bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiscale Modeling Indicates That Temperature Dependent [Ca2+]iSpiking in Astrocytes Is Quantitatively Consistent with Modulated SERCA Activity
Authors: Komin Niko , Moein Mahsa , Ellisman Mark H. , Skupin Alexander
Published: August 2015

Changes in the cytosolic Ca2+concentration ([Ca2+]i) are the most predominant active signaling mechanism in astrocytes that can modulate neuronal activity and is assumed to influence neuronal plasticity. Although Ca2+signaling in astrocytes has been intensively studied in the past, our understanding of the signaling mechanism and its impact on tissue level is still incomplete. Here we revisit our previously published data on the strong temperature dependence of Ca2+signals in both cultured primary astrocytes and astrocytes in acute brain slices of mice. We apply multiscale modeling to test the hypothesis that the temperature dependent[Ca2+]ispiking is mainly caused by the increased activity of the sarcoendoplasmic reticulum ATPases (SERCAs) that remove Ca2+from the cytosol into the endoplasmic reticulum. Quantitative comparison of experimental data with multiscale simulations supports the SERCA activity hypothesis. Further analysis of multiscale modeling and traditional rate equations indicates that the experimental observations are a spatial phenomenon where increasing pump strength leads to a decoupling of Ca2+release sites and subsequently to vanishing[Ca2+]ispikes.
Modulation of Intrathymic Sphingosine-1-Phosphate Levels Promotes Escape of Immature Thymocytes to the Periphery with a Potential Proinflammatory Role in Chagas Disease
Authors: Flávia Nardy Ana , Santos Leonardo , Freire-de-Lima Célio Geraldo , Morrot Alexandre
Published: August 2015

The sphingosine-1-phosphate (S1P) system regulates both thymic and lymph nodes T cell egress which is essential for producing and maintaining the recycling T cell repertoire. Infection with the protozoan parasiteTrypanosoma cruziinduces a hormonal systemic deregulation that has impact in the thymic S1P homeostasis that ultimately promotes the premature exit of immature CD4−CD8−T cells expressing TCR and proinflamatory cytokines to peripheral lymphoid organs, where they may interfere with adaptive immune responses. In what follows, we review recent findings revealing escape of these immature T cells exhibiting an activation profile to peripheral compartments of the immune system in both experimental murine and human models of Chagas disease.
Expression Pattern of Fatty Acid Binding Proteins in Celiac Disease Enteropathy
Authors: Bottasso Arias Natalia M. , García Marina , Bondar Constanza , Guzman Luciana , Redondo Agustina , Chopita Nestor , Córsico Betina , Chirdo Fernando G.
Published: August 2015

Celiac disease (CD) is an immune‐mediated enteropathy that develops in genetically susceptible individuals following exposure to dietary gluten. Severe changes at the intestinal mucosa observed in untreated CD patients are linked to changes in the level and in the pattern of expression of different genes. Fully differentiated epithelial cells express two isoforms of fatty acid binding proteins (FABPs): intestinal and liver, IFABP and LFABP, respectively. These proteins bind and transport long chain fatty acids and also have other important biological roles in signaling pathways, particularly those related to PPARγ and inflammatory processes. Herein, we analyze the serum levels of IFABP and characterize the expression of both FABPs at protein and mRNA level in small intestinal mucosa in severe enteropathy and normal tissue. As a result, we observed higher levels of circulating IFABP in untreated CD patients compared with controls and patients on gluten‐free diet. In duodenal mucosa a differential FABPs expression pattern was observed with a reduction in mRNA levels compared to controls explained by the epithelium loss in severe enteropathy. In conclusion, we report changes in FABPs’ expression pattern in severe enteropathy. Consequently, there might be alterations in lipid metabolism and the inflammatory process in the small intestinal mucosa.
Hypoglycemic Effect of Aqueous and Methanolic Extract ofArtemisia afraon Alloxan Induced Diabetic Swiss Albino Mice
Authors: Issa Idris Ahmed , Hussen Bule Mohammed
Published: August 2015

Diabetes mellitus is metabolic syndrome that causes disability, early death, and many other complications. Currently insulin and many synthetic drugs are used in diabetes treatment. However, these pharmaceutical drugs are too expensive particularly for sub-Saharan population in addition to their undesirable side effects. The present study was aimed to evaluate antidiabetic effect and toxicity level ofArtemisia afrawhich was collected from its natural habitat in Bale Zone, around Goba town, 455 km southeast of Addis Ababa. Air dried aerial parts ofArtemisia afrawere separately extracted with both distilled water and 95% methanol. Oral acute toxicity test was conducted on healthy Swiss albino mice. Antidiabetic effect of the aqueous and methanolic extracts ofArtemisia afrawas separately evaluated on alloxan induced diabetic mice at doses of 500, 750, and 1000 mg/Kg body weight orally. The results indicate that mean lethal dose (LD50) for aqueous extract ofArtemisia afrawas 9833.4 mg/Kg. Blood glucose level was significantly decreased by 24% (p<0.005) and 56.9% (p<0.0004) in groups that received aqueous extract ofArtemisia afraat dose of 500 mg/Kg and 750 mg/Kg, respectively. The methanolic extract ofArtemisia afraalso significantly lowered blood glucose by 49.8% (p<0.0001) at doses of 1000 mg/kg on the 5th hr. Aqueous extract ofArtemisia afrawas regarded as nontoxic and safe since its LD50was found above 5000 mg/Kg. Aqueous extract showed higher effect at relatively lower dose as compared to methanolic extract. The aqueous extract was screened positive for phytochemicals like flavonoids, polyphenols, and tannins that were reported to have antioxidant activity.
A Segmented Signal Progression Model for the Modern Streetcar System
Authors: Wang Baojie , Wang Wei , Hu Xiaojian , Li Xiaowei
Published: August 2015

