bluuebunny/crossref_metadata_2025 huggingface dataset:
Streptococcus panodentis sp. nov. from the oral cavities of chimpanzees
Authors: Okamoto Masaaki , Imai Susumu , Miyanohara Mayu , Saito Wataru , Momoi Yasuko , Nomura Yoshiaki , Ikawa Tomoko , Ogawa Takumi , Miyabe‐Nishiwaki Takako , Kaneko Akihisa , Watanabe Akino , Watanabe Shohei , Hayashi Misato , Tomonaga Masaki , Hanada Nobuhiro
Published: August 2015

Three strains TKU9, TKU49 and TKU50T, were isolated from the oral cavities of chimpanzees (Pan troglodytes). The isolates were all gram‐positive, facultative anaerobic cocci that lacked catalase activity. Analysis of partial 16S rRNA gene sequences showed that the most closely related species was Streptococcus infantis (96.7%). The next most closely related species to the isolates were S. rubneri, S. mitis, S. peroris and S. australis (96.6 to 96.4%). Based on the rpoB and gyrB gene sequences, TKU50T was clustered with other member of the mitis group. Enzyme activity and sugar fermentation patterns differentiated this novel bacterium from other members of the mitis group streptococci. The DNA G + C content of strain TKU50T was 46.7 mol%, which is the highest reported value for members of the mitis group (40–46 mol%). On the basis of the phenotypic characterization, partial 16S rRNA gene and sequences data for two housekeeping gene (gyrB and rpoB), we propose a novel taxa, S. panodentis for TKU 50T (type strain = CM 30579T = DSM 29921T), for these newly described isolates.
Comparison of Distributions of Wave Heights From Nonlinear Schröedinger Equation Simulations and Laboratory Experiments
Authors: Zhang Huidong , Cherneva Zhivelina , Guedes Soares Carlos , Onorato Miguel
Published: August 2015

Numerical simulations of the nonlinear Schrödinger (NLS) equation are performed by imposing randomly synthesized free surface displacement at the wave maker characterized by the Joint North Sea Wave Project (JONSWAP) spectrum and compared with four different sea states generated in the deepwater wave basin of Marintek. The comparisons show that the numerical simulations have a high degree of agreement with the laboratory experiments although a little overestimation can be observed, especially in the severe sea state. Thus, the simulations still catch the main characteristics of extreme waves and provide an important physical insight into their generation. The coefficient of kurtosis λ40 presents a similar spatial evolution trend with the abnormal wave density, and the nonlinear Gram–Charlier (GC) model is used to predict the wave height distribution. It is demonstrated again that the theoretical approximation based on the GC expansion can describe large wave heights reasonably well in most cases. However, if the sea state is severe, wave breaking can significantly decrease the actual tail of wave height distribution, and discrepancy occurs when comparing with the numerical simulation. Moreover, the number of waves also plays an important role on the prediction of extreme wave height.
Immune-mediated pathology in Duchenne muscular dystrophy
Authors: Rosenberg Amy S. , Puig Montserrat , Nagaraju Kanneboyina , Hoffman Eric P. , Villalta S. Armando , Rao V. Ashutosh , Wakefield Lalage M. , Woodcock Janet
Published: August 2015

Immunopathology contributes to the destruction and fibrosis of muscle in Duchenne muscular dystrophy, reducing the efficacy of dystrophin-replacement therapies.
Dynamic Random-Access Stored-Program Machine for Runtime Code Modification
Authors: Rudy Jarosław
Published: August 2015

This paper is concerned with the study of possibility of performing changes to existing running programs with the use of the RAM and RASP models of computation. A new model of computation is defined with the capability of performing runtime changes. Theoretical properties, including time and space complexities, of the defined models are presented and proven. A number of simple empirical tests are conducted in order to prove the ability to perform runtime changes as well as support obtained theoretical results. The paper concludes that the defined model has virtually no affect on performance when there are no changes and the performance with changes is easily manageable. Moreover, the results can be used to develop runtime change capabilities for a wide range of programming languages and paradigms.
Rashba Effect and Beating Patterns in the THz Magneto-Photoresponse of a HgTe-Based Two-Dimensional Electron Gas
Authors: Pakmehr M. , Brüne C. , Buhmann H. , Molenkamp L. W. , McCombe B. D.
Published: August 2015

HgTe quantum wells with a gapped single Dirac cone electronic dispersion relation have been investigated by THz magneto-photoresponse (PR) and magneto-transport measurements. The QW sample has the conventional band alignment with the well thickness (6.1 nm) slightly smaller than the critical thickness for the topological phase transition. The effective gap of this structure is roughly 10 meV, and the large sheet density ([Formula: see text] m-2) of the two-dimensional electron gas (2DEG) results in a very large Fermi energy ([Formula: see text] meV). We have found several interesting effects at these high densities. In this paper we focus on an observed beating of quantum oscillations in the PR signal (at 1.83 THz) and compare it with direct measurements of oscillations in the longitudinal magneto-resistance (Rxx). The mechanism for the PR is cyclotron resonance absorption heating of the electrons (an electron bolometric effect). We attribute the beating to Rashba splitting of the spin states, which is barely observable in direct Rxx measurements under strong gate-induced electric fields.
Multiscale Region Projection Method to Discriminate Between Printed and Handwritten Text on Registration Forms
Authors: Tan J. , Lai J.-H. , Wang P. , Bi N.
Published: August 2015

