bluuebunny/crossref_metadata_2025 huggingface dataset:
Antifungal Activity of Phenyl Derivative of Pyranocoumarin fromPsoralea corylifoliaL. Seeds by Inhibition of Acetylation Activity of Trichothecene 3-O-Acetyltransferase (Tri101)
Authors: Srinivasan Sangeetha , Sarada D. V. L.
Published: June 2012

Antifungal activity of petroleum ether extract ofPsoralea corylifoliaL. seed, tested againstFusariumsp. namely,Fusarium oxysporum, Fusarium moniliforme,andFusarium graminearum, was evaluated by agar well diffusion assay. The chromatographic fractionation of the extract yielded a new phenyl derivative of pyranocoumarin (PDP). The structure of the PDP was confirmed using spectroscopic characterization (GC-MS, IR, and NMR), and a molecular mass ofm/z414 [M-2H]+with molecular formula C27H28O4was obtained. The PDP had a potent antifungal activity with a minimum inhibitory concentration of 1 mg/mL againstFusariumsp. Molecular docking using Grid-Based Ligand Docking with Energetics (GLIDE, Schrodinger) was carried out with the Tri101, trichothecene 3-O-acetyltransferase, as target protein to propose a mechanism for the antifungal activity. The ligand PDP showed bifurcated hydrogen bond interaction with active site residues at TYR 413 and a single hydrogen bond interaction at ARG 402 with a docking score −7.19 and glide energy of −45.78 kcal/mol. This indicated a strong binding of the ligand with the trichothecene 3-O-acetyltransferase, preventing as a result the acetylation of the trichothecene mycotoxin and destruction of the “self-defense mechanism” of theFusariumsp.
Involvement of Inflammation and Adverse Vascular Remodelling in the Blood Pressure Raising Effect of Repeatedly Heated Palm Oil in Rats
Authors: Ng Chun-Yi , Kamisah Yusof , Faizah Othman , Jubri Zakiah , Qodriyah Hj Mohd Saad , Jaarin Kamsiah
Published: June 2012

Oil thermoxidation during deep frying generates harmful oxidative free radicals that induce inflammation and increase the risk of hypertension. This study aimed to investigate the effect of repeatedly heated palm oil on blood pressure, aortic morphometry, and vascular cell adhesion molecule-1 (VCAM-1) expression in rats. Male Sprague-Dawley rats were divided into five groups: control, fresh palm oil (FPO), one-time-heated palm oil (1HPO), five-time-heated palm oil (5HPO), or ten-time-heated palm oil (10HPO). Feeding duration was six months. Blood pressure was measured at baseline and monthly using tail-cuff method. After six months, the rats were sacrificed and the aortic arches were dissected for morphometric and immunohistochemical analyses. FPO group showed significantly lower blood pressure than all other groups. Blood pressure was increased significantly in 5HPO and 10HPO groups. The aortae of 5HPO and 10HPO groups showed significantly increased thickness and area of intima-media, circumferential wall tension, and VCAM-1 than other groups. Elastic lamellae were disorganised and fragmented in 5HPO- and 10HPO-treated rats. VCAM-1 expression showed a significant positive correlation with blood pressure. In conclusion, prolonged consumption of repeatedly heated palm oil causes blood pressure elevation, adverse remodelling, and increased VCAM-1, which suggests a possible involvement of inflammation.
Evaluation of the Effects of Acupuncture on Blood Flow in Humans with Ultrasound Color Doppler Imaging
Authors: Takayama Shin , Watanabe Masashi , Kusuyama Hiroko , Nagase Satoru , Seki Takashi , Nakazawa Toru , Yaegashi Nobuo
Published: June 2012

Color Doppler imaging (CDI) can be used to noninvasively create images of human blood vessels and quantitatively evaluate blood flow in real-time. The purpose of this study was to assess the effects of acupuncture on the blood flow of the peripheral, mesenteric, and retrobulbar arteries by CDI. Statistical significance was defined asPvalues less than 0.05. Blood flow in the radial and brachial arteries was significantly lower during needle stimulation on LR3 than before in healthy volunteers, but was significantly higher after needle stimulation than before. LR3 stimulation also resulted in a significant decrease in the vascular resistance of the short posterior ciliary artery and no significant change of blood flow through the superior mesenteric artery (SMA) during acupuncture. In contrast, ST36 stimulation resulted in a significant increase in blood flow through the SMA and no significant change in the vascular resistance of the retrobulbar arteries. Additionally, acupuncture at previously determined acupoints in patients with open-angle glaucoma led to a significant reduction in the vascular resistance of the central retinal artery and short posterior ciliary artery. Our results suggest that acupuncture can affect blood flow of the peripheral, mesenteric, and retrobulbar arteries, and CDI can be useful to evaluate hemodynamic changes by acupuncture.
Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing
Authors: Gille Johan J. P. , Floor Karijn , Kerkhoven Lianne , Ameziane Najim , Joenje Hans , de Winter Johan P.
Published: June 2012

Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and a high risk of malignancies. FA is heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis of FA needs to be confirmed by testing cells for sensitivity to cross-linking agents in a chromosomal breakage test. As a second step, DNA testing can be employed to elucidate the genetic subtype of the patient and to identify the familial mutations. This knowledge allows preimplantation genetic diagnosis (PGD) and enables prenatal DNA testing in future pregnancies. Although simultaneous testing of all FA genes by next generation sequencing will be possible in the near future, this technique will not be available immediately for all laboratories. In addition, in populations with strong founder mutations, a limited test using Sanger sequencing and MLPA will be a cost-effective alternative. We describe a strategy and optimized conditions for the screening ofFANCA, FANCB, FANCC, FANCE, FANCF,andFANCGand present the results obtained in a cohort of 54 patients referred to our diagnostic service since 2008. In addition, the follow up with respect to genetic counseling and carrier screening in the families is discussed.
Infantile Amoebiasis: A Case Report
Authors: Zibaei Mohammad , Firoozeh Farzaneh , Azargoon Alireza
Published: June 2012

Amoebiasis continues to be a major cause of morbidity and mortality in children in developing countries.Entamoeba histolyticainfections are commonly observed in tropical and subtropical regions of the world including Iran. In developed countriesEntamoeba histolyticainfections are commonly seen in travelers, recent immigrants, homosexual men, and inmates of institutions. The disease is more severe in the two extremes of life. This paper paper describes a four-month-old male infant withEntamoeba histolyticapresenting initially with refusal of feeds, hyperactive bowel sound, vomiting, and diarrhea. A fecal sample was positive forEntamoeba histolyticaby Lugol's iodine solution and the concentration technique. He was successfully treated with metronidazole for 5 days. This case illustrates thatEntamoebaspecies could be pathogenic in young infant; therefore, awareness of the infection, aggressive approach to diagnosis, and early initiation of treatment continue to be critical component of infection control.
The Effects of Clinical Hypnosis versus Neurolinguistic Programming (NLP) before External Cephalic Version (ECV): A Prospective Off-Centre Randomised, Double-Blind, Controlled Trial
Authors: Reinhard Joscha , Peiffer Swati , Sänger Nicole , Herrmann Eva , Yuan Juping , Louwen Frank
Published: June 2012

Objective. To examine the effects of clinical hypnosis versus NLP intervention on the success rate of ECV procedures in comparison to a control group.Methods. A prospective off-centre randomised trial of a clinical hypnosis intervention against NLP of women with a singleton breech fetus at or after 370/7(259 days) weeks of gestation and normal amniotic fluid index. All 80 participants heard a 20-minute recorded intervention via head phones. Main outcome assessed was success rate of ECV. The intervention groups were compared with a control group with standard medical care alone ().Results. A total of 42 women, who received a hypnosis intervention prior to ECV, had a 40.5% (), successful ECV, whereas 38 women, who received NLP, had a 44.7% () successful ECV (). The control group had similar patient characteristics compared to the intervention groups (). In the control group () 27.3% () had a statistically significant lower successful ECV procedure than NLP () and hypnosis and NLP ().Conclusions. These findings suggest that prior clinical hypnosis and NLP have similar success rates of ECV procedures and are both superior to standard medical care alone.
An Evaluation of the Role of Sensory Drive in the Evolution of Lake Malawi Cichlid Fishes
Authors: Smith Adam R. , van Staaden Moira J. , Carleton Karen L.
Published: June 2012

Although the cichlids of Lake Malawi are an important model system for the study of sensory evolution and sexual selection, the evolutionary processes linking these two phenomena remain unclear. Prior works have proposed that evolutionary divergence is driven by sensory drive, particularly as it applies to the visual system. While evidence suggests that sensory drive has played a role in the speciation of Lake Victoria cichlids, the findings from several lines of research on cichlids of Lake Malawi are not consistent with the primary tenets of this hypothesis. More specifically, three observations make the sensory drive model implausible in Malawi: (i) a lack of environmental constraint due to a broad and intense ambient light spectrum in species rich littoral habitats, (ii) pronounced variation in receiver sensory characteristics, and (iii) pronounced variability in male courtship signal characteristics. In the following work, we synthesize the results from recent studies to draw attention to the importance of sensory variation in cichlid evolution and speciation, and we suggest possible avenues of future research.
Goal-Directed Fluid Therapy Using Stroke Volume Variation Does Not Result in Pulmonary Fluid Overload in Thoracic Surgery Requiring One-Lung Ventilation
Authors: Haas Sebastian , Eichhorn Volker , Hasbach Ted , Trepte Constantin , Kutup Asad , Goetz Alwin E. , Reuter Daniel A.
Published: June 2012

Background. Goal-directed fluid therapy (GDT) guided by functional parameters of preload, such as stroke volume variation (SVV), seems to optimize hemodynamics and possibly improves clinical outcome. However, this strategy is believed to be rather fluid aggressive, and, furthermore, during surgery requiring thoracotomy, the ability of SVV to predict volume responsiveness has raised some controversy. So far it is not known whether GDT is associated with pulmonary fluid overload and a deleterious reduction in pulmonary function in thoracic surgery requiring one-lung-ventilation (OLV). Therefore, we assessed the perioperative course of extravascular lung water index (EVLWI) and -ratio during and after thoracic surgery requiring lateral thoracotomy and OLV to evaluate the hypothesis that fluid therapy guided by SVV results in pulmonary fluid overload.Methods. A total of 27 patients (group T) were enrolled in this prospective study with 11 patients undergoing lung surgery (group L) and 16 patients undergoing esophagectomy (group E). Goal-directed fluid management was guided by SVV (SVV < 10%). Measurements were performed directly after induction of anesthesia (baseline—BL), 15 minutes after implementation OLV (OLVimpl15), and 15 minutes after termination of OLV (OLVterm15). In addition, postoperative measurements were performed at 6 (6postop), 12 (12postop), and 24 (24postop) hours after surgery. EVLWI was measured at all predefined steps. The -ratio was determined at each point during mechanical ventilation (group L: BL-OLVterm15; group E: BL-24postop).Results. In all patients (group T), there was no significant change in EVLWI during the observation period (BL: 7.8 ± 2.5, 24postop: 8.1 ± 2.4 mL/kg). A subgroup analysis for group L and group E also did not reveal significant changes of EVLWI. The -ratio decreased significantly during the observation period (group L: BL: 462 ± 140, OLVterm15: 338 ± 112 mmHg; group E: BL: 389 ± 101, 24postop: 303 ± 74 mmHg) but remained >300 mmHg except during OLV.Conclusions. SVV-guided fluid management in thoracic surgery requiring lateral thoracotomy and one-lung ventilation does not result in pulmonary fluid overload. Although oxygenation was reduced, pulmonary function remained within a clinically acceptable range.
Interactive Evolutionary Computation for Analyzing Human Awareness Mechanisms
Authors: Takagi Hideyuki
Published: June 2012