This paper is on the purpose of developing a segmented signal progression model for modern streetcar system. The new method is presented with the following features: (1) the control concept is based on the assumption of only one streetcar line operating along an arterial under a constant headway and no bandwidth demand for streetcar system signal progression; (2) the control unit is defined as a coordinated intersection group associated with several streetcar stations, and the control joints must be streetcar stations; (3) the objective function is built to ensure the two-way streetcar arrival times distributing within the available time of streetcar phase; (4) the available time of streetcar phase is determined by timing schemes, intersection structures, track locations, streetcar speeds, and vehicular accelerations; (5) the streetcar running speed is constant separately whether it is in upstream or downstream route; (6) the streetcar dwell time is preset according to historical data distribution or charging demand. The proposed method is experimentally examined in Hexi New City Streetcar Project in Nanjing, China. In the experimental results, the streetcar system operation and the progression impacts are shown to affect transit and vehicular traffic. The proposed model presents promising outcomes through the design of streetcar system segmented signal progression, in terms of ensuring high streetcar system efficiency and minimizing negative impacts on transit and vehicular traffic.
Evaluation of Physicochemical Properties of South African Cashew Apple Juice as a Biofuel Feedstock
Authors: Deenanath Evanie Devi , Rumbold Karl , Daramola Michael , Falcon Rosemary , Iyuke Sunny
Published: August 2015

Cashew apple juice (CAJ) is one of the feedstocks used for biofuel production and ethanol yield depends on the physical and chemical properties of the extracted juice. As far as can be ascertained, information on physical and chemical properties of South African cashew apple juice is limited in open literature. Therefore, this study provides information on the physical and chemical properties of the South African cashew apple juice. Physicochemical characteristics of the juice, such as specific gravity, pH, sugars, condensed tannins, Vitamin C, minerals, and total protein, were measured from a mixed variety of cashew apples. Analytical results showed the CAJ possesses specific gravity and pH of 1.050 and 4.52, respectively. The highest sugars were glucose (40.56 gL−1) and fructose (57.06 gL−1). Other chemical compositions of the juice were condensed tannin (55.34 mgL−1), Vitamin C (112 mg/100 mL), and total protein (1.78 gL−1). The minerals content was as follows: zinc (1.39 ppm), copper (2.18 ppm), magnesium (4.32 ppm), iron (1.32 ppm), sodium (5.44 ppm), and manganese (1.24 ppm). With these findings, South African CAJ is a suitable biomass feedstock for ethanol production.
Damage Analysis and Evaluation of High Strength Concrete Frame Based on Deformation-Energy Damage Model
Authors: Lin Huang-bin , Tang Shou-gao , Lan Cheng
Published: August 2015

A new method of characterizing the damage of high strength concrete structures is presented, which is based on the deformation energy double parameters damage model and incorporates both of the main forms of damage by earthquakes: first time damage beyond destruction and energy consumption. Firstly, test data of high strength reinforced concrete (RC) columns were evaluated. Then, the relationship between stiffness degradation, strength degradation, and ductility performance was obtained. And an expression for damage in terms of model parameters was determined, as well as the critical input data for the restoring force model to be used in analytical damage evaluation. Experimentally, the unloading stiffness was found to be related to the cycle number. Then, a correction for this changing was applied to better describe the unloading phenomenon and compensate for the shortcomings of structure elastic-plastic time history analysis. The above algorithm was embedded into an IDARC program. Finally, a case study of high strength RC multistory frames was presented. Under various seismic wave inputs, the structural damages were predicted. The damage model and correction algorithm of stiffness unloading were proved to be suitable and applicable in engineering design and damage evaluation of a high strength concrete structure.
Demonstration of Emulator-Based Bayesian Calibration of Safety Analysis Codes: Theory and Formulation
Authors: Yurko Joseph P. , Buongiorno Jacopo , Youngblood Robert
Published: August 2015

System codes for simulation of safety performance of nuclear plants may contain parameters whose values are not known very accurately. New information from tests or operating experience is incorporated into safety codes by a process known as calibration, which reduces uncertainty in the output of the code and thereby improves its support for decision-making. The work reported here implements several improvements on classic calibration techniques afforded by modern analysis techniques. The key innovation has come from development of code surrogate model (or code emulator) construction and prediction algorithms. Use of a fast emulator makes the calibration processes used here with Markov Chain Monte Carlo (MCMC) sampling feasible. This work uses Gaussian Process (GP) based emulators, which have been used previously to emulate computer codes in the nuclear field. The present work describes the formulation of an emulator that incorporates GPs into a factor analysis-type or pattern recognition-type model. This “function factorization” Gaussian Process (FFGP) model allows overcoming limitations present in standard GP emulators, thereby improving both accuracy and speed of the emulator-based calibration process. Calibration of a friction-factor example using a Method of Manufactured Solution is performed to illustrate key properties of the FFGP based process.
Clique-Based Clustering of Correlated SNPs in a Gene Can Improve Performance of Gene-Based Multi-Bin Linear Combination Test
Authors: Yoo Yun Joo , Kim Sun Ah , Bull Shelley B.
Published: August 2015