Techniques to identify printed and handwritten text in scanned documents differ significantly. In this paper, we address the question of how to discriminate between each type of writing on registration forms. Registration-form documents consist of various type zones, such as printed text, handwriting, table, image, noise, etc., so segmenting the various zones is a challenge. We adopt herein an approach called “multiscale-region projection” to identify printed text and handwriting. An important aspect of our approach is the use of multiscale techniques to segment document images. A new set of projection features extracted from each zone is also proposed. The classification rules are mining and are used to discern printed text and table lines from handwritten text. The proposed system was tested on 11[Formula: see text]118 samples in two registration-form-image databases. Some possible measures of efficiency are computed, and in each case the proposed approach performs better than traditional methods.
EFFECT OF TiO2PARTICLES ON MICRO-HARDNESS, CORROSION, WEAR AND FRICTION OF Ni–P–TiO2COMPOSITE COATINGS AT DIFFERENT ANNEALING TEMPERATURES
Authors: GADHARI PRASANNA , SAHOO PRASANTA
Published: August 2015

The present study investigates the effect of titania particles on the micro-hardness, wear resistance, corrosion resistance and friction of electroless Ni–P–TiO2composite coatings deposited on mild steel substrates at different annealing temperatures. The experimental results confirmed that the amount of TiO2particles incorporated in the coatings increases with increase in the concentration of particles in the electroless bath. In presence of TiO2particles, hardness, wear resistance and corrosion resistance of the coating improve significantly. At higher annealing temperature, wear resistance increases due to formation of hard Ni3P phase and incorporation of titania particles in the coated layer. Charge transfer resistance and corrosion current density of the coatings reduce with an increase in TiO2particles, whereas corrosion potential increases. Microstructure changes and composition of the composite coating due to heat treatment are studied with the help of scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDXA) and X-ray diffraction (XRD) analysis.
Average of the first invariant factor of the reductions of abelian varieties of CM type
Authors: Kim Sungjin
Published: August 2015

For a field of definition [Formula: see text] of an abelian variety [Formula: see text] and prime ideal [Formula: see text] of [Formula: see text] which is of a good reduction for [Formula: see text], the structure of [Formula: see text] as abelian group is: [Formula: see text] where [Formula: see text], [Formula: see text], and [Formula: see text] for [Formula: see text]. We are interested in finding an asymptotic formula for the number of prime ideals [Formula: see text] with [Formula: see text], [Formula: see text] has a good reduction at [Formula: see text], [Formula: see text]. We succeed in proving this under the assumption of the Generalized Riemann Hypothesis (GRH). Unconditionally, we achieve a short range asymptotic for abelian varieties of CM type, and the full cyclicity theorem for elliptic curves over a number field containing the CM field.
One-Step Synthesis of Immobilized BiOCl Film with Excellent Adsorption Capacity for Dyes
Authors: Chen Hongbin , Fu Wangmiao , Yu Xiang , Zhu Yi , Meng Hui , Tang Jinpeng , Zhang Yuanming
Published: August 2015

A facile one-step method was developed for the first time to fabricate BiOCl film on Cu substrate by simply dipping the Cu substrate in the mixed solution containing HCl, glycol, H2O2 and BiCl3. This method shows the advantages of a simple technique, uniform and controllable morphology, as well as easy mass production. The absorption capacity of BiOCl film was investigated by adsorption of Rhodamine B and Congo red (CR) and their maximum adsorption capacities were 1667[Formula: see text]mg[Formula: see text]g[Formula: see text] and 1429[Formula: see text]mg[Formula: see text]g[Formula: see text], respectively. The negative values of free energy and the positive values of enthalpy suggested that the adsorption were spontaneous and endothermic, respectively. Moreover, both adsorptions were matched with the pseudo-second-order equation. This film could be reused and the recycle rates for Rhodamine B and CR were still about 95% and 75% after five cycles, respectively. The adsorption mechanism revealed that hydrogen bond mainly accounted for the adsorption of dyes.
Electrogravitational stability of streaming compound jets
Authors: Hasan Alfaisal A.
Published: August 2015

The electrohydrodynamic stability of a self-gravitating streaming compound jet has been investigated for all modes of perturbation. The jets are immersed in a dielectric motionless tenuous medium pervaded by varying electric field. A second-order integro-differential equation of Mathieu type has been derived and some reported works are recovered as limiting cases from it.
A Flooding Induced Station Blackout Analysis for a Pressurized Water Reactor Using the RISMC Toolkit
Authors: Mandelli Diego , Prescott Steven , Smith Curtis , Alfonsi Andrea , Rabiti Cristian , Cogliati Joshua , Kinoshita Robert
Published: August 2015

