bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Ontology and 3D Software for the Diseases of Spine
Authors: Lee Seungbock , Lee Sangho , Seo Dongmin , Yoo Kwan-Hee , Kim Sukil
Published: August 2015

KISTI is carrying out an e-Spine project for spinal diseases to prepare for the aged society, so-called NAP. The purpose of the study is to build a spine ontology that represents the anatomical structure and disease information which is compatible with simulation model of KISTI. The final use of the ontology includes diagnosis of diseases and setting treatment directions by the clinicians. The ontology was represented using 3D software. Twenty diseases were selected to be represented after discussions with a spine specialist. Several ontology studies were reviewed, reference books were selected for each disease and were organized in MS Excel. All the contents were then reviewed by the specialists. Altova SemanticWorks and Protégé were used to code spine ontology with OWL Full model. Links to the images from KISTI and sample images of diseases were included in the ontology. The OWL ontology was also reviewed by the specialists again with Protégé. We represented unidirectional ontology from anatomical structure to disease, images, and treatment. The ontology was human understandable. It would be useful for the education of medical students or residents studying diseases of spine. But in order for the computer to understand the ontology, a new model with OWL DL or Lite is needed.
Learner-Directed Nutrition Content for Medical Schools to Meet LCME Standards
Authors: Hark Lisa A. , Deen Darwin D. , Morrison Gail
Published: August 2015

Deficiencies in medical school nutrition education have been noted since the 1960s. Nutrition-related non-communicable diseases, including heart disease, stroke, cancer, diabetes, and obesity, are now the most common, costly, and preventable health problems in the US. Training medical students to assess diet and nutritional status and advise patients about a healthy diet, exercise, body weight, smoking, and alcohol consumption are critical to reducing chronic disease risk. Barriers to improving medical school nutrition content include lack of faculty preparation, limited curricular time, and the absence of funding. Several new LCME standards provide important impetus for incorporating nutrition into existing medical school curriculum as self-directed material. Fortunately, with advances in technology, electronic learning platforms, and web-based modules, nutrition can be integrated and assessed across all four years of medical school at minimal costs to medical schools. Medical educators have access to a self-study nutrition textbook,Medical Nutrition and Disease, Nutrition in Medicine© online modules, and the NHLBINutrition Curriculum Guide for Training Physicians. This paper outlines how learner-directed nutrition content can be used to meet several US and Canadian LCME accreditation standards. The health of the nation depends upon future physicians’ ability to help their patients make diet and lifestyle changes.
Role of Biomarkers in Diagnosis and Prognostic Evaluation of Acute Pancreatitis
Authors: Meher Susanta , Mishra Tushar Subhadarshan , Sasmal Prakash Kumar , Rath Satyajit , Sharma Rakesh , Rout Bikram , Sahu Manoj Kumar
Published: August 2015

Acute pancreatitis is a potentially life threatening disease. The spectrum of severity of the illness ranges from mild self-limiting disease to a highly fatal severe necrotizing pancreatitis. Despite intensive research and improved patient care, overall mortality still remains high, reaching up to 30–40% in cases with infected pancreatic necrosis. Although little is known about the exact pathogenesis, it has been widely accepted that premature activation of digestive enzymes within the pancreatic acinar cell is the trigger that leads to autodigestion of pancreatic tissue which is followed by infiltration and activation of leukocytes. Extensive research has been done over the past few decades regarding their role in diagnosis and prognostic evaluation of severe acute pancreatitis. Although many standalone biochemical markers have been studied for early assessment of severity, C-reactive protein still remains the most frequently used along with Interleukin-6. In this review we have discussed briefly the pathogenesis and the role of different biochemical markers in the diagnosis and severity evaluation in acute pancreatitis.
Pattern Recognition Methods and Features Selection for Speech Emotion Recognition System
Authors: Partila Pavol , Voznak Miroslav , Tovarek Jaromir
Published: August 2015