Gene-based analysis of multiple single nucleotide polymorphisms (SNPs) in a gene region is an alternative to single SNP analysis. The multi-bin linear combination test (MLC) proposed in previous studies utilizes the correlation among SNPs within a gene to construct a gene-based global test. SNPs are partitioned into clusters of highly correlated SNPs, and the MLC test statistic quadratically combines linear combination statistics constructed for each cluster. The test has degrees of freedom equal to the number of clusters and can be more powerful than a fully quadratic or fully linear test statistic. In this study, we develop a new SNP clustering algorithm designed to find cliques, which are complete subnetworks of SNPs with all pairwise correlations above a threshold. We evaluate the performance of the MLC test using the clique-based CLQ algorithm versus using the tag-SNP-based LDSelect algorithm. In our numerical power calculations we observed that the two clustering algorithms produce identical clusters about 40~60% of the time, yielding similar power on average. However, because the CLQ algorithm tends to produce smaller clusters with stronger positive correlation, the MLC test is less likely to be affected by the occurrence of opposing signs in the individual SNP effect coefficients.
On Data Space Selection and Data Processing for Parameter Identification in a Reaction-Diffusion Model Based on FRAP Experiments
Authors: Kindermann Stefan , Papáček Štěpán
Published: August 2015

Fluorescence recovery after photobleaching (FRAP) is a widely used measurement technique to determine the mobility of fluorescent molecules within living cells. While the experimental setup and protocol for FRAP experiments are usually fixed, data (pre)processing represents an important issue. The aim of this paper is twofold. First, we formulate and solve the problem ofrelevantFRAP data selection. The theoretical findings are illustrated by the comparison of the results of parameter identification when the full data set was used and the case when theirrelevant data set(data with negligible impact on the confidence interval of the estimated parameters) was removed from the data space. Second, we analyze and compare two approaches of FRAP data processing. Our proposition, surprisingly for the FRAP community, claims that the data set represented by the FRAP recovery curves in form of a time series (integrated data approachcommonly used by the FRAP community) leads to a larger confidence interval compared to thefull(spatiotemporal)data approach.
Flax Fiber Hydrophobic Extract Inhibits Human Skin Cells Inflammation and Causes Remodeling of Extracellular Matrix and Wound Closure Activation
Authors: Styrczewska Monika , Kostyn Anna , Kulma Anna , Majkowska-Skrobek Grazyna , Augustyniak Daria , Prescha Anna , Czuj Tadeusz , Szopa Jan
Published: August 2015

Inflammation is the basis of many diseases, with chronic wounds amongst them, limiting cell proliferation and tissue regeneration. Our previous preclinical study of flax fiber applied as a wound dressing and analysis of its components impact on the fibroblast transcriptome suggested flax fiber hydrophobic extract use as an anti-inflammatory and wound healing preparation. The extract contains cannabidiol (CBD), phytosterols, and unsaturated fatty acids, showing great promise in wound healing. Inin vitroproliferation and wound closure tests the extract activated cell migration and proliferation. The activity of matrix metalloproteinases in skin cells was increased, suggesting activation of extracellular components remodeling. The expression of cytokines was diminished by the extract in a cannabidiol-dependent manner, butβ-sitosterol can act synergistically with CBD in inflammation inhibition. Extracellular matrix related genes were also analyzed, considering their importance in further stages of wound healing. The extract activated skin cell matrix remodeling, but the changes were only partially cannabidiol- andβ-sitosterol-dependent. The possible role of fatty acids also present in the extract is suggested. The study shows the hydrophobic flax fiber components as wound healing activators, with anti-inflammatory cannabidiol acting in synergy with sterols, and migration and proliferation promoting agents, some of which still require experimental identification.
In VitroandIn VivoHepatic Differentiation of Adult Somatic Stem Cells and Extraembryonic Stem Cells for Treating End Stage Liver Diseases
Authors: Hu Chenxia , Li Lanjuan
Published: August 2015

The shortage of liver donors is a major handicap that prevents most patients from receiving liver transplantation and places them on a waiting list for donated liver tissue. Then, primary hepatocyte transplantation and bioartificial livers have emerged as two alternative treatments for these often fatal diseases. However, another problem has emerged. Functional hepatocytes for liver regeneration are in short supply, and they will dedifferentiate immediatelyin vitroafter they are isolated from liver tissue. Alternative stem-cell-based therapeutic strategies, including hepatic stem cells (HSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), are more promising, and more attention has been devoted to these approaches because of the high potency and proliferation ability of the cells. This review will focus on the general characteristics and the progress in hepatic differentiation of adult somatic stem cells and extraembryonic stem cellsin vitroandin vivofor the treatment of end stage liver diseases. The hepatic differentiation of stem cells would offer an ideal and promising source for cell therapy and tissue engineering for treating liver diseases.
Activation of Apoptotic Signal in Endothelial Cells through Intracellular Signaling Molecules Blockade in Tumor-Induced Angiogenesis
Authors: Bazmara Hossein , Soltani M. , Raahemifar Kaamran , Sefidgar Mostafa , Bazargan Majid , Naeenian Mojtaba Mousavi , Elkamel Ali
Published: August 2015