In this paper we evaluate the impact of a power uprate on a pressurized water reactor (PWR) for a tsunami-induced flooding test case. This analysis is performed using the RISMC toolkit: the RELAP-7 and RAVEN codes. RELAP-7 is the new generation of system analysis codes that is responsible for simulating the thermal-hydraulic dynamics of PWR and boiling water reactor systems. RAVEN has two capabilities: to act as a controller of the RELAP-7 simulation (e.g., component/system activation) and to perform statistical analyses. In our case, the simulation of the flooding is performed by using an advanced smooth particle hydrodynamics code called NEUTRINO. The obtained results allow the user to investigate and quantify the impact of timing and sequencing of events on system safety. In addition, the impact of power uprate is determined in terms of both core damage probability and safety margins.
Making an IMPACT: The Story of a Medical Student-Designed, Peer-Led Healthy Eating and Physical Activity Curriculum
Authors: Chatterjee Avik , Rusher Thomas N. , Nugent Julia , Herring Kenneth W. , Rose Lindsey M. , Nehama Dean , Muth Natalie D.
Published: August 2015

Despite the importance of healthful dietary choices in combating the childhood obesity epidemic, neither primary and secondary schools nor medical schools provide adequate nutrition education. In 2005, two medical students at the University of North Carolina started the Improving Meals and Physical Activity in Children and Teens (IMPACT) program, which utilized a peer-educator model to engage medical students and high school students in teaching 4th graders about healthy eating and physical activity. Over the years, medical student leaders of IMPACT continued the program, orienting the curriculum around the 5-2-1-0 Let’s Go campaign, aligning the IMPACT curriculum with North Carolina state curricular objectives for 4th graders and engaging and training teams of health professional students to deliver the program. The IMPACT project demonstrates how medical and other health professional students can successfully promote nutrition and physical activity education for themselves and for children through community-based initiatives. Ongoing efforts are aimed at increasing family participation in the curriculum to maximize changes in eating and physical activity of IMPACT participants and ensuring sustainability of the organization by engaging health professional student participants in continuing to improve the program.
New Results on Passivity Analysis of Stochastic Neural Networks with Time-Varying Delay and Leakage Delay
Authors: Li YaJun , Huang Zhaowen
Published: August 2015

The passivity problem for a class of stochastic neural networks systems (SNNs) with varying delay and leakage delay has been further studied in this paper. By constructing a more effective Lyapunov functional, employing the free-weighting matrix approach, and combining with integral inequality technic and stochastic analysis theory, the delay-dependent conditions have been proposed such that SNNs are asymptotically stable with guaranteed performance. The time-varying delay is divided into several subintervals and two adjustable parameters are introduced; more information about time delay is utilised and less conservative results have been obtained. Examples are provided to illustrate the less conservatism of the proposed method and simulations are given to show the impact of leakage delay on stability of SNNs.
Is Self-Reported Physical Activity Participation Associated with Lower Health Services Utilization among Older Adults? Cross-Sectional Evidence from the Canadian Community Health Survey
Authors: Fisher Koren L. , Harrison Elizabeth L. , Reeder Bruce A. , Sari Nazmi , Chad Karen E.
Published: August 2015

Purpose. To examine relationships between leisure time physical activity (LTPA) and health services utilization (H) in a nationally representative sample of community-dwelling older adults.Methods. Cross-sectional data from 56,652 Canadian Community Health Survey respondents aged ≥ 50 years (48% M; 52% F; mean age 63.5 ± 10.2 years) were stratified into three age groups and analysed using multivariate generalized linear modeling techniques. Participants were classified according to PA level based on self-reported daily energy expenditure. Nonleisure PA (NLPA) was categorized into four levels ranging from mostly sitting to mostly lifting objects.Results. Active 50–65-year-old individuals were 27% less likely to report any GP consultationsORadj=0.73; P<0.001and had 8% fewer GP consultations annually(IRRadj=0.92; P<0.01)than their inactive peers. Active persons aged 65–79 years were 18% less likely than inactive respondents to have been hospitalized overnight in the previous year(ORadj=0.82, P<0.05). Higher levels of NLPA were significantly associated with lower levels of HSU, across all age groups.Conclusion. Nonleisure PA appeared to be a stronger predictor of all types of HSU, particularly in the two oldest age groups. Considering strategies that focus on reducing time spent in sedentary activities may have a positive impact on reducing the demand for health services.
Supporting Image Search with Tag Clouds: A Preliminary Approach
Authors: Guerra Francesco , Simonini Giovanni , Vincini Maurizio
Published: August 2015

Algorithms and techniques for searching in collections of data address a challenging task, since they have to bridge the gap between the ways in which users express their interests, through natural language expressions or keywords, and the ways in which data is represented and indexed. When the collections of data include images, the task becomes harder, mainly for two reasons. From one side the user expresses his needs through one medium (text) and he will obtain results via another medium (some images). From the other side, it can be difficult for a user to understand the results retrieved; that is why a particular image is part of the result set. In this case, some techniques for analyzing the query results and giving to the users some insight into the content retrieved are needed. In this paper, we propose to address this problem by coupling the image result set with a tag cloud of words describing it. Some techniques for building the tag cloud are introduced and two application scenarios are discussed.
Active Aging: Exploration into Self-Ratings of “Being Active,” Out-of-Home Physical Activity, and Participation among Older Australian Adults Living in Four Different Settings
Authors: Aird Rosemary L. , Buys Laurie
Published: August 2015