The impact of the classification method and features selection for the speech emotion recognition accuracy is discussed in this paper. Selecting the correct parameters in combination with the classifier is an important part of reducing the complexity of system computing. This step is necessary especially for systems that will be deployed in real‐time applications. The reason for the development and improvement of speech emotion recognition systems is wide usability in nowadays automatic voice controlled systems. Berlin database of emotional recordings was used in this experiment. Classification accuracy of artificial neural networks, k‐nearest neighbours, and Gaussian mixture model is measured considering the selection of prosodic, spectral, and voice quality features. The purpose was to find an optimal combination of methods and group of features for stress detection in human speech. The research contribution lies in the design of the speech emotion recognition system due to its accuracy and efficiency.
Entropy-Based Weighting for Multiobjective Optimization: An Application on Vertical Turning
Authors: Rocha Luiz Célio Souza , Paiva Anderson Paulo de , Balestrassi Pedro Paulo , Severino Geremias , Rotela Junior Paulo
Published: August 2015

In practical situations, solving a given problem usually calls for the systematic and simultaneous analysis of more than one objective function. Hence, a worthwhile research question may be posed thus: In multiobjective optimization, what can facilitate for the decision maker choosing the best weighting? Thus, this study attempts to propose a method that can identify the optimal weights involved in a multiobjective formulation. The proposed method uses functions of Entropy and Global Percentage Error as selection criteria of optimal weights. To demonstrate its applicability, this method was employed to optimize the machining process for vertical turning, maximizing the productivity and the life of cutting tool, and minimizing the cost, using as the decision variables feed rate and rotation of the cutting tool. The proposed optimization goals were achieved with feed rate = 0.37 mm/rev and rotation = 250 rpm. Thus, the main contributions of this study are the proposal of a structured method, differentiated in relation to the techniques found in the literature, of identifying optimal weights for multiobjective problems and the possibility of viewing the optimal result on the Pareto frontier of the problem. This viewing possibility is very relevant information for the more efficient management of processes.
Evaluation of the Antioxidant Activities and Tyrosinase Inhibitory Property from Mycelium Culture Extracts
Authors: Park Ki Moon , Kwon Kyung Min , Lee Seung Ho
Published: August 2015

Since mushrooms have many bioactive components, they have been used as components in folk medicine. Because mycelium has an advantage when it comes to large-scale production, this study aimed to evaluate the antioxidant properties and anti-tyrosinase activity from 55 mycelia in culture media. Relatively high 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity was detected from the ethanol extract of culture media including mycelium (EECiM) ofMorchella esculentavar.esculenta(MEVE),Auricularia polytricha(APO),Tremella aurantia(TAU),Volvariella bombycina(VBO), andOudemansiellasp. (Osp), which also showed strong reducing power and inhibitory activity in relation to the thiobarbituric acid (TBA) value. On the other hand, relatively high tyrosinase inhibitory activity was detected inInonotus mikadoi(IMI),Coriolus versicolor(CVE),Volvariella volvacea(VVO),Panellus serotinus(PSE),Auricularia auricula(AAU), andFomitopsissp. (Fsp). Interestingly, the APO EECiM exhibited the highest DPPH radical scavenging rate (77.5 ± 4.3%) and reducing power (1.18 ± 0.041), while the highest inhibitory power of the TBA value and antityrosinase activity were detected in that of TAU (64.5 ± 4.1%) and IMI (46.0 ± 7.5%), respectively. Overall, our study suggested potential candidates for EECiMs that exhibited powerful antioxidant and tyrosinase inhibitory properties and might be used as natural antioxidant tyrosinase inhibitor.
Heuristic Approach to Select Opportunistic Routing Forwarders (HASORF) to Enhance Throughput for Wireless Sensor Networks
Authors: Zikria Yousaf Bin , Nosheen Summera , Choi Jin-Ghoo , Kim Sung Won
Published: August 2015