Tumor-induced angiogenesis is the bridge between avascular and vascular tumor growth phases. In tumor-induced angiogenesis, endothelial cells start to migrate and proliferate toward the tumor and build new capillaries toward the tumor. There are two stages for sprout extension during angiogenesis. The first stage is prior to anastomosis, when single sprouts extend. The second stage is after anastomosis when closed flow pathways or loops are formed and blood flows in the closed loops. Prior to anastomosis, biochemical and biomechanical signals from extracellular matrix regulate endothelial cell phenotype; however, after anastomosis, blood flow is the main regulator of endothelial cell phenotype. In this study, the critical signaling pathways of each stage are introduced. A Boolean network model is used to map environmental and flow induced signals to endothelial cell phenotype (proliferation, migration, apoptosis, and lumen formation). Using the Boolean network model, blockade of intracellular signaling molecules of endothelial cell is investigated prior to and after anastomosis and the cell fate is obtained in each case. Activation of apoptotic signal in endothelial cell can prevent the extension of new vessels and may inhibit angiogenesis. It is shown that blockade of a few signaling molecules in endothelial cell activates apoptotic signal that are proposed as antiangiogenic strategies.
Simultaneous Bilateral Spontaneous Pneumothorax Revealed Birt-Hogg-Dubè Syndrome
Authors: Tamburrini Alessandro , Sellitri Francesco , Tacconi Federico , Brancati Francesco , Mineo Tommaso Claudio
Published: August 2015

Simultaneous bilateral spontaneous pneumothorax is a very rare clinical event, comprising approximately 1% of all spontaneous pneumothoraces. Clinical signs and symptoms may vary from mild chest pain and dyspnea to severe respiratory failure; nevertheless immediate treatment is mandatory as this condition can deteriorate and progress to tension pneumothorax. An underlying lung disease has been commonly described; in most istances primary or secondary tumors, interstitial diseases, and infectious diseases. Birt-Hogg-Dubè syndrome is a rare inherited disorder clinically characterized by multiple fibrofolliculomas, renal tumors, lung cysts, and, in ~24% of the patients, occurrence of spontaneous pneumothorax. In this case, we firstly report the concurrence of these rare conditions, as a patient presenting a simultaneous bilateral spontaneous pneumothorax was diagnosed with Birt-Hogg-Dubè syndrome based on the typical radiological findings and genetic testing of the folliculin gene located on chromosome 17.
When the Midline Diastema Is Not Characteristic of the “Ugly Duckling” Stage
Authors: Tanaka Orlando Motohiro , Morino Alessandro Yuske Kusano , Machuca Oscar Fernando , Schneider Neblyssa Ágatha
Published: August 2015

This case report presents the interceptive orthodontic treatment of a 9-year, 5-month-old boy with class I malocclusion, a 9.0-mm maxillary midline diastema, and deviation from the midline. The treatment goals were to decrease the magnitude of the diastema and to simulate the characteristics of the “ugly duckling” stage. Braces were placed on the first molars and the maxillary central incisors. The biomechanics of the anchors on the first molars elicited substantial mesial movement of the left central incisor to match the midline. A flat wire segment was bonded onto the palatal surface of the central incisors for retention.
Motor-Skill Learning Is Dependent on Astrocytic Activity
Authors: Padmashri Ragunathan , Suresh Anand , Boska Michael D. , Dunaevsky Anna
Published: August 2015

Motor-skill learning induces changes in synaptic structure and function in the primary motor cortex through the involvement of a long-term potentiation- (LTP-) like mechanism. Although there is evidence that calcium-dependent release of gliotransmitters by astrocytes plays an important role in synaptic transmission and plasticity, the role of astrocytes in motor-skill learning is not known. To test the hypothesis that astrocytic activity is necessary for motor-skill learning, we perturbed astrocytic function using pharmacological and genetic approaches. We find that perturbation of astrocytes either by selectively attenuating IP3R2 mediated astrocyte Ca2+signaling or using an astrocyte specific metabolic inhibitor fluorocitrate (FC) results in impaired motor-skill learning of a forelimb reaching-task in mice. Moreover, the learning impairment caused by blocking astrocytic activity using FC was rescued by administration of the gliotransmitter D-serine. The learning impairments are likely caused by impaired LTP as FC blocked LTP in slices and prevented motor-skill training-induced increases in synaptic AMPA-type glutamate receptorin vivo. These results support the conclusion that normal astrocytic Ca2+signaling during a reaching task is necessary for motor-skill learning.
Durability Evolution of RC Bridge under Coupling Action of Chloride Corrosion and Carbonization Based on DLA Model
Authors: He Haoxiang , Li Ruifeng , Chen Kui
Published: August 2015