We examined whether self-ratings of “being active” among older people living in four different settings (major city high and lower density suburbs, a regional city, and a rural area) were associated with out-of-home participation and outdoor physical activity. A mixed-methods approach (survey, travel diary, and GPS tracking over a one-week period) was used to gather data from 48 individuals aged over 55 years. Self-ratings of “being active” were found to be positively correlated with the number of days older people spent time away from home but unrelated to time traveled by active means (walking and biking). No significant differences in active travel were found between the four study locations, despite differences in their respective built environments. The findings suggest that additional strategies to the creation of “age-friendly” environments are needed if older people are to increase their levels of outdoor physical activity. “Active aging” promotion campaigns may need to explicitly identify the benefits of walking outdoors to ambulatory older people as a means of maintaining their overall health, functional ability, and participation within society in the long-term and also encourage the development of community-based programs in order to facilitate regular walking for this group.
Performance Investigation and Structure Optimization of a Flat Dual-Function Solar Collector
Authors: Ma Jinwei , Wang Haitao , Wang Yanping , Sun Wei , Ji Jie
Published: August 2015

The performance of a dual-function solar collector (DFSC) that can work as either water heater or air heater depending on seasonal requirement is investigated via both experimental and numerical approaches in this paper. The numerical results are well consistent with the experimental results. Daily efficiency of the thermosiphon system with DFSC is more than 55% in water heating mode and the instantaneous air heating efficiency of the collector reaches 60%. The effects of inner parameters on the thermal efficiency of the collector are analyzed by numerical simulations of the operation of DFSC in two working modes. It is found that the depths of the two air channels in DFSC have an optimal range suitable for both working modes. The thickness of back insulation should be no less than 0.06 m to prevent heat loss via backboard, and the diameter and number of copper tubes show notable effect on the efficiency of DFSC in water heating mode but slight effect in air heating mode.
Leisure Engagement: Medical Conditions, Mobility Difficulties, and Activity Limitations—A Later Life Perspective
Authors: Nilsson Ingeborg , Nyqvist Fredrica , Gustafson Yngve , Nygård Mikael
Published: August 2015

Objectives. This study aims to investigate the impact of medical conditions, mobility difficulties, and activity limitations on older people’s engagement in leisure activities.Methods. The analyses are based on a cross regional survey carried out in 2010 in the Bothnia region (Northern Sweden and Western Finland). A posted questionnaire, which included questions on different aspects of leisure engagement, medical history, and health, was sent out to older persons in the region. The final sample consisted of 5435 persons aged 65, 70, 75, and 80 years. The data was analyzed by using ordinary least squares (OLS) multivariate regression.Results. The most important predictor of leisure engagement abstention among older people is the prevalence of activity limitations, whereas mobility difficulties and medical conditions play less important roles. The strong negative association between activity limitations and leisure engagement remains significant even after we control for individual, sociodemographic characteristics, and country.Discussion. This study provides a window into leisure engagement in later life and factors influencing the magnitude of engagement in leisure activities.
Exponential H∞ Synchronization of Chaotic Cryptosystems Using an Improved Genetic Algorithm
Authors: Hsiao Feng-Hsiag
Published: August 2015

This paper presents a systematic design methodology for neural‐network‐ (NN‐) based secure communications in multiple time‐delay chaotic (MTDC) systems with optimal H∞ performance and cryptography. On the basis of the Improved Genetic Algorithm (IGA), which is demonstrated to have better performance than that of a traditional GA, a model‐based fuzzy controller is then synthesized to stabilize the MTDC systems. A fuzzy controller is synthesized to not only realize the exponential synchronization, but also achieve optimal H∞ performance by minimizing the disturbance attenuation level. Furthermore, the error of the recovered message is stated by using the n‐shift cipher and key. Finally, a numerical example with simulations is given to demonstrate the effectiveness of our approach.
Impact of a 2-Day Critical Care Ultrasound Course during Fellowship Training: A Pilot Study
Authors: Dinh Vi Am , Giri Paresh C. , Rathinavel Inimai , Nguyen Emilie , Hecht David , Dorotta Ihab , Nguyen H. Bryant , Chrissian Ara A.
Published: August 2015

Objectives. Despite the increasing utilization of point-of-care critical care ultrasonography (CCUS), standards establishing competency for its use are lacking. The purpose of this study was to evaluate the effectiveness of a 2-day CCUS course implementation on ultrasound-naïve critical care medicine (CCM) fellows.Methods. Prospective evaluation of the impact of a two-day CCUS course on eight CCM fellows’ attitudes, proficiency, and use of CCUS. Ultrasound competency on multiple organ systems was assessed including abdominal, pulmonary, vascular, and cardiac systems. Subjects served as self-controls and were assessed just prior to, within 1 week after, and 3 months after the course.Results. There was a significant improvement in CCM fellows’ written test scores, image acquisition ability, and pathologic image interpretation 1 week after the course and it was retained 3 months after the course. Fellows also had self-reported increased confidence and usage of CCUS applications after the course.Conclusions. Implementation of a 2-day critical care ultrasound course covering general CCUS and basic critical care echocardiography using a combination of didactics, live models, and ultrasound simulators is effective in improving critical care fellows’ proficiency and confidence with ultrasound use in both the short- and long-term settings.
CVID Associated with Systemic Amyloidosis
Authors: Esenboga Saliha , Çagdas Ayvaz Deniz , Saglam Ayhan Arzu , Peynircioglu Banu , Sanal Ozden , Tezcan Ilhan
Published: August 2015