Biological schemes provide useful resources for designing adaptive routing protocols for wireless sensor networks (WSNs). The key idea behind using bioinspired routing is to find the optimal path to the destination. Similarly, the idea of opportunistic routing (OR) is to find the least number of hops to deliver the data to the destination. Numerous routing schemes have been proposed in WSNs while targeting various performance goals, such as throughput, delay, and link quality. Recently, OR schemes have come onto the scene in comparison with the traditional routing algorithms. The performance of OR schemes, however, highly depends on the selection of forwarder nodes. In this paper, we consider a chain network topology, where nodes are separated by an equal distance. The throughput of the chain network is analyzed mathematically, and based on the analysis results, a heuristic algorithm is proposed to choose the forwarder nodes. We evaluate the performance of the proposed Heuristic Approach to Select Opportunistic Routing Forwarders (HASORF) by using the ns-2 simulator and compare it with previous schemes, such as random routing, Extremely Opportunistic Routing (ExOR), and Simple Opportunistic Adaptive Routing (SOAR). The empirical results show that our proposed scheme achieves the best performance among them.
Effects of M2+ (M = Ca, Sr, and Ba) Addition on Crystallization and Microstructure of SiO2-MgO-Al2O3-B2O3-K2O-F Glass
Authors: Garai Mrinmoy , Sasmal Nibedita , Karmakar Basudeb
Published: August 2015

In understanding the effect of K+ substitution by M2+ (M = Ca, Sr, and Ba) on crystallization and microstructural properties of boroaluminosilicate glass system, the SiO2-MgO-Al2O3-B2O3-MgF2-K2O-Li2O-AlPO4 glasses were prepared by single-step melt-quenching at 1500°C. Density of base glass (2.64 g·cm−3) is found to be decreased in presence of CaO and SrO. Tg is increased by 5–10°C and Td decreased by 13–20°C on addition of M2+. The variation of Tg, Td and decrease of thermal expansion (CTE) from 7.55 to 6.67–6.97 (×10−6/K, at 50–500°C) in substituting K+ by M2+ are attributed to the higher field-strength of Ca2+, Sr2+, and Ba2+. Opaque mica glass-ceramics were derived from the transparent boroaluminosilicate glasses by controlled heat treatment at 1050°C (duration = 4 h); and the predominant crystalline phase was identified as fluorophlogopite (KMg3AlSi3O10F2) by XRD and FTIR study. Glass-ceramic microstructure reveals that the platelike mica flake crystals predominate in presence of K2O and CaO but restructured to smaller droplet like spherical shaped mica on addition of SrO and BaO. Wide range of CTE values (9.54–13.38 × 10−6/K at 50–800°C) are obtained for such glass-ceramics. Having higher CTE value after crystallization, the CaO containing SiO2-MgO-Al2O3-B2O3-MgF2-K2O-Li2O-AlPO4 glass can be useful as SOFC sealing material.
Does Intensive Glucose Control Prevent Cognitive Decline in Diabetes? A Meta-Analysis
Authors: Peñaherrera-Oviedo Carlos , Moreno-Zambrano Daniel , Palacios Michael , Duarte-Martinez María Carolina , Cevallos Carlos , Gamboa Ximena , Jurado María Beatriz , Tamariz Leonardo , Palacio Ana , Santibañez Rocío
Published: August 2015

Diabetes mellitus is associated with cognitive decline and impaired performance in cognitive function tests among type 1 and type 2 diabetics. Even though the use of tight glucose control has been limited by a reported higher mortality, few reports have assessed the impact of treatment intensity on cognitive function. We conducted a meta-analysis to evaluate if an intensive glucose control in diabetes improves cognitive function, in comparison to standard therapy. We included 7 studies that included type 1 or type 2 diabetics and used standardized tests to evaluate various cognitive function domains. Standardized mean differences (SMDs) were calculated for each domain. We found that type 1 diabetics get no cognitive benefit from a tight glucose control, whereas type 2 diabetics get some benefit on processing speed and executive domains but had worse performances in the memory and attention domains, along with a higher incidence of mortality when using intensive glucose control regimes.
Fractalkine Signaling and Microglia Functions in the Developing Brain
Authors: Arnoux Isabelle , Audinat Etienne
Published: August 2015