We discuss the importance of establishing awareness science and show the idea of using interactive evolutionary computation (IEC) as a tool for analyzing awareness mechanism and making awareness models. First, we describe the importance of human factors in computational intelligence and that IEC is one of approaches for the so-called humanized computational intelligence. Second, we show examples that IEC is used as an analysis tool for human science. As analyzing human awareness mechanism is in this kind of analyzing human characteristics and capabilities, IEC may be able to be used for this purpose. Based on this expectation, we express one idea for analyzing the awareness mechanism. This idea is to make an equivalent model of an IEC user using a learning model and find latent variables that connect inputs and outputs of the user model and that help to understand or explain the inputs-outputs relationship. Although there must be several definitions of awareness, this idea is based on one definition that awareness is to find out unknown variables that helps our understanding. If we establish a method for finding the latent variables automatically, we can realize an awareness model in computer.
Understanding the Economics of Transportation Projects
Authors: Schultz Grant G. , Searle Jeremy E.
Published: June 2012

Understanding the economic impacts of transportation projects is essential for decision makers, officials, and stakeholders as they determine the best course of action for their jurisdiction. Economic impacts can guide decisions of future projects and help explain past economic fluctuations. This study uses an evaluative (ex-post) analysis process to assess the generative economic impacts of transportation projects after completion that can be used to identify the economic impacts of transportation projects while quantifying their relationship. Both pre- and postconstruction data were collected and used to compare the trends of sales tax revenue and employment numbers adjacent to transportation projects in Utah over a 10-year period. Plots of the trends before, during, and after construction for each project in the analysis were generated. A formal process was created for completing the analysis for future study. Results indicate that there is a positive relationship between transportation improvement projects and sales tax revenues. This relationship amounts to approximately a 4.0 percent increase in trends compared to the state overall. Employment demonstrated a 4.5 percent increase compared to the state overall. Although the results are not considered statistically significant, they are considered practically significant and add to the literature on this topic.
Examining the Factors Associated with Paid Employment of Clients Enrolled in First Episode of Psychosis Programs
Authors: Dewa Carolyn S. , Trojanowski Lucy , Cheng Chiachen , Loong Desmond
Published: June 2012

Schizophrenia is one of the most debilitating mental disorders. For a significant portion of individuals who suffer from this disorder, onset occurs in young adulthood, arresting important social and educational development that is necessary for future successful labor force participation. The purpose of this paper is to contribute to the literature about clients enrolled in first episode psychosis programs and psychosocial outcomes by examining the factors associated with paid employment among young adults who have experienced their first psychotic episodes. In this paper, we consider the association of socioeconomic factors to employment. Our results suggest that in addition to treatment, socioeconomic factors such as receipt of public disability benefits and educational attainment are associated with employment status. These results can help to inform future directions for the enhancement of psychosocial programs in FEP models to promote paid employment.
Measuring of Electrical Properties of MWNT‐Reinforced PAN Nanocomposites
Authors: Almuhamed Sliman , Khenoussi Nabyl , Schacher Laurence , Adolphe Dominique , Balard Henri
Published: June 2012

Nano‐web sheets of polyacrylonitrile (PAN) reinforced by carbon nanotubes (CNT) were prepared by electrospinning process. Multi wall nanotubes (MWNT) were dispersed mechanically by high shear mixing using a homogenizer device. It has been found that the spinning solution presented an electrical percolation threshold less than 0.5 wt.% of MWNT. Electrical volume and surface conductivity of the obtained nano‐webs was studied by measuring the electrical volume resistance and surface resistance thanks to home‐made plate electrodes. Scanning electron microscope (SEM) has been used to characterize the nano‐web sheets produced. The average filament diameters range from 320 to 750 nm depending on the concentration of CNT and of PAN. From an electrical point of view, it has been observed that the electrical volume conductivity increases by about six orders of magnitude from 2 × 10−12 S/m for pristine PAN to 4 × 10−6 S/m for PAN charged by MWNT. Increasing the pressure on the specimen induces an exponential decrease of the volume resistivity while surface resistivity shows no significant changes, neither between pristine PAN and reinforced nano‐webs, nor among reinforced nano‐web in relation to MWNT concentration (in the limit of the study). This observed behavior is very interesting in the context of sensor developments.
Hyperfractionated Radiotherapy with Concurrent Cisplatin/5-Fluorouracil for Locoregional Advanced Head and Neck Cancer: Analysis of 105 Consecutive Patients
Authors: Zaboli David , Tan Marietta , Gogineni Hrishikesh , Lake Spencer , Fan Katherine , Zahurak Marianna L. , Messing Barbara , Ulmer Karen , Zinreich Eva S. , Levine Marshall A. , Tang Mei , Pai Sara I. , Blanco Ray G. , Saunders John R. , Best Simon R. , Califano Joseph A. , Ha Patrick K.
Published: June 2012