Common variable immunodeficiency (CVID) is a frequent primary immune deficiency (PID), which consists of a heterogeneous group of disorders and can present with recurrent infections, chronic diarrhea, autoimmunity, chronic pulmonary and gastrointestinal diseases, and malignancy. Secondary amyloidosis is an uncommon complication of CVID. We report an unusual case of a 27-year-old male patient who presented with recurrent sinopulmonary infections, chronic diarrhea, and hypogammaglobulinemia and was diagnosed with CVID. The patient was treated with intravenous immunoglobulin (IVIg) therapy once every 21 days and daily trimethoprim-sulfamethoxazole for prophylaxis. Two years after initial diagnosis, the patient was found to have progressive decline in IgG levels (as low as 200–300 mg/dL) despite regular Ig infusions. The laboratory tests revealed massive proteinuria and his kidney biopsy showed accumulation of AA type amyloid. We believe that the delay in the diagnosis of CVID and initiation of Ig replacement therapy caused chronic inflammation due to recurrent infections in our patient and this led to an uncommon and life-threatening complication, amyloidosis. Patients with CVID require regular follow-up for the control of infections and assessment of adequacy of Ig replacement therapy. Amyloidosis should be kept in the differential diagnosis when managing patients with CVID.
Probabilistic Dynamics for Integrated Analysis of Accident Sequences considering Uncertain Events
Authors: Alzbutas Robertas
Published: August 2015

The analytical/deterministic modelling and simulation/probabilistic methods are used separately as a rule in order to analyse the physical processes and random or uncertain events. However, in the currently used probabilistic safety assessment this is an issue. The lack of treatment of dynamic interactions between the physical processes on one hand and random events on the other hand causes the limited assessment. In general, there are a lot of mathematical modelling theories, which can be used separately or integrated in order to extend possibilities of modelling and analysis. The Theory of Probabilistic Dynamics (TPD) and its augmented version based on the concept of stimulus and delay are introduced for the dynamic reliability modelling and the simulation of accidents in hybrid (continuous-discrete) systems considering uncertain events. An approach of non-Markovian simulation and uncertainty analysis is discussed in order to adapt the Stimulus-Driven TPD for practical applications. The developed approach and related methods are used as a basis for a test case simulation in view of various methods applications for severe accident scenario simulation and uncertainty analysis. For this and for wider analysis of accident sequences the initial test case specification is then extended and discussed. Finally, it is concluded that enhancing the modelling of stimulated dynamics with uncertainty and sensitivity analysis allows the detailed simulation of complex system characteristics and representation of their uncertainty. The developed approach of accident modelling and analysis can be efficiently used to estimate the reliability of hybrid systems and at the same time to analyze and possibly decrease the uncertainty of this estimate.
Spectra and Charge Transport of Polar Molecular Photoactive Layers Used for Solar Cells
Authors: Li Yuanzuo , Qi Dawei , Sun Chaofan , Zhao Meiyu
Published: August 2015

The ground state structures, HOMO and LUMO energy levels, band gapsΔH-L, ionization potentials (IP), and electron affinities (EA) of three types of copolymer P1 and its derivatives P2, P3, and PBDT-BTA were investigated by using density functional theory (DFT) with B3LYP and 6-31G (d) basis set. On the base of optimized structures of ground states, their absorption spectra were obtained by using TD-DFT//Cam-B3LYP/6-31 G (d). Research shows that with the increasing conjugated units, HOMO energy levels increased, LUMO energy levels decreased, and band gaps decreased gradually. Moreover, their ionization potentials decreased and electron affinities increased along with the increase of conjugated chains, and absorption spectra red-shifted. In addition, the side chain has a significant effect on the properties of ground and excited states. In order to investigate the influence of conjugated units and side chain on the charge transport, their hole and electron reorganization energies were calculated, and the results indicated that Pb have a good hole transport capability. Considering the practical application, the HOMO and LUMO energy levels, band gaps, and absorption spectra under external electric field were studied, and the results proved that the external electric field has an effect on the optical and electronic properties.
Abstract 1000: Tyrosine kinase receptor EGFR regulates the switch between cell survival and cell death induced by autophagy under hypoxia in cancer cells
Authors: Gibson Spencer B. , Chen Yongqiang , Henson Elizabeth S. , Huang Daniel
Published: August 2015

Autophagy is an intracellular lysosomal degradation pathway characterized by the formation of autophagosomes. The primary function of autophagy is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxia regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, we have previously demonstrated that autophagy contributes to hypoxia induced cell death in cancer cells. In this study, we demonstrated that autophagy flux increased under hypoxia over time. At 4 hours of hypoxia, autophagy promoted cell survival whereas, at 48 hours of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of epidermal growth factor receptor (EGFR) increased at 4 hours and decreased at later times. This correlated with the ability of EGFR to bind with Beclin-1 at 4 hours but not 48 hours under hypoxia. Knocking down or inhibiting EGFR resulted in increased autophagy and cell death under hypoxia. In contrast, when EGFR was re-activated by the addition of EGF, the level of autophagy was reduced and amount of cell death decreased. Hypoxia led to autophagic excessive degradation of the lipid raft protein caveolin-1 (CAV1) that is known to bind to EGFR and activate EGFR in a ligand-independent manner under hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was increased under hypoxia and amount of autophagy and cell death decreased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy under hypoxia.