Microglial cells are the resident macrophages of the central nervous system (CNS). Besides their classical roles in pathological conditions, these immune cells also dynamically interact with neurons and influence their structure and function in physiological conditions. The neuronal chemokine fractalkine and its microglial receptor CX3CR1 are one important signaling pathway involved in these reciprocal interactions. In the present review, we will discuss recent evidence indicating that fractalkine signaling also determines several functions of microglial cells during normal CNS development. It has been known for a decade that microglial cells influence the neuronal death that normally occurs during CNS development. Surprisingly, recent evidence indicates that they can also support survival of developing neurons, control axon outgrowth, and laminar positioning of subsets of interneurons in the forebrain. Moreover, microglial cells influence the maturation of synaptic circuits at early postnatal stages: their phagocytic activity allows them to eliminate inappropriate synapses and they can also influence the functional expression of synaptic proteins by releasing mediators. Fractalkine signaling controls these functions of microglial cells in part by regulating their timely recruitment at sites of developing synapses. Finally, on-going research suggests that this signaling pathway is also a key player in neurodevelopmental disorders.
Risk-Based Clustering for Near Misses Identification in Integrated Deterministic and Probabilistic Safety Analysis
Authors: Di Maio Francesco , Vagnoli Matteo , Zio Enrico
Published: August 2015

In integrated deterministic and probabilistic safety analysis (IDPSA), safe scenarios and prime implicants (PIs) are generated by simulation. In this paper, we propose a novel postprocessing method, which resorts to a risk-based clustering method for identifying Near Misses among the safe scenarios. This is important because the possibility of recovering these combinations of failures within a tolerable grace time allows avoiding deviations to accident and, thus, reducing the downtime (and the risk) of the system. The postprocessing risk-significant features for the clustering are extracted from the following: (i) the probability of a scenario to develop into an accidental scenario, (ii) the severity of the consequences that the developing scenario would cause to the system, and (iii) the combination of (i) and (ii) into the overall risk of the developing scenario. The optimal selection of the extracted features is done by a wrapper approach, whereby a modified binary differential evolution (MBDE) embeds aK-means clustering algorithm. The characteristics of the Near Misses scenarios are identified solving a multiobjective optimization problem, using the Hamming distance as a measure of similarity. The feasibility of the analysis is shown with respect to fault scenarios in a dynamic steam generator (SG) of a nuclear power plant (NPP).
FT-IR Characterization of Pollen Biochemistry, Viability, and Germination Capacity inSaintpauliaH. Wendl. Genotypes
Authors: Buta Erzsebet , Cantor Maria , Ștefan Răzvan , Pop Rodica , Mitre Ioana , Buta Mihai , Sestraș Radu E.
Published: August 2015

FT-IR characterization of pollen biochemistry was analyzed to detect possible connection with the viability (by staining with potassium iodide, 25%) and the germination capacity (on solid nutrient medium), in 15Saintpauliagenotypes. Vibrational spectroscopy indicates that the pollen ofS. ionanthagenotype “Red Velvet” is rich in proteins, lipids, triglycerides, and esters and has a viability of 88.4% and a low germination capacity (27.16%). ForS. ionantha“Jolly Red” and “Lucky Ladybug” genotypes, pollen showed high viability (88.81–91.49%) and low germination capacity (23.02–9.17%), even though the pollen is rich in carbohydrates.S. ionantha“Aloha Orchid” genotype has the highest percentage of viability (94.32%) and germination capacity (45.73%) and a rich content of carbohydrates and polygalacturonic acids. InS. rupicolaandS. ionanthagenotypes, the rich content of polygalacturonic acids, lipids, and carbohydrates favourably influenced the germination capacity. Spectroscopic result indicates, through different absorbance band intensity, a possible link between biochemical composition, viability, and germination capacity ofSaintpauliapollen. To determine exactly the relation between biochemistry and biological processes, it is necessary to initiate quantitative researches.
Enabling Valuation of Nutrition Integration into MBBS Program
Authors: Schoendorfer Niikee , Schafer Jennifer
Published: August 2015

Good nutrition is the foundation for good health. While basic nutritional assessment is part of many medical consultations, it remains underutilized despite becoming increasingly recognized as important for chronic disease prevention and management. Many studies identify shortfalls in physicians’ knowledge and attitudes toward nutrition as a result of inadequate emphasis in medical school. Additional teaching about nutrition and nutritional assessment procedures was integrated within a first year module of a MBBS program. Blended learning techniques were employed to facilitate student engagement and sessions were evaluated via student response system technology (clickers) or minute paper feedback. The initial survey to all medical students (n=1037) documented that less than half (45%) felt they could discuss nutrition with patients. The majority (n=606) regularly consulted the internet for nutrition information, while only 163 utilised peer-reviewed journals. With the first year cohort (n=297) “clickers” revealed that 91% felt nutrition important to health care and 82% felt it important in general practice. 71% found using clickers an interesting enhancement, whilst 70% noted the nutrition content informative. Early nutrition teaching was well received by students. Long-term increases in nutritional information dissemination, particularly by influential health care workers, might benefit not only economies but also the health of society as a whole.
A Novel Method of Increasing Medical Student Nutrition Awareness and Education
Authors: Schoettler Cynthia L. , Lee Jennifer N. , Ireland Kathy A. , Lenders Carine M.
Published: August 2015