Objective. We reviewed a cohort of patients with previously untreated locoregional advanced head and neck squamous cell carcinoma (HNSCC) who received a uniform chemoradiotherapy regimen.Methods. Retrospective review was performed of 105 patients with stage III or IV HNSCC treated at Greater Baltimore Medical Center from 2000 to 2007. Radiation included 125 cGy twice daily for a total 70 Gy to the primary site. Chemotherapy consisted of cisplatin (12 mg/m2/h) daily for five days and 5-fluorouracil (600 mg/m2/20 h) daily for five days, given with weeks one and six of radiation. All but seven patients with N2 or greater disease received planned neck dissection after chemoradiotherapy. Primary outcomes were overall survival (OS), locoregional control (LRC), and disease-free survival (DFS).Results. Median followup of surviving patients was 57.6 months. Five-year OS was 60%, LRC was 68%, and DFS was 56%. Predictors of increased mortality included age ≥55, female gender, hypopharyngeal primary, and T3/T4 stage. Twelve patients developed locoregional recurrences, and 16 patients developed distant metastases. Eighteen second primary malignancies were diagnosed in 17 patients.Conclusions. The CRT regimen resulted in favorable outcomes. However, locoregional and distant recurrences cause significant mortality and highlight the need for more effective therapies to prevent and manage these events.
Temperature‐Driven Spin Reorientation Transition in CoPt/AlN Multilayer Films
Authors: Cai Wupeng , Muraishi Shinji , Shi Ji , Nakamura Yoshio , Liu Wei , Yu Ronghai
Published: June 2012

Spin reorientation transition phenomena from out‐of‐plane to in‐plane direction with increasing temperature are observed for the 500°C annealed CoPt/AlN multilayer films with different CoPt layer thicknesses. CoPt‐AlN interface and volume anisotropy contributions, favoring out‐of‐plane and in‐plane magnetization, respectively, are separately determined at various temperatures. Interface anisotropy exhibits much stronger temperature dependence than volume contribution, hence the temperature‐driven spin reorientation transition occurs. Interface anisotropy in this work consists of Néel interface anisotropy and magnetoelastic effect. Magnetoelastic effect degrades rapidly and changes its sign from positive to negative above 200°C, because of the involvement of stress state in CoPt films with temperature. By contrast, Néel interface anisotropy decays slowly, estimated from a Néel mean field model. Thus, the strong temperature dependence of CoPt‐AlN interface anisotropy is dominated by the change of magnetoelastic effect.
Pathological Significance of Mitochondrial Glycation
Authors: Pun Pamela Boon Li , Murphy Michael P.
Published: June 2012

Glycation, the nonenzymatic glycosylation of biomolecules, is commonly observed in diabetes and ageing. Reactive dicarbonyl species such as methylglyoxal and glyoxal are thought to be major physiological precursors of glycation. Because these dicarbonyls tend to be formed intracellularly, the levels of advanced glycation end products on cellular proteins are higher than on extracellular ones. The formation of glycation adducts within cells can have severe functional consequences such as inhibition of protein activity and promotion of DNA mutations. Although several lines of evidence suggest that there are specific mitochondrial targets of glycation, and mitochondrial dysfunction itself has been implicated in disease and ageing, it is unclear if glycation of biomolecules specifically within mitochondria induces dysfunction and contributes to disease pathology. We discuss here the possibility that mitochondrial glycation contributes to disease, focussing on diabetes, ageing, cancer, and neurodegeneration, and highlight the current limitations in our understanding of the pathological significance of mitochondrial glycation.
Large-Scale Measurements of Thermospheric Dynamics with a Multisite Fabry-Perot Interferometer Network: Overview of Plans and Results from Midlatitude Measurements
Authors: Makela Jonathan J. , Meriwether John W. , Ridley Aaron J. , Ciocca Marco , Castellez Michael W.
Published: June 2012

The North American Thermosphere Ionosphere Observing Network (NATION), comprising a new network of Fabry-Perot interferometers (FPIs), to be deployed in the Midwest of the United States of America is described. FPIs will initially be deployed to four sites to make coordinated measurements of the neutral winds and temperature in the Earth's thermosphere using measurements of the 630 nm redline emission. The observing strategy of the network will take into account local observing conditions, and common volume measurements from multiple sites will be made in order to estimate local vector wind quantities. The network described is expandable, and as additional FPI sites are installed in North America, or elsewhere, the goal of providing the upper atmospheric research community with a robust dataset of neutral winds and temperatures can be achieved.
The Group Interview Experience as a Tool for Admission to Teacher Education
Authors: Leshem Shosh
Published: June 2012