Chloride attack and carbonization are the main factors which affect the durability of concrete structures, and the respective theoretical models are systematically established. However, the quantitative analysis and models about the coupling effect of chloride attack and carbonization are less, so the precision and level of durability analysis of reinforced concrete are restricted. Diffusion-limited aggregation (DLA) model can finely simulate the process of gas diffusion and condensation with randomness and fractal characteristics, which is suitable for revealing the durability evolution process of the chloride attack, carbonization, and the coupling action in concrete. Based on the principle of DLA, considering the factors such as diffusion depth, concrete properties, and exposure conditions which influence the characteristics of chloride diffusion and carbonization, as well as the coupling effect, an integrated DLA model is established. The concentration of carbon dioxide and chloride at any time and any location can be obtained and dynamically displayed based on the DLA model. The performance predict method for concrete and steel bars considering fatigue effect is presented based on DLA, according to the demand for bridge durability analysis. Numerical examples show that the method can dynamically and intensively simulate the durability evolution process of reinforced concrete bridge.
A Tool to Improve Accuracy of Parental Measurements of Preschool Child Height
Authors: Yorkin Meredith , Spaccarotella Kim , Martin-Biggers Jennifer , Lozada Carolina , Hongu Nobuko , Quick Virginia , Byrd-Bredbenner Carol
Published: August 2015

Background.Parent-reported measurement of child height is common in public health research but may be inaccurate, especially for preschoolers. A standardized protocol and tools to improve measurement accuracy are needed. The purpose of this study was to develop and test materials to improve parents’ accuracy when measuring their preschooler’s height.Methods.In Phase A, 24 parents were observed measuring child height using written instructions and an easy-to-read tape measure; after each of 3 testing rounds, instructions were refined based on observed errors and parent versus researcher measurements. In Phase B, a video replaced written instructions and was refined over 4 rounds with 37 parents.Results.The height kit with written instructions, tape measure, plumb line, and explanatory video helped parents accurately measure child height. Compared to written instructions alone, parents rated the video as having significantly greater clarity and likelihood of improving measurements. Although no significant differences in accuracy were found between paper and video instructions, observations indicated written instructions were more difficult for parents with less education to use with fidelity.Conclusions.The kit may improve parent measurement of preschooler height, thereby improving accuracy of body mass index calculations, tracking of obesity prevalence, and obesity prevention and treatment.
Abstract 1007: Elucidating a role for the translation initiation factor, eIF4G1, in resistance to therapy in inflammatory breast cancer (IBC)
Authors: Price Arianna , Edwards Courtney M. , Evans Myron K. , Devi Gayathri
Published: August 2015

Inflammatory breast cancer (IBC) is a highly invasive and aggressive breast cancer with relatively low survival rates compared with other locally advanced breast cancers. IBC is characterized by its rapid development of resistance to radio- and chemotherapies, which may in part be due to altered translational control driven by overexpression of the translation initiation factor, eIF4G1. This protein has been shown to enhance translation of eukaryotic mRNAs with internal ribosome entry sites (IRES) and enhanced translation in IBC may play a role in the survival of tumor cells during cellular stress, when translation would normally be suppressed. Some inhibitors of apoptosis proteins have 5′-untranslated regions (UTRs) that allow for IRES-mediated translation, and inhibition of apoptosis is one mechanism by which IBC cells have previously been shown to become resistant to therapy. Translational up-regulation of an inhibitor of apoptosis protein in therapy-resistant clones of IBC cell lines has been observed, which is of importance as the 5′UTR of such proteins contain highly active IRES elements. Regulation of such protein expression by eIF4G1-mediated IRES translation may be one reason for this observed therapeutic resistance. We knocked down eIF4G1 in a resistant IBC cell line (rSUM149) and assessed cellular viability after treatment with a powerful apoptosis inducer, TRAIL to evaluate the effect of targeted eIF4G1 knockdown on drug resistance in IBC. We observed that targeted knockdown of eIF4G1 sensitizes rSUM149 cells to TRAIL, significantly decreasing cellular viability. Additionally, using a novel culture system we show that inhibition of eIF4G1 expression decreases both the number of size of tumor emboli, a characteristic feature of IBC progression. These findings demonstrate a vital role for eIF4G1 for the development of therapeutic resistance and ultimately the aggressive pathobiology of IBC.

Citation Format: Arianna Price, Courtney M. Edwards, Myron K. Evans, Gayathri Devi. Elucidating a role for the translation initiation factor, eIF4G1, in resistance to therapy in inflammatory breast cancer (IBC). [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 1007. doi:10.1158/1538-7445.AM2015-1007
Abstract 1009: Cytotoxic effect of ginsenosides C-K and PPD on glioblastoma cells through cell cycle arrest and down-regulation of cell adhesion proteins
Authors: Kim Eunsoo , Wanderi Cheryl , Choi Chulhee , Choi Kyungsun
Published: August 2015

Ginsenosides, pharmacologically active components of ginseng have been shown to have strong anticancer effects; however, their effect on glioblastoma has not been extensively evaluated. Here, we investigated the anticancer effect and the molecular mechanisms of ginsenosides on glioblastoma. Among 12 ginsenosides tested, compound-K (C-K) and protopanaxadiol (PPD), significantly reduced U251MG cell viability in dose- and time-dependent manner. This cytotoxic effect was accompanied by decreased expression of cell adhesion proteins including N-Cadherin and Integrin β1, which led to reduced phosphorylation of focal adhesion kinase. Furthermore, we observed the reduction of Cyclin D1 and subsequent G1-phase cell cycle arrest. We further demonstrated that C-K and PPD inhibited the phosphorylation of Akt and extracellular signal regulated kinase. Conversely, C-K and PPD stimulated phosphorylation of JNK and cleavage of PARP.