Medical nutrition education in most US medical schools is lacking, despite an epidemic of lifestyle related chronic conditions and high rates of malnutrition in hospitals. In a unique response to this deficit, students at Boston University School of Medicine have created a novel student interest group entitled Student Nutrition Awareness and Action Council (SNAAC). This student group is unique in that it focuses on interprofessional collaboration and development of concrete practice skills and works to fill educational gaps. The goal of SNAAC is to increase medical student knowledge, attitude, and skills in medical nutrition through providing extracurricular activities and partnering with official medical school curriculum committees. To accomplish this, SNAAC has developed a multipartite group overseen by a mentoring team composed of a physician nutrition specialist, registered dietitian, and a mental health provider. SNAAC provides nutrition oriented opportunities for members and the student body at large. Participation is high because it fills an educational gap, offers a unique focus on expanding nutrition awareness and education, and provides opportunities for student leadership and professional development. We encourage other medical schools to use the SNAAC student involvement model to increase nutrition awareness and facilitate the incorporation of medical nutrition in their curriculum.
The Role of the Risk-Neutral Jump Size Distribution in Single-Factor Interest Rate Models
Authors: Gómez-Valle L. , Martínez-Rodríguez J.
Published: August 2015

We obtain a result that relates the risk-neutral jump size of interest rates with yield curve data. This function is unobservable; therefore, this result opens a way to estimate the jump size directly from data in the markets together with the risk-neutral drift and jump intensity estimations. Then, we investigate the finite sample performance of this approach with a test problem. Moreover, we analyze the effect of estimating the risk-neutral jump size instead of assuming that it is artificially absorbed by the jump intensity, as usual in the interest rate literature. Finally, an application to US Treasury Bill data is also illustrated.
ICT Learning by Older Adults and Their Attitudes toward Computer Use
Authors: González Antonio , Ramírez María Paz , Viadel Vicente
Published: August 2015

Information and communication technologies have proven to be an effective way of helping older adults improve independence outcomes, but such technologies are yet not widely used by this segment of the population. This paper aims to study computer use and senior citizens’ attitudes toward computer technology in the context of a 20-hour course in basic skills. A questionnaire was used to conduct pre- and postcourse analyses with a sample of 191 adults over the age of 60. The findings show that direct contact with computers generates more positive attitudes toward computer use and also positive relationships with attitudes, user behavior, training expectations, and self-confidence. Results are discussed in the light of need-to-know attitudes toward computer use and training in new technologies as an opportunity for life-long learning and for improving quality of life in old age.
Simulation-Based Sensor Location Model for Arterial Street
Authors: Yu Qinxiao , Zhu Ning , Li Geng , Ma Shoufeng
Published: August 2015

Traffic sensors serve as an important way to a number of intelligent transportation system applications which rely heavily on real-time data. However, traffic sensors are costly. Therefore, it is necessary to optimize sensor placement to maximize various benefits. Arterial street traffic is highly dynamic and the movement of vehicles is disturbed by signals and irregular vehicle maneuver. It is challenging to estimate the arterial street travel time with limited sensors. In order to solve the problem, the paper presents travel time estimation models that rely on speed data collected by sensor. The relationship between sensor position and vehicle trajectory in single link is investigated. A sensor location model in signalized arterial is proposed to find the optimal sensor placement with the minimum estimation error of arterial travel time. Numerical experiments are conducted in 3 conditions: synchronized traffic signals, green wave traffic signals, and vehicle-actuated signals. The results indicate that the sensors should not be placed in vehicle queuing area. Intersection stop line is an ideal sensor position. There is not any fixed sensor position that can cope with all traffic conditions.
Quadrotor Trajectory Tracking Based on Quasi-LPV System and Internal Model Control
Authors: He ZeFang , Zhao Long
Published: August 2015