This study deals with qualitative aspects of group interviews as a tool in selecting students for a teacher education program. It presents findings from insider research on the dynamics of group interviews, focusing on participants' experiences and the meanings they attribute to them. The aim of the study is to gain a better understanding of the group interview as an effective tool for the selection of candidates for teacher education. The participants were 107 candidates in ten groups. Data from observations, interviews, and questionnaires were gathered to examine variables that affect the performance of the candidates in the interview. The findings highlight the complexities of group interviews as a filtering tool, foremost cultural and social aspects that affect assessors' and participants' performance. Notwithstanding the complexities, the findings demonstrate the utility of the group interview in filtering out unsuitable candidates and, possibly, in marketing the institution.
Bark Beetles,Pityogenes bidentatus, Orienting to Aggregation Pheromone Avoid Conifer Monoterpene Odors When Flying but Not When Walking
Authors: Byers John A.
Published: June 2012

Previous studies and data presented here suggest that odors from healthy host Scotch pine (Pinus sylvestris) and nonhost Norway spruce (Picea abies), as well as major monoterpenes of these trees at natural release rates, significantly reduce the attraction of flying bark beetles,Pityogenes bidentatus, of both sexes to their aggregation pheromone components grandisol andcis-verbenol in the field, as tested by slow rotation of trap pairs. In contrast,P. bidentatusmales and females walking in an open-arena olfactometer in the laboratory did not avoid monoterpene vapors at release rates spanning several orders of magnitude in combination with aggregation pheromone. The bark beetle may avoid monoterpenes when flying as a mechanism for avoiding nonhost species, vigorous and thus unsuitable host trees, as well as harmful resinous areas of hosts. Inhibition of this flight avoidance response in beetles after landing would allow them to initiate, or to find and enter, gallery holes with high monoterpene vapor concentrations in order to feed and reproduce.
The Solution of a Class of Singularly Perturbed Two‐Point Boundary Value Problems by the Iterative Reproducing Kernel Method
Authors: Li Zhiyuan , Wang YuLan , Tan Fugui , Wan Xiaohui , Nie Tingfang
Published: June 2012

In (Wang et al., 2011), we give an iterative reproducing kernel method (IRKM). The main contribution of this paper is to use an IRKM (Wang et al., 2011), in singular perturbation problems with boundary layers. Two numerical examples are studied to demonstrate the accuracy of the present method. Results obtained by the method indicate that the method is simple and effective.
A Novel BLDC-Like DTC Control Technique for Induction Motors
Authors: Rossi Andrea , Concari Carlo
Published: June 2012

DC brushless motors are widely adopted for their simplicity of control, even in sensorless configuration, and their high torque density. On the other hand, induction motors are very economical due to the absence of permanent magnets; for the same reason they can easily be driven in the flux-weakening region to attain a wide speed range. Nevertheless, high dynamic induction motors drives, based on field-oriented (FOC) or predictive control, require large amounts of computing power and are rather sensitive to motor parameter variations. This paper presents a simple DTC induction motor control algorithm based on a well-known BLDC control technique, which allows to realize a high dynamic induction motor speed control with wide speed range. The firmware implementation is very compact and occupies a low amount of program memory, comparable to volt-per-Hertz- (V/f-) based control algorithms. The novel control algorithm presents also good performance and low current ripple and can be implemented on a low-cost motion control DSP without resorting to high-frequency PWM.
miRNA Biomarkers in Cyst Fluid Augment the Diagnosis and Management of Pancreatic Cysts
Authors: Matthaei Hanno , Wylie Dennis , Lloyd Maura B. , Dal Molin Marco , Kemppainen Jon , Mayo Skye C. , Wolfgang Christopher L. , Schulick Richard D. , Langfield Laura , Andruss Bernard F. , Adai Alex T. , Hruban Ralph H. , Szafranska-Schwarzbach Anna E. , Maitra Anirban
Published: June 2012

Purpose: The diagnosis of pancreatic cystic lesions has increased dramatically. Most are benign, whereas some, such as intraductal papillary mucinous neoplasms (IPMN), represent precursors of pancreatic adenocarcinoma. Therapeutic stratification of IPMNs is challenging without precise information on dysplasia grade and presence of invasion. We assessed the diagnostic benefit of using miRNAs as biomarkers in pancreatic cyst fluid, focusing on IPMNs because of their frequency and malignant potential.

Experimental Design: RNA was extracted from 55 microdissected formalin-fixed, paraffin-embedded (FFPE) IPMN specimens, and 65 cyst fluid specimens aspirated following surgical resection. Expression of 750 miRNAs was evaluated with TaqMan miRNA Arrays using 22 FFPE and 15 cyst fluid specimens. Differential expression of selected miRNA candidates was validated in 33 FFPE and 50 cyst fluid specimens using TaqMan miRNA Assays.

Results: We identified 26 and 37 candidate miRNAs that distinguish low-grade from high-grade IPMNs using FFPE and cyst fluid specimens, respectively. A subset of 18 miRNAs, selected from FFPE and cyst fluid data, separated high-grade IPMNs from low-grade IPMNs, serous cystadenomas (SCA) and uncommon cysts, such as solid pseudopapillary neoplasms (SPN) and cystic pancreatic neuroendocrine tumors (PanNET). A logistic regression model using nine miRNAs allowed prediction of cyst pathology implying resection (high-grade IPMNs, PanNETs, and SPNs) versus conservative management (low-grade IPMNs, SCAs), with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1.

Conclusions: We found candidate miRNAs that helped identify patients with high-grade IPMN and exclude nonmucinous cysts. These classifiers will require validation in a prospective setting to ultimately confirm their clinical usefulness. Clin Cancer Res; 18(17); 4713–24. ©2012 AACR.
Deregulation of a Hox Protein Regulatory Network Spanning Prostate Cancer Initiation and Progression
Authors: Chen James L. , Li Jianrong , Kiriluk Kyle J. , Rosen Alex M. , Paner Gladell P. , Antic Tatjana , Lussier Yves A. , Vander Griend Donald J.
Published: June 2012

Purpose: The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare.