Citation Format: Spencer B. Gibson, Yongqiang Chen, Elizabeth S. Henson, Daniel Huang. Tyrosine kinase receptor EGFR regulates the switch between cell survival and cell death induced by autophagy under hypoxia in cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1000. doi:10.1158/1538-7445.AM2015-1000
Abstract 1005: Dual targeting of MEK/MAPK1/2 and pro-survival autophagy to optimize antiestrogen treatment toward the eradication of antiestrogen resistant breast cancer
Authors: Manning Mathew , Takhar Suchreet , Periyasamy-Thandavan Sudharsan , Cheng Michael , Barrett Thomas , Hill William , Browning Darren , Thangaraju Muthusamy , McGee-Lawrence Meghan , Schoenlein Patricia V.
Published: August 2015

In past studies, we showed that pro-survival autophagy mediates resistance to antiestrogen-induced apoptosis and facilitates the emergence of antiestrogen resistant breast cancer cells (Sammadar et al., Molecular Cancer Ther. 9, 2008). We also identified the pro-apoptotic BimEL protein as a key death effector of antiestrogen treatment and determined that BimEL pro-apoptotic activity is abrogated by a MEK1/MAPK1/2-dependent phosphorylation (Periyasamy-Thandavan et al., Breast Cancer Res. 14, 2012). In this study, we tested the hypothesis that the MEK1/MAPK1/2/BimEL signaling node simultaneously regulates antiestrogen- induced pro-survival autophagy and apoptosis in ER+ breast cancer cells. In our approach, we utilized T47-D and MCF-7 breast cancer cells and modulated the activity of MEK1/MAPK1/2/ BimEL expression with U0126, a small molecule inhibitor of MEK1, BimEL cDNA over-expression, or siRNA targeting under a variety of endocrine treatments. We also conducted studies in the presence or absence of the pan-caspase inhibitor ZVAD-fmk so that autophagy levels/function could be analyzed independent of effects mediated by BimEL-dependent caspase activation. Autophagic flux was measured by comparing the levels of lipidated LC3II in cell populations undergoing the different treatments in the presence or absence of chloroquine (CQ), a lysosomotropic agent that prevents autolysosomal turnover. These studies determined that: 1) dephosphorylated BimEL significantly attenuates autophagic flux, but primarily as a consequence of BimEL-induced caspase-activation; (2) BimEL-dependent apoptotic death induced in antiestrogen-treated ER+ breast cancer cells by MEK1 inhibition is not dependent on autophagy; and (3) agents that selectively target autophagy (i.e. CQ and spautin) enhance apoptosis induced by MEK1 blockade in breast cancer cells undergoing endocrine treatment. Based on these pre-clinical in vitro studies, we postulate that the eradication of antiestrogen resistant breast cancer will require the targeting of MEK1/MAPK1/2 to activate BimEL and pro-survival autophagy to eradicate cells surviving BimEL-dependent apoptosis.

Citation Format: Mathew Manning, Suchreet Takhar, Sudharsan Periyasamy-Thandavan, Michael Cheng, Thomas Barrett, William Hill, Darren Browning, Muthusamy Thangaraju, Meghan McGee-Lawrence, Patricia V. Schoenlein. Dual targeting of MEK/MAPK1/2 and pro-survival autophagy to optimize antiestrogen treatment toward the eradication of antiestrogen resistant breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1005. doi:10.1158/1538-7445.AM2015-1005
Abstract 1012: Discovery and synthesis of novel autophagy inhibitors with anti-proliferative activity in lung and pancreatic cancer cells
Authors: Sironi Juan , Ulrik Nordstroem Lars , Aranda Evelyn , Shcherba Marina , Perez-Soler Roman , Wu Peng , Schwartz Edward L.
Published: August 2015

Autophagy is an emerging therapeutic target in cancer chemotherapy. It is a regulated catabolic process that degrades damaged cellular proteins and organelles, and helps to maintain cellular homeostasis and biosynthesis during nutrient starvation, metabolic stress, oncogenic transformation, and in response to chemotherapeutic drugs. Recent studies using mouse genetic models of lung and pancreatic cancer reported dramatic tumor regressions when autophagy was ablated, either genetically or pharmacologically, in either the tumors or systemically in the mouse. These studies provide pre-clinical proof of principle that strategies to inhibit autophagy can be therapeutically efficacious in solid tumors. The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines, however low potency may limit their antitumor efficacy clinically. As part of our ongoing chemistry program to discover novel autophagy inhibitors, we synthesized a series of chloroquine analogs which retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460, HCC827, H520 and H1703 human lung cancer cell lines, and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had IC50s ranging from 5.8 μM to 11 μM in the cells, and was 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62, and induced apoptosis. The increases in LC3-II levels by the analogs were inversely correlated with their growth inhibitory IC50s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. In contrast to HCQ, the cytotoxic actions of EAD1 were not reversible after a 24 hour treatment. Furthermore, the mechanism of action of EAD1 appears to partially differ from that of HCQ, including possible interactions with mTOR/TORC1-mediated pathways. EAD1 is a viable lead compound for evaluation of the anti-tumor activity of autophagy inhibitors in vivo.

