 698 patients (20.9%) received PPIs. Patients receiving a PPI had a higher risk profile at baseline. Multivariate analysis showed that PPI treatment was not independently associated with the occurrence of ST [adjusted HR 1.8 (95% CI: 0.7–4.7), p=0.23] or MI [adjusted HR 1.3 (0.8–2.3), p=0.11]. PPI treatment was significantly associated with death [adjusted HR 2.2 (1.1–4.3), p=0.02] and death or ST [adjusted HR 3.3(1.7–6.7), p=0.02]. Concomitant treatment with a PPI in patients receiving dual antiplatelet treatment after coronary stenting is not an independent predictor of ST. The higher mortality is probably due to confounding as patients on PPIs had a higher risk profile at baseline.
New insights into the structural elements involved in the skin haemorrhage induced by snake venom metalloproteinases
Authors: Oliveira Ana , Paes Leme Adriana , Asega Amanda , Camargo Antonio , Fox Jay , Serrano Solange
Published: July 2010

Haemorrhage induced by snake venom metalloproteinases (SVMPs) is a complex phenomenon resulting in capillary disruption and extravasation. This study analysed structural elements important for the interaction of four Bothrops jararaca SVMPs of different domain organisation and glycosylation levels with plasma and extracellular matrix proteins: HF3 (P-III class) is highly glycosylated and ~80 times more haemorrhagic than bothropasin (P-III class), which has a minor carbohydrate moiety; BJ-PI (P-I class) is not haemorrhagic and the DC protein is composed of disintegrin-like/cysteine-rich domains of bothropasin. HF3, bothropasin and BJ-PI showed different degradation profiles of fibrinogen, fibronectin, vitronectin, von Willebrand factor, collagens IV and VI, laminin and Matrigel™; however, only bothropasin degraded collagen I. In solid-phase binding assays HF3 and bothropasin interacted with fibrinogen, fibronectin, laminin, collagens I and VI; the DC protein bound only to collagens I and VI; however, no binding of BJ-PI to these proteins was detected. N-deglycosylation caused loss of structural stability of bothropasin and BJ-PI but HF3 remained intact, although its haemorrhagic and fibrinogenolytic activities were partially impaired. Nevertheless, N-deglycosylated HF3 bound with higher affinity to collagens I and VI, although its proteolytic activity upon these collagens was not enhanced. This study demonstrates that features of carbohydrate moieties of haemorrhagic SVMPs may play a role in their interaction with substrates of the extracellular matrix, and the ability of SVMPs to degrade proteins in vitro does not correlate to their ability to cause haemorrhage, suggesting that novel, systemic approaches are necessary for understanding the mechanism of haemorrhage generation by SVMPs.
Recombinant activated factor VII does not reduce bleeding in rabbits treated with aspirin and clopidogrel
Authors: Hindy-François Clemence , Bachelot-Loza Christilla , Bonniec Bernard Le , Grelac Francoise , Dizier Blandine , Godier Anne , Emmerich Joseph , Gaussem Pascale , Samama Charles-Marc
Published: July 2010

Combined antiplatelet agents (cAPA), aspirin plus clopidogrel, increase the risk of bleeding. We hypothesised that recombinant activated FVIIa (rFVIIa), which normalises thrombin generation in platelet-rich plasma from patients treated with cAPA, could limit this bleeding risk. It was the objective of this study to investigate the efficacy and safety of rFVIIa compared to placebo, in a bleeding and thrombosis model in rabbits treated with aspirin and clopidogrel. New-Zealand rabbits, randomised into two groups (Placebo1, n=36 ; cAPA, n=34), were anaesthetised, ventilated and monitored for blood pressure, temperature and carotid blood flow. The Folts model was applied to a carotid artery. Cyclic flow reductions (CFR) were recorded over a first 20-min period (Obs1). Each rabbit was then randomly assigned into one of three subgroups (Placebo2, 40 μg/kg rFVIIa, 160 μg/kg rFVIIa) and CFR were monitored for a second 20-min period (Obs2). Ear bleeding time (BT) was measured at the end of each period. Hepatosplenic (HS) section was performed at the end of the experiment and HS blood loss defines the primary endpoint. Secondary endpoints were thrombosis (CFR), prothrombin time, platelet aggregation, and thrombin generation. Non- parametric statistical tests were used (p<0.05). cAPA significantly increased HS blood loss, BT and suppressed CFR compared to Placebo1 (p<0.05). rFVIIa injection did not modify HS blood loss, BT or CFR rate in Placebo1 rabbits nor in cAPA animals. These effects were unaffected by either rFVIIa dose. rFVIIa accelerated thrombin generation but had no effect on platelet aggregation in citrated platelet-rich plasma. rFVIIa did not modify HS blood loss associated with cAPA in rabbits.
Clinical and genetic findings in five female patients with haemophilia A: Identification of a novel missense mutation, p.Phe2127Ser
Authors: Venceslá Adoración , Alvárez-Román María Teresa , Rivas Isabel , Fernández Ihosvany , Butta Nora , Baena Manel , Fuentes-Prior Pablo , Tizzano Eduardo , Jiménez-Yuste Víctor , Martín-Salces Mónica
Published: July 2010