Experimental Design: We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein–protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets.

Results: Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors.

Conclusion: These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression. Clin Cancer Res; 18(16); 4291–302. ©2012 AACR.
Genome-Wide Somatic Copy Number Alterations in Low-Grade PanINs and IPMNs from Individuals with a Family History of Pancreatic Cancer
Authors: Hong Seung-Mo , Vincent Audrey , Kanda Mitsuro , Leclerc Julie , Omura Noriyuki , Borges Michael , Klein Alison P. , Canto Marcia Irene , Hruban Ralph H. , Goggins Michael
Published: June 2012

Purpose: Characterizing the earliest chromosomal alterations of pancreatic precursor neoplasms from individuals with a familial aggregation of pancreatic cancer may provide clues as to the loci of pancreatic cancer susceptibility genes.

Experimental Design: We used Illumina 370/660K SNP arrays to conduct genome-wide copy number analysis in 60 benign neoplasms [58 mostly low-grade pancreatic intraepithelial neoplasias (PanIN) and intraductal papillary mucinous neoplasms (IPMN) and two pancreatic neuroendocrine tumors (PNET)] and matched normal tissues from 16 individuals with a family history of pancreatic cancer. PanINs and IPMNs were analyzed for KRAS codon 12/13 mutations.

Results: Of 40 benign neoplasms with adequate SNP calls and allele ratios, somatic chromosomal copy number changes were identifiable in only nine lesions, including eight of the 38 PanIN/IPMNs (two of which had identical alterations) and one of the two PNETs. Only two precursor lesions had more than one somatic copy number alteration. In contrast, the overwhelming majority (∼95%) of PanINs harbored KRAS mutations. The chromosomal alterations identified included nine chromosomal arms affected by chromosomal loss and two by chromosomal gain. Copy number loss spanning 9p21.3 was identified in three precursor lesions; two precursors had chromosomal losses affecting 6q and 17p.

Conclusions: Low- and intermediate-grade PanINs and IPMNs from patients with a family history of pancreatic cancer harbor few if any somatic chromosomal alterations. The absence of a locus of recurrent chromosomal loss in most low-grade pancreatic cancer precursor lesions supports the hypothesis that there is no one tumor suppressor gene locus consistently involved in initiating familial pancreatic neoplasia. Clin Cancer Res; 18(16); 4303–12. ©2012 AACR.
Liver X Receptor Activation Reduces Angiogenesis by Impairing Lipid Raft Localization and Signaling of Vascular Endothelial Growth Factor Receptor-2
Authors: Noghero Alessio , Perino Alessia , Seano Giorgio , Saglio Elisa , Sasso Giuseppe Lo , Veglio Franco , Primo Luca , Hirsch Emilio , Bussolino Federico , Morello Fulvio
Published: June 2012

Objective—

Liver X receptors (LXRα, LXRβ) are master regulators of cholesterol homeostasis. In the endothelium, perturbations of cell cholesterol have an impact on fundamental processes. We, therefore, assessed the effects of LXR activation on endothelial functions related to angiogenesis in vitro and in vivo.

Methods and Results—

LXR agonists (T0901317, GW3965) blunted migration, tubulogenesis, and proliferation of human umbilical vein endothelial cells. By affecting endothelial cholesterol homeostasis, LXR activation impaired the compartmentation of vascular endothelial growth factor receptor-2 in lipid rafts/caveolae and led to defective phosphorylation and downstream signaling of vascular endothelial growth factor receptor-2 upon vascular endothelial growth factor-A stimulation. Consistently, the antiangiogenic actions of LXR agonists could be prevented by coadministration of exogenous cholesterol. LXR agonists reduced endothelial sprouting from wild-type but not from LXRα
−/−
/LXRβ
−/−
knockout aortas and blunted the vascularization of implanted angioreactors in vivo. Furthermore, T0901317 reduced the growth of Lewis lung carcinoma grafts in mice by impairing angiogenesis.

Conclusion—

Pharmacological activation of endothelial LXRs reduces angiogenesis by restraining cholesterol-dependent vascular endothelial growth factor receptor-2 compartmentation and signaling. Thus, administration of LXR agonists could exert therapeutic effects in pathological conditions characterized by uncontrolled angiogenesis.
Crosstalk Between Reticular Adherens Junctions and Platelet Endothelial Cell Adhesion Molecule-1 Regulates Endothelial Barrier Function
Authors: Fernández-Martín Laura , Marcos-Ramiro Beatriz , Bigarella Carolina L. , Graupera Mariona , Cain Robert J. , Reglero-Real Natalia , Jiménez Anaïs , Cernuda-Morollón Eva , Correas Isabel , Cox Susan , Ridley Anne J. , Millán Jaime
Published: June 2012

Objective—

Endothelial cells provide a barrier between the blood and tissues, which is reduced during inflammation to allow selective passage of molecules and cells. Adherens junctions (AJ) play a central role in regulating this barrier. We aim to investigate the role of a distinctive 3-dimensional reticular network of AJ found in the endothelium.