Citation Format: Juan Sironi, Lars Ulrik Nordstroem, Evelyn Aranda, Marina Shcherba, Roman Perez-Soler, Peng Wu, Edward L. Schwartz. Discovery and synthesis of novel autophagy inhibitors with anti-proliferative activity in lung and pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1012. doi:10.1158/1538-7445.AM2015-1012
Abstract 103: Abundant expression of enhancer of zeste homolog 2 in small cell lung cancer
Authors: Watanabe Yasutaka , Koyama Nobuyuki , Iwai Yuki , Miwa Chihiro , Koyama Shinichiro
Published: August 2015

Background: Enhancer of Zeste Homolog 2 (EZH2) is a catalytic component of polycomb repressive complexes and functions as a histon methyltransferase for H3 lysine 27 residues. EZH2 overexpression promotes tumor progression and metastasis, leading to a poor prognosis. Small cell lung cancer (SCLC) is characterized by highly invasive and metastatic potentials compared with non-small cell lung cancer (NSCLC), whereas these are very limited information about whether EZH expression is associated with clinical and biological differences between both tumor types. The objective of the current study is to elucidate the role of EZH2 in the phenotypic characteristics of SCLC

Method: EZH2 expressions in staging-matched tumor samples from 34 patients with SCLC and NSCLC consisting of adenocarcinoma (Ad) and squamous cell carcinoma (SCC) were evaluated using immunohistochemistry. The extent and location of immunohistochemical staining for EZH2 was assessed according to the immunoreactive score (IRS) evaluating the proportion of cells that express EZH2 protein and the intensity of its staining. Percentage of the cancer area stained in high-power fields was measured. Staining intensity was graded as 0 (negative), 1 (weak), 2 (moderate), and 3 (strong); percentage of positive cells was scored as 0 (negative), 2 (from 11 to 50%), 3 (from 51 to 80%), and 4 (> 80%). The IRS taken from the multiplication of these two scores (values from 0-12) was defined as follows: 0 as negative, values 1-3 as weak, values 4, 6 as positive, and multiplication values 8, 9, 12 as strongly positive.

Results:Thirty-four patients analyzed contained, 16 (47%) of surgical stage I, 10 (29%) of Stage II, 7 (21%) of Stage III, and one (3%) of Stage IV. The patient's clinical characteristic among three groups (SCLC, Ad, and SCC group) are summarized. Sex (M/F) = (27/7, 20/14, and 31/3). Mean Age = (68.2, 65.3, and 70.4). Mean Smoking Index (the number of cigarettes per day×smoking years) = (1236, 526, and 1222). Negative staining was noted in one SCLC, five Ads, and four SCCs, weakly positive in 0 SCLC, 17 Ads, and 15 SCCs, positive in 8 SCLCs, 2 Ads, and 9 SCCs and strongly positive in 25 SCLCs, 10 Ads, and 6 SCCs. Mean IRS was 9.5 in SCLCs, 4.5 in Ads, and 3.8 in SCCs. The immunohistochemical analysis of EZH2 expression levels based on the staining intensity and the percentage of positive cells was significantly higher with SCLC (p<0.001).

Conclusion:EZH2 expression may determine the clinical and biological characteristics of SCLC.

Citation Format: Yasutaka Watanabe, Nobuyuki Koyama, Yuki Iwai, Chihiro Miwa, Shinichiro Koyama. Abundant expression of enhancer of zeste homolog 2 in small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 103. doi:10.1158/1538-7445.AM2015-103
Abstract 1030: Loss of PHLPPs protects against colitis by inhibiting epithelial apoptosis through upregulating AKT activity
Authors: Wen Yang-an , Li Xin , Goretsky Tatiana , Barrett Terrence A. , Gao Tianyan
Published: August 2015

Background & Aims: PHLPP, a novel family of protein phosphatases, plays an important role in balancing cellular signaling pathways that control cell death and proliferation. Loss of PHLPP expression promotes colorectal cancer (CRC) tumorigenesis and progression. Intestine epithelial cells (IECs) apoptosis contributes to the development of inflammatory bowel disease (IBD), and patients with IBD are at increased risk for CRC. We investigated the functional importance of PHLPP in intestinal inflammation.

Methods: Both Phlpp1 and Phlpp2 genes were deleted in mice. The effect of PHLPP double knockout (DKO) on the development of acute colitis was examined in dextran sulfate sodium salt (DSS)-treated mice. Biochemical and histological analyses were conducted to determine the extent of tissue inflammation and colon epithelial cell apoptosis. The expression of PHLPP proteins was examined in DSS-treated mice and IBD patient samples.