These results collectively indicate that ginsenosides C-K and PPD may provide a new strategy to treat malignant glioblastoma that are quite resistant to conventional anti-cancer treatment. (This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea;grant number : HI14C0042)

Citation Format: Eunsoo Kim, Cheryl Wanderi, Chulhee Choi, Kyungsun Choi. Cytotoxic effect of ginsenosides C-K and PPD on glioblastoma cells through cell cycle arrest and down-regulation of cell adhesion proteins. [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 1009. doi:10.1158/1538-7445.AM2015-1009
Abstract 1016: Caveolin-1-dependent and -independent uPAR signaling pathways contribute to ganglioside GT1b-induced early apoptosis in A549 lung cancer cells
Authors: Jang Hyun-Jin , Chung Young-Ho , Park Junsoo , Jang Ik-Soon
Published: August 2015

Urokinase receptor interacts with α5β1-integrin and enhances cancer cell proliferation and metastasis. Activation of α5β1-integrin requires caveolin-1 and is regulated by uPAR, which upregulates persistently the activated ERK necessary for tumor growth. In this study, we show that the ganglioside GT1b induces proapoptotic signaling through two uPAR-ERK signaling pathways in A549 lung cancer cells. GT1b downregulated the expression of α5β1 integrin, caveolin-1, fibronectin, FAK, and ERK, whereas GT1b upregulated the expression of p53 and uPAR, suggesting GT1b mediated depletion of caveolin-1 in uPAR-expressing A549 cells also disrupts uPAR/integrin complexes, resulting in downregulation of fibronectin-α5β1-integrin-ERK signaling. Following p53 siRNA treatment, FAK and ERK expression was recovered, meaning the presence of reentry uPAR-FAK-ERK signaling pathway. These findings reveal that GT1b is involved in both caveolin-1-dependent uPAR-α5β1-integrin-ERK signaling and caveolin-1-independent uPAR-FAK-ERK signaling. These results suggest a novel function of GT1b as a dual regulator of ERK by modulating caveolin-1 and p53

Citation Format: Hyun-Jin Jang, Young-Ho Chung, Junsoo Park, Ik-Soon Jang. Caveolin-1-dependent and -independent uPAR signaling pathways contribute to ganglioside GT1b-induced early apoptosis in A549 lung 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 1016. doi:10.1158/1538-7445.AM2015-1016
Abstract 1019: hnRNPA2/B1 upregulates COX-2 expression and tumor growth and predicts poor prognosis in human lung cancers
Authors: Wang Jingshu , Xuan Yang , Guo Wei , Du Guangwei , Deng Wuguo
Published: August 2015

Constitutive high expression of COX-2 can promote tumor development and has been regarded as a hallmarker for cancers. However, the excise regulation mechanism of COX-2 and its role in lung tumoirgenesis remains unknown. In this study, we discovered and identified hnRNPA2/B1 as a novel regulator of COX-2 promoter in non-small cell lung cancer (NSCLC) cells by a DNA probe-biotin-streptavidin-agarose pulldown and proteomic technique. We showed that hnRNPA2/B1 specifically bound to COX-2 core promoter region, activated COX-2 promoter activity and up-regulated COX-2 expression. Knockdown of hnRNPA2/B1 expression by siRNA significantly suppressed tumor cell growth in NSCLC cell lines in vitro and in a animal model in vivo by inhibiting COX-2 expression. In contrast, overexpression of hnRNPA2/B1 promoted COX-2 expression and tumor cell growth in NSCLC cells. Micro-tissue array and immunohistochemical assay showed that hnRNPA2/B1 expression correlated with COX-2 expression and high expression of hnRNPA2/B1 and COX-2 was associated with worse prognosis in patients with NSCLCs. Mechanistically, hnRNPA2/B1 functions as a regulator of COX-2 to control tumor growth through its interaction with p300, a transcriptional co-activator, in NSCLC cells. Immunoprecipitation and confocal immunofluorescence microscope analysis confirmed the direct interaction of hnRNPA2/B1 with p300 proteins. Overexpression of p300, but not its histon acetyltransferase domain deletion mutation, enhanced the acetylation of hnRNPA2/B1, facilitated the binding of hnRNPA2/B1 to COX-2 promoter, thereby promoted COX-2 expression and tumor cell growth. Therefore, these results indicate that hnRNPA2/B1 acts as an activator to regulate COX-2 expression and tumor growth through the interaction with p300 in NSCLC cells and suggest that the hnRNPA2/B1/COX-2 signaling is a potential therapeutic target for lung cancers.

Note: This abstract was not presented at the meeting.