Methods and Results—

In endothelial AJ, vascular endothelial-cadherin recruits the cytoplasmic proteins β-catenin and p120-catenin. β-catenin binds to α-catenin, which links AJ to actin filaments. AJ are usually described as linear structures along the actin-rich intercellular contacts. Here, we show that these AJ components can also be organized in reticular domains that contain low levels of actin. Reticular AJ are localized in areas where neighboring cells overlap and encompass the cell adhesion receptor platelet endothelial cell adhesion molecule-1 (PECAM-1). Superresolution microscopy revealed that PECAM-1 forms discrete structures distinct from and distributed along AJ, within the voids of reticular domains. Inflammatory tumor necrosis factor-α increases permeability by mechanisms that are independent of actomyosin-mediated tension and remain incompletely understood. Reticular AJ, but not actin-rich linear AJ, were disorganized by tumor necrosis factor-α. This correlated with PECAM-1 dispersal from cell borders. PECAM-1 inhibition with blocking antibodies or small interfering RNA specifically disrupted reticular AJ, leaving linear AJ intact. This disruption recapitulated typical tumor necrosis factor-α–induced alterations of barrier function, including increased β-catenin phosphorylation, without altering the actomyosin cytoskeleton.

Conclusion—

We propose that reticular AJ act coordinately with PECAM-1 to maintain endothelial barrier function in regions of low actomyosin-mediated tension. Selective disruption of reticular AJ contributes to permeability increase in response to tumor necrosis factor-α.
Molecular Imaging of Vascular Endothelial Growth Factor Receptors in Graft Arteriosclerosis
Authors: Zhang Jiasheng , Razavian Mahmoud , Tavakoli Sina , Nie Lei , Tellides George , Backer Joseph M. , Backer Marina V. , Bender Jeffrey R. , Sadeghi Mehran M.
Published: June 2012

Objective—

Vascular endothelial growth factor (VEGF) signaling plays a key role in the pathogenesis of vascular remodeling, including graft arteriosclerosis. Graft arteriosclerosis is the major cause of late organ failure in cardiac transplantation. We used molecular near-infrared fluorescent imaging with an engineered Cy5.5-labeled single-chain VEGF tracer (scVEGF/Cy) to detect VEGF receptors and vascular remodeling in human coronary artery grafts by molecular imaging.

Methods and Results—

VEGF receptor specificity of probe uptake was shown by flow cytometry in endothelial cells. In severe combined immunodeficiency mice, transplantation of human coronary artery segments into the aorta followed by adoptive transfer of allogeneic human peripheral blood mononuclear cells led to significant neointima formation in the grafts over a period of 4 weeks. Near-infrared fluorescent imaging of transplant recipients at 4 weeks demonstrated focal uptake of scVEGF/Cy in remodeling artery grafts. Uptake specificity was demonstrated using an inactive homolog of scVEGF/Cy. scVEGF/Cy uptake predominantly localized in the neointima of remodeling coronary arteries and correlated with VEGF receptor-1 but not VEGF receptor-2 expression. There was a significant correlation between scVEGF/Cy uptake and transplanted artery neointima area.

Conclusion—

Molecular imaging of VEGF receptors may provide a noninvasive tool for detection of graft arteriosclerosis in solid organ transplantation.
Genetic and Pharmacological Manipulation of Urotensin II Ameliorate the Metabolic and Atherosclerosis Sequalae in Mice
Authors: You Zhipeng , Genest Jacques , Barrette Pierre-Olivier , Hafiane Anouar , Behm David J. , D’Orleans-Juste Pedro , Schwertani Adel Giaid
Published: June 2012

Objective—

Urotensin II (UII) is a potent vasoactive peptide that binds to the urotensin receptor–coupled receptor-14 (known as UT) and exerts a wide range of actions in humans and experimental animals. We tested the hypothesis that UII gene deletion or UT blockade ameliorate experimental atherosclerosis.

Methods and Results—

We observed a significant reduction in weight gain, visceral fat, blood pressure, circulating plasma lipids, and proatherogenic cytokines and improvement of glucose tolerance in UII knockout mice compared with wild type (
P
<0.05). Deletion of UII after an apolipoprotein E knockout resulted in a significant reduction in serum cytokines, adipokines, and aortic atherosclerosis compared with apolipoprotein E knockout mice. Similarly, treatment of apolipoprotein E knockout mice fed on high-fat diet with the UT antagonist SB657510A reduced weight gain, visceral fat, and hyperlipidemia and improved glucose tolerance (
P
<0.05) and attenuated the initiation and progression of atherosclerosis. The UT antagonist also decreased aortic extracellular signal-regulated kinase 1/2 phosphorylation and oxidant formation and serum level of cytokines (
P
<0.05).

Conclusion—

These findings demonstrate for the first time the role of UII gene deletion in atherosclerosis and suggest that the use of pharmaceutical agents aimed at blocking the UII pathway may provide a novel approach in the treatment of atherosclerosis and its associated precursors such as obesity, hyperlipidemia, diabetes mellitus, and hypertension.
Role of Endothelial N-Glycan Mannose Residues in Monocyte Recruitment During Atherogenesis
Authors: Scott David W. , Chen Jie , Chacko Balu K. , Traylor James G. , Orr Anthony W. , Patel Rakesh P.
Published: June 2012

Objective—

Upregulated expression of endothelial adhesion molecules and subsequent binding to cognate monocytic receptors are established paradigms in atherosclerosis. However, these proteins are the scaffolds, with their posttranslational modification with sugars providing the actual ligands. We recently showed that tumor necrosis factor-α increased hypoglycosylated (mannose-rich) N-glycans on the endothelial surface. In the present study, our aim was to determine whether (1) hypoglycosylated N-glycans are upregulated by proatherogenic stimuli (oscillatory flow) in vitro and in vivo, and (2) mannose residues on hypoglycosylated endothelial N-glycans mediate monocyte rolling and adhesion.