Severe manifestations of X-linked recessive disorders such as haemophilia A (HA) are rare in females. Here we describe the clinical and genetic findings in five female HA patients from two different Spanish families. Three sisters born to consanguineous parents presented moderate bleeding due to a known mutation (p.Ser1791Pro) detected in a homozygous state. In the second family, two sisters with Morris syndrome (46,XY) and mild/moderate illness were hemizygous for a novel missense mutation, p.Phe2127Ser. The mutation is predicted to impair binding to the factor VIII (FVIII) carrier protein, von Willebrand factor, and thus increased clearance of FVIII from plasma. Clinical and molecular characterisation of these patients is essential to optimise follow-up, genetic counselling and treatment of the disease.
Interlaboratory variation in heparin monitoring: Lessons from the Quality Management Program of Ontario coagulation surveys
Authors: Raby Anne , Moffat Karen , Flynn Greg , Crowther Mark , Cuker Adam
Published: July 2010

Unfractionated heparin (UFH) monitoring is subject to substantial inter-laboratory variation. We analysed results of annual coagulation surveys administered by the Quality Management Program – Laboratory Services (Toronto, ON, Canada) from 2003 to 2007 to evaluate variation in UFH monitoring across Ontario. Participating laboratories performed an activated partial thromboplastin time (APTT) utilising their local methodology on lyophilised human plasma spiked with UFH. In the 2006 and 2007 surveys, laboratories licensed to perform anti-Xa assays also reported anti-Xa activity results. The APTT differed significantly between heparin-sensitive and heparin-insensitive methods (p<0.0005). Within-method variation was observed and increased with increasing heparin concentration. Among laboratories performing an APTT and anti-Xa, the coefficient of variation was greater in the anti-Xa than in the APTT for both the 2006 (64.0% vs. 10.5%) and 2007 (15.0% vs. 11.6%) surveys. Substantial interlaboratory variation in UFH monitoring, both between and within APTT methods, was observed and was not reduced by use of an anti-Xa assay.
Endothelial-derived microparticles: Biological conveyors at the crossroad of inflammation, thrombosis and angiogenesis
Authors: Leroyer Aurélie , Anfosso Francine , Lacroix Romaric , Sabatier Florence , Simoncini Stéphanie , Njock Sébastien , Jourde Noémie , Brunet Philippe , Camoin-Jau Laurence , Sampol José , Dignat-George Françoise
Published: July 2010

Endothelial microparticles (EMP) are complex vesicular structures that can be shed by activated or apoptotic endothelial cells. EMP are composed of a phospholipid bilayer that exposes transmembrane proteins and receptors and encloses cytosolic components such as enzymes, transcription factors and mRNA derived from their parent cells. Thus, EMP behave as biological conveyors playing a key role in the tuning of vascular homeostasis. This review focuses on the multifaceted roles of EMP, notably in coagulation, inflammation and angiogenesis and also on the mechanisms that trigger their formation. In this context, EMP could compromise vascular homeostasis and then represent key players in the pathogenesis of several inflammatory and thrombotic diseases. Consequently, elucidating their role and their mechanisms of formation will bring new insights into the understanding of endothelial-associated diseases. Moreover, in the future, it can open novel therapeutic perspectives based on the inhibition of EMP release.