Internal model control (IMC) design method based on quasi-LPV (Linear Parameter Varying) system is proposed. In this method, the nonlinear model is firstly transformed to the linear model based on quasi-LPV method; then, the quadrotor nonlinear motion function is transformed to transfer function matrix based on the transformation model from the state space to the transfer function; further, IMC is designed to control the controlled object represented by transfer function matrix and realize quadrotor trajectory tracking. The performance of the controller proposed in this paper is tested by tracking for three reference trajectories with drastic changes. The simulation results indicate that the control method proposed in this paper has stronger robustness to parameters uncertainty and disturbance rejection performance.
Effect of Car Rear Shape on Pollution Dispersion in Near Wake Region
Authors: Hu Xing-Jun , Yang Han-Bo , Yang Bo , Li Xiu-Cheng , Lei Yu-Long
Published: August 2015

Dispersion of vehicle exhaust gas is a primary source of air pollution in urban areas. Thus, it has become an important subject in the automotive field. This paper consists of two parts. First, the fastback MIRA model was selected as study object and a standardκ-εtwo-equation turbulence model was used. The simulation results were compared and analyzed with experimental data. The feasibility of the turbulence model and grid strategy was then verified, and the results were used in the next research step. Second, we used propane as tracer gas while ignoring the effect of the vehicle wake field force on this gas. The tracer gas diffusion in the wake flow field was then simulated through fastback, notchback, and square-back MIRA models. This study focuses on analyzing the characteristics of wake field diffusion effects, particularly in the near wake of a vehicle.
Multiswarm Particle Swarm Optimization with Transfer of the Best Particle
Authors: Wei Xiao-peng , Zhang Jian-xia , Zhou Dong-sheng , Zhang Qiang
Published: August 2015

We propose an improved algorithm, for a multiswarm particle swarm optimization with transfer of the best particle called BMPSO. In the proposed algorithm, we introduce parasitism into the standard particle swarm algorithm (PSO) in order to balance exploration and exploitation, as well as enhancing the capacity for global search to solve nonlinear optimization problems. First, the best particle guides other particles to prevent them from being trapped by local optima. We provide a detailed description of BMPSO. We also present a diversity analysis of the proposed BMPSO, which is explained based on the Sphere function. Finally, we tested the performance of the proposed algorithm with six standard test functions and an engineering problem. Compared with some other algorithms, the results showed that the proposed BMPSO performed better when applied to the test functions and the engineering problem. Furthermore, the proposed BMPSO can be applied to other nonlinear optimization problems.
Mal de Debarquement Syndrome: A Rare Entity—A Case Report and Review of the Literature
Authors: Nwagwu Veronica , Patel Rakesh , Okudo Jerome
Published: August 2015

Mal de Debarquement Syndrome (MDS) is a rare, understudied, underdiagnosed, and self-limiting condition. Etiology and incidence are unknown. It is characterized by abnormal sensation of motion/balance reported after travel by air, land, and sea; being reexposed to motion/activity relieves it. Symptoms may last from minutes to years. Workup though required reveals no findings; it is a diagnosis of exclusion. While no efficacious treatment exists, amitriptyline and benzodiazepines as well as supportive therapy have proved to be useful. We have described a 40-year-old Caucasian female who presented for the evaluation of persistent rocking and swaying sensation after a ship cruise which lasted for one week. Patient was treated with benzodiazepines after extensive workup and is now stable. A high index of suspicion is required to make a diagnosis.
Abstract 1006: Celastrol modulated Taz and induced cell apoptosis in vitro
Authors: Wang Shuren
Published: August 2015

Celastrol is derived from the Chinese medicinal plant Tripterygium wilfordii, which has attracted great attention for its potent anticancer effects. Celastrol has been found to inhibit the proliferation, induce apoptosis, and suppress invasion/migration and angiogenesis both in vitro and in vivo. In our current study, we treated the HEK293 cells with the Celastrol(0.75μM) for 24h and found that Celastrol could reduce the expression of TAZ in HEK293 cells.