Methods and Results—

Staining with the mannose-specific lectins concanavalin A and lens culinaris agglutinin was increased in human aortic endothelial cells exposed to oscillatory shear or tumor necrosis factor-α and at sites of plaque development and progression in both mice and human vessels. Increasing surface N-linked mannose by inhibiting N-glycan processing potentiated monocyte adhesion under flow during tumor necrosis factor-α stimulation. Conversely, enzymatic removal of high-mannose N-glycans, or masking mannose residues with lectins, significantly decreased monocyte adhesion under flow. These effects occurred without altering induced expression of adhesion molecule proteins.

Conclusion—

Hypoglycosylated (high mannose) N-glycans are present on the endothelial cell surface at sites of early human lesion development and are novel effectors of monocyte adhesion during atherogenesis.
Spatiotemporal Behavior of High Dominant Frequency During Paroxysmal and Persistent Atrial Fibrillation in the Human Left Atrium
Authors: Jarman Julian W.E. , Wong Tom , Kojodjojo Pipin , Spohr Hilmar , Davies Justin E. , Roughton Michael , Francis Darrel P. , Kanagaratnam Prapa , Markides Vias , Davies D. Wyn , Peters Nicholas S.
Published: June 2012

Background—

Sites of high dominant frequency (DF
peak
) are thought to indicate the location of drivers of atrial fibrillation (AF), but characterization of their spatiotemporal distribution and stability, critical to their relevance as targets for catheter ablation, requires simultaneous global mapping of the left atrium.

Methods and Results—

Noncontact electrograms recorded simultaneously from 256 left atrial sites during spontaneous AF were analyzed. After subtraction of the ventricular component, fast Fourier transform identified the DF at each site. Focal areas of DF
peak
were defined as those having a DF >20% above all neighboring sites. Twenty-four patients with spontaneous AF (11 paroxysmal and 13 persistent) were studied. In paroxysmal AF, sites of DF
peak
(mean DF, 11.6±2.9 Hz) were observed in 100% of patients (present during 65% of the mapping period). In contrast, DF
peak
was detected in only 31% of patients with persistent AF (
P
<0.001) and for only 5% of the mapping period (
P
<0.001). In both groups, locations of DF
peak
varied widely in both consecutive and separated segments of AF (κ coefficient range, -0.07–0.22). Activation sequences around sites of DF
peak
did not demonstrate centrifugal activation that would be expected from focal drivers.

Conclusions—

Focal areas of high DF are more frequent in paroxysmal than persistent AF, are spatiotemporally unstable, are not the source of centrifugal activation, and are not, therefore, indicative of fixed drivers of AF. In the absence of spatiotemporal stability, the success of ablation at sites of DF
peak
cannot be explained by elimination of fixed drivers.
In Situ Confocal Imaging in Intact Heart Reveals Stress-Induced Ca
2+
Release Variability in a Murine Catecholaminergic Polymorphic Ventricular Tachycardia Model of Type 2 Ryanodine Receptor
R4496C+/−
Mutation
Authors: Chen Biyi , Guo Ang , Gao Zhan , Wei Sheng , Xie Yu-Ping , Chen S.R. Wayne , Anderson Mark E. , Song Long-Sheng
Published: June 2012

Background—

Catecholaminergic polymorphic ventricular tachycardia is directly linked to mutations in proteins (eg, type 2 ryanodine receptor [RyR2]
R4496C
) responsible for intracellular Ca
2+
homeostasis in the heart. However, the mechanism of Ca
2+
release dysfunction underlying catecholaminergic polymorphic ventricular tachycardia has only been investigated in isolated cells but not in the in situ undisrupted myocardium.

Methods and Results—

We investigated in situ myocyte Ca
2+
dynamics in intact Langendorff-perfused hearts (ex vivo) from wild-type and RyR2
R4496C+/−
mice using laser scanning confocal microscopy. We found that myocytes from both wild-type and RyR2
R4496C+/−
hearts displayed uniform, synchronized Ca
2+
transients. Ca
2+
transients from beat to beat were comparable in amplitude with identical activation and decay kinetics in wild-type and RyR2
R4496C+/−
hearts, suggesting that excitation-contraction coupling between the sarcolemmal Ca
2+
channels and mutated RyR2
R4496C+/−
channels remains intact under baseline resting conditions. On adrenergic stimulation, RyR2
R4496C+/−
hearts exhibited a high degree of Ca
2+
release variability. The varied pattern of Ca
2+
release was absent in single isolated myocytes, independent of cell cycle length, synchronized among neighboring myocytes, and correlated with catecholaminergic polymorphic ventricular tachycardia. A similar pattern of action potential variability, which was synchronized among neighboring myocytes, was also revealed under adrenergic stress in intact hearts but not in isolated myocytes.

Conclusions—

Our studies using an in situ confocal imaging approach suggest that mutated RyR2s are functionally normal at rest but display a high degree of Ca
2+
release variability on intense adrenergic stimulation. Ca
2+
release variability is a Ca
2+
release abnormality, resulting from electric defects rather than the failure of the Ca
2+
release response to action potentials in mutated ventricular myocytes. Our data provide important insights into Ca
2+
release and electric dysfunction in an established model of catecholaminergic polymorphic ventricular tachycardia.