Results: In ulcerative colitis and Crohn's disease patient samples, both PHLPP1 and PHLPP2 protein expression was markedly decreased in colitis tissues compared to that in uninvolved tissues. In mice, PHLPP expression was significantly reduced in colonic epithelial cells following induction of colitis by DSS. Mechanistically, the inflammation-induced downregulation of PHLPP was mediated through proteasome-dependent protein degradation. Compared with wild-type mice, PHLPP DKO mice were protected from colitis induced by the DSS treatment as demonstrated by lower histopathological scores, and this reduced susceptibility to colitis was associated with decreased apoptosis and increased Akt activity in colonic epithelial cells. Furthermore, epithelial organoids derived from colon and small intestine of PHLPP DKO mice are more resistant to inflammation-induced apoptosis upon Akt activation.

Conclusion: These results indicated that PHLPP contributes to the pathogenesis of colitis by controlling epithelial cell apoptosis. Downregulation of PHLPP at the onset of inflammation plays a role in protecting intestinal epithelial cell injury by inhibiting apoptosis. However, prolonged PHLPP-loss may promote colon cancer initiation in IBD patients.

Citation Format: Yang-an Wen, Xin Li, Tatiana Goretsky, Terrence A. Barrett, Tianyan Gao. Loss of PHLPPs protects against colitis by inhibiting epithelial apoptosis through upregulating AKT activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1030. doi:10.1158/1538-7445.AM2015-1030
Abstract 1031: Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src
Authors: Guy Stephanie , Magee Patrick , Geletu Mulu , Arulanandam Rozanne , Raptis Leda
Published: August 2015

The signal transducer and activator of transcription-3 (Stat3) plays an important role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr-705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3: Engagement of cadherins such as cadherin-11 (cad11), a cell to cell adhesion protein known to be involved in metastasis, induces a dramatic increase in the levels of the Rac and Cdc42 small GTPases, and this leads to interleukin-6 transcription and Stat3 activation. Stat3 in turn, downregulates the p53 tumor suppressor and upregulates anti-apoptotic genes, thus offering a potent survival signal.

A large number of oncogenes such as activated Src-527 activate the E2F transcription factor family, which induce the expression of genes involved in cell division. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for antiapoptotic signals. Since cad11 activates Stat3, a potent survival factor, we examined the effect of cad11 downregulation upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Forced expression of high levels of activated Src caused a dramatic reduction in cad11 levels. On the other hand, intermediate Src levels, which are the levels that are physiologically relevant, did allow cad11 expression, albeit at lower levels. Paradoxically, cells expressing high Src levels had actually lower Stat3 than cells expressing intermediate Src levels. This could be due to the observed downregulatory effect of Src upon cad11, and it demonstrates that cad11 is a more potent Stat3 activator than Src. Cad11 knockdown through shRNA expression in cells expressing intermediate Src levels, caused a dramatic reduction in Stat3 activity and induced apoptosis. That is, the residual amounts of cad11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Taken together, these findings indicate that cad11, despite its presumed structural role, and in addition to its known role in promoting metastasis, it is actually also necessary for full neoplastic transformation by the Src oncogene.

Citation Format: Stephanie Guy, Patrick Magee, Mulu Geletu, Rozanne Arulanandam, Leda Raptis. Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1031. doi:10.1158/1538-7445.AM2015-1031
Abstract 1035: An angiogenic role of E-cadherin-positive exosomes in ovarian cancer
Authors: Tang Maggie K. S. , Wong Alice Sze Tsai
Published: August 2015

Angiogenesis, the induction of vasculature, is a vital step for metastasis. Loss of E-cadherin is a well-established marker for tumor metastasis. In ovarian cancer, a highly metastatic tumor that is rapidly lethal, we and others have previously shown the deregulated pattern of E-cadherin and its close association with tumor progression. Although E-cadherin is synthesized as a transmembrane molecule, it can be shed from the cell surface (sE-cad) which accounts for a rapid removal of functional E-cadherin. Here, in addition to ectodomain shedding, we show for the first time that sE-cad can be actively released from ovarian cancer cells in the form of exosomes. These sE-cad-positive exosomes play a critical role in angiogenesis which stimulated the migration, permeability, and tubulogenesis of human umbilical vein endothelial cells in vitro, and promoted functional neovascularization in vivo. In search of the underlying mechanisms by which sE-cad-positive exosomes might regulate angiogenic endothelial cells, which lack E-cadherin, we showed that a novel heterophilic crosstalk between sE-cad and VE-cadherin. Moreover, such angiogenic effect was mediated through activation of the phosphatidylinositol 3-kinase/Akt-beta-catenin signaling cascade. These results uncover a new angiogenic function for sE-cad and a novel paradigm for sE-cad production which may have potential clinical implications (This study was supported by RGC grant HKU781013).

Citation Format: Maggie K. S. Tang, Alice Sze Tsai Wong. An angiogenic role of E-cadherin-positive exosomes in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1035. doi:10.1158/1538-7445.AM2015-1035