Citation Format: Jingshu Wang, Yang Xuan, Wei Guo, Guangwei Du, Wuguo Deng. hnRNPA2/B1 upregulates COX-2 expression and tumor growth and predicts poor prognosis in human lung cancers. [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 1019. doi:10.1158/1538-7445.AM2015-1019
Abstract 1020: Latent membrane protein 1 N-C interaction of EBV facilitates (nuclear factor kappa-light-chain-enhancer of activated B cells transcriptional activity
Authors: Hsu Cheng-Lung , Li Hsin-Pai , Kuo Yung-Chia , Tsang Ngan-Ming , Chang Yu-Sun
Published: August 2015

Background: Epstein-Barr virus latent membrane protein 1 (LMP1) is known to be involved in the carcinogenesis of numerous cancers, including nasopharyngeal carcinoma and lymphoma. The C-terminus of LMP1 can recruit a spectrum of host cell cytosolic signaling molecules to exert its effects on downstream pathways. However, the function of the cytosolic N-terminus of LMP1 is not clear.

Methods: Partial deletion or point mutation of the N-terminus of LMP1 were made.

Results: Sequence analysis showed that not only were the lengths of LMP1 N- and C-termini different, so too were their distributions of charged amino acid side chains, with negatively charged amino acids being abundant in the C-terminus and positively charged amino acids dominating in the N-terminus. We found that deletion or mutation of N-terminal positively charged amino acids weakened the effects of LMP1 on nuclear factor NF-κB transcriptional activity. Furthermore, co-expressing a short N-terminal peptide of LMP1 enhanced the effect of full-length LMP1 on NF-κB transcriptional activity. We further demonstrated that the LMP1 N- and C-termini interact, which facilitated downstream signal transduction. Mutation of N-termial positively charged side chain amino acid could weaken LMP1 effect on cell motility.

Conclusion: LMP1 N- and C-termini could interact and facilitate NF-κB transcriptional activity and cell motility.

Citation Format: Cheng-Lung Hsu, Hsin-Pai Li, Yung-Chia Kuo, Ngan-Ming Tsang, Yu-Sun Chang. Latent membrane protein 1 N-C interaction of EBV facilitates (nuclear factor kappa-light-chain-enhancer of activated B cells transcriptional 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 1020. doi:10.1158/1538-7445.AM2015-1020
Abstract 1026: Role of Group I Paks in MPNST cell proliferation, migration and invasion
Authors: Semenova Galina , Chernoff Jonathan
Published: August 2015

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas that arise in patients with neurofibromatosis (NF1) or sporadically. MPNSTs are typically chemoresistant, while surgical removal is limited due to invasiveness of the tumors. Recent studies that attempted to discover rational MPNST therapies identified MEK/ERK, PI3K/mTORC1 and Wnt/β-catenin pathways among the most critical for MPNST development and progression. As Group I p21-activated kinases (Paks) are known to regulate all three of these signaling pathways in many cell types, we proposed assess the potential of these kinases as potential therapeutic target for MPNST.

Using genetic and biochemical approaches we showed that loss of PAK1-3 activity significantly suppressed MPNST cell proliferation, as well as migration and invasion capacity. Treatment with specific small molecule PAK1-3 inhibitors Frax1036 and IPA-3 caused reduction of mTORC1 and β-catenin signaling in MPNST cells. MEK/ERK signaling, however, appeared to be intact or upregulated upon chemical Pak inhibition in most of the MPNST cell lines analyzed. Dual inhibition of PAK and MEK (PD0325901) resulted in synergistic cytotoxic effect on MPNST cells. Collectively, these findings suggest that Pak inhibitors might be useful for MPNST therapy, as single agents or in combinatorial treatment strategies.

Citation Format: Galina Semenova, Jonathan Chernoff. Role of Group I Paks in MPNST cell proliferation, migration and invasion. [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 1026. doi:10.1158/1538-7445.AM2015-1026
Abstract 1029: Receptor-interacting protein kinase 1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy
Authors: Yan Xu Guang , Luan Qi , Jin Lei , Jiang Chen Chen , Tay Kwang Hong , Lai Fritz , Liu Xiao Ying , Liu Yi Lun , Guo Su Tang , Tseng Hsin-Yi , Zhang Xu Dong
Published: August 2015

Although receptor-interacting protein kinase 1 (RIP1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in response of cells to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIP1 functions as an important pro-survival mechanism in melanoma cells undergoing ER stress through activation of autophagy. While pharmacological induction of ER stress upregulated RIP1 and triggered autophagy in melanoma cells resistant to ER stress-induced apoptosis, knockdown of RIP1 inhibited autophagy and rendered the cells sensitive to killing by ER stress, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIP1 enhanced induction of autophagy and conferred resistance of melanoma cells to killing by ER stress. Activation of JNK, which phosphorylated the BH3-only protein Bim leading to its dissociation from Beclin-1, was involved in ER stress-induced, RIP1-mediated activation of autophagy in melanoma cells. On the other hand, activation of the transcription factor heat shock factor protein 1 (HSF1) downstream of the IRE1/XBP1 axis of the unfolded protein response was responsible for the increase in RIP1 in melanoma cells undergoing ER stress. Collectively, these results identify upregulation of RIP1 as an important adaptive mechanism of melanoma cells to ER stress by protecting against cell death through activation of autophagy, and suggest that targeting the autophagy-activating mechanism of RIP1 may be a useful strategy to enhance sensitivity of melanoma cells to therapeutic agents that induce ER stress.

Citation Format: Xu Guang Yan, Qi Luan, Lei Jin, Chen Chen Jiang, Kwang Hong Tay, Fritz Lai, Xiao Ying Liu, Yi Lun Liu, Su Tang Guo, Hsin-Yi Tseng, Xu Dong Zhang. Receptor-interacting protein kinase 1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy. [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 1029. doi:10.1158/1538-7445.AM2015-1029
Abstract 1032: The acetylcholine signaling pathway: A novel molecular target for lung cancers
Authors: Brown Kathleen C. , Lau Jamie K. , Perry Haley E. , Thornhill Brent A. , Stevenson Cathryn D. , Rollyson William D. , Stover Cody A. , Jones Dennie V. , Pulliam Joseph F. , Dasgupta Piyali
Published: August 2015

Cigarette smoking is a major risk factor for all types of lung cancers. Nicotine, the addictive component of cigarettes, accelerates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). We show that both human SCLCs and NSCLCs contain all proteins of the acetylcholine signaling pathway, namely nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). ACh functions as an autocrine growth factor for human lung cancer cells. Lung adenocarcinoma (LAC), squamous cell carcinoma (SCC-L) and invasive mucinous adenocarcinoma (IMA) express a diverse array of nAChRs. In addition, normal human lung cells also express nAChRs and other ACh signaling proteins. Nicotine amplifies the ACh signaling loop in human lung cancer cells. It increases the levels of alpha7-nAChR subunit in human SCC-Ls. The alpha7-nAChR is responsible for the proliferative and pro-angiogenic activity of nicotine in lung cancer. The level of alpha7-nAChR was analyzed in human SCC-L samples isolated from patients. It was found that the level of alpha7-nAChR in SCC-L patients (who are heavy smokers) was much higher than that of moderate smoker suffering from SCC-Ls. Nicotine was also found to elevate the levels of ChAT and VAChT in human lung cancers. The acetylcholine signaling pathway may be a useful molecular target for the diagnosis and therapy of human lung cancers in smokers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes.

Citation Format: Kathleen C. Brown, Jamie K. Lau, Haley E. Perry, Brent A. Thornhill, Cathryn D. Stevenson, William D. Rollyson, Cody A. Stover, Dennie V. Jones, Joseph F. Pulliam, Piyali Dasgupta. The acetylcholine signaling pathway: A novel molecular target for lung cancers. [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 1032. doi:10.1158/1538-7445.AM2015-1032
Abstract 1039: Leucine-rich α2 glycoprotein modulates the effect of TGFβ1 on the growth of lewis lung carcinoma cells
Authors: Takemoto Norihiko , Serada Satoshi , Fujimoto Minoru , Inohara Hidenori , Naka Tetsuji
Published: August 2015

Background:

Leucine-rich α2 glycoprotein (LRG) is an approximately 50 kDa serum glycoprotein. It has been reported that the expression levels of LRG were elevated in the sera and tissues in several cancers. While it has been demonstrated that LRG modulated TGFβ1 signaling in endothelial cells and resulted in the promotion of pathogenic angiogenesis, the precise function of LRG in cancer remains unclear. The aim of this study was to investigate the role of LRG on the cellular response by TGFβ1 in Lewis lung carcinoma (LLC) cells.

Methods:

Parental LLC, mLRG-overexpressing LLC or control vector transfected LLC cells were subcutaneously transplanted into LRG knockout (KO) or Wild-type (WT) C57BL/6J mice and tumor growth was monitored. Cell proliferation treated with TGFβ1 was evaluated by WST-8 assay. Caspase activity was measured with Caspase-GloTM assay kit, protein expression levels were analyzed by western blotting and gene expression was analyzed with quantitative real-time PCR. LLC tumor growth were monitored in LRG KO or WT mice treated with TGFβRI inhibitor (SB431542) or vehicle. Apoptosis of LLC tumor was evaluated by TUNEL staining.

Result:

In LRG KO mice, LLC tumor growth was significantly increased compared with that in WT mice. In contrast, overexpression of mLRG significantly inhibited the growth of LLC tumors in WT mice. Treatment of TGFβ1 inhibited the proliferation of LLC cells in vitro. Addition of TGFβ1 strongly inhibited the proliferation of mLRG-overexpressing LLC cells than control vector LLC cells by induction of apoptosis. By TGFβ1 stimulation, induction of apoptosis via activation of smad2 and downstream signaling pathway was significantly increased in mLRG overexpressing LLC compared with control LLC cells in vitro. Treatment of TGFβRI inhibitor significantly enhanced growth and inhibited apoptosis of LLC tumor in WT mice compared with LRG KO mice.

Conclusion:

We found that LRG promoted TGFβ1-induced apoptosis in LLC, in vitro and in vivo. LRG is involved in the enhancement of TGFβ1-smad signal transduction.

Citation Format: Norihiko Takemoto, Satoshi Serada, Minoru Fujimoto, Hidenori Inohara, Tetsuji Naka. Leucine-rich α2 glycoprotein modulates the effect of TGFβ1 on the growth of lewis lung carcinoma 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 1039. doi:10.1158/1538-7445.AM2015-1039