To better evaluate the effect of TAZ on HEK293 cells, cell growth curve and colony formation assay were performed. HEK293/TAZ and HEK293/control cells were plated at a density of 50 cells/mm2 in triplicate for 5 days and HEK293/TAZ and HEK293/control cells were seeded into six-well plates of 500 cells/well for two weeks. The result showed that HEK293/TAZ grew obviously faster and could form more colonies than HEK293/control cells. To further address the effect of TAZ in vivo, equal numbers(1.5×106) of HEK293/TAZ and HEK293/control cells were injected bilateral subcutaneously into nude mice. The mice were sacrificed 40 days after injection. We found that the latency of tumor formation in nude mice injected with HEK293/TAZ cells was shorter than the tumor injected with HEK293/control cells. Furthermore, HEK293/TAZ cells could lead to a larger tumor size compared to the HEK293/control cells. Our data indicated that the overexpression of TAZ could significantly promote cell proliferation in vitro and in vivo.

Furthermore, after HEK293/TAZ and HEK293/control cells were treated with Celastrol(0.75μM) for 24h, the data showed that the less PARP cleavage was definitely observed in HEK293/TAZ cells than HEK293/control cells by Western blotting. Moreover, 18.9% of HEK293/TAZ cells were TUNEL-positive, compared with 83.2% of HEK293/control cells after Celastrol treatment(0.75μM, 24h). Our data indicated that overexpression of TAZ could overcome partially the cell apoptosis induced by Celastrol in vitro.

In summary, our finding prompts that Celastrol could suppress growth of tumor cells through the modulation of TAZ, and the mechanism how TAZ plays its function needs to be further explored.

Citation Format: Shuren Wang. Celastrol modulated Taz and induced cell apoptosis in vitro. [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 1006. doi:10.1158/1538-7445.AM2015-1006
Abstract 1008: Cytoplasmic p53 protects against MG132-induced apoptosis in a cell state-dependent manner
Authors: Cheng Ho Wa (Jacky) , Legesse-Miller Aster
Published: August 2015

Since the approval of proteasome inhibitor, Bortezomib, for use in multiple myeloma in 2003, pharmacological proteasome inhibitors has been shown to be an important strategy for treating many types of cancer. While proteasome inhibitors induce apoptosis in certain rapidly proliferating cancer cells, some cells enters quiescence and survives. The mechanism by which quiescent cells become resistant to proteasome inhibitors is largely unknown. The tumor suppressor protein p53 plays an essential role in establishing and maintain quiescence in human cells. It also regulates several cell survival mechanisms, including cell cycle arrest, autophagy, and activation of reactive oxygen detoxifying enzymes. Here, we investigated the role of p53 in establishing resistance against proteasome inhibitors in quiescent cells. We found that MG132 (a know proteasome inhibitor) treatment induces the accumulation of p53 and its downstream target p21 more in quiescent cells than in proliferating primary human fibroblasts. shRNA mediated down-regulation of p53 sensitizes both proliferating and quiescent fibroblasts to MG132-mediated apoptosis and cell death, suggesting that p53 plays a protective role in all cell states. Additional experiments demonstrated that proliferating fibroblasts are susceptible to inhibition of cytoplasmic p53 activity, whereas quiescent fibroblasts are sensitive to inhibition of nuclear p53 activity. These findings suggest that p53 induces different protective mechanisms against MG132-mediated cell death, depending of the proliferative state of the cells. Autophagy, an alternative degradation pathway regulated by p53, is also induced in both cell states upon MG132 treatment. Identification of p53-mediated regulatory mechanisms that are activated in quiescent cells in response to proteasome inhibition may help to suggest strategies for improving the effectiveness of proteasome inhibitors in treating cancer. This work was supported by NCI K01 CA128887 to Aster Legesse-Miller.

Citation Format: Ho Wa (Jacky) Cheng, Aster Legesse-Miller. Cytoplasmic p53 protects against MG132-induced apoptosis in a cell state-dependent manner. [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 1008. doi:10.1158/1538-7445.AM2015-1008
Abstract 1013: Understanding the molecular pathways underlying radio-sensitization of non-small cell lung cancer (NSCLC) by vitamin D (EB1089)
Authors: Sharma Khushboo , Thekkudan Theresa , Gewirtz David , Harada Hisashi , Torti Frank , Torti Suzy
Published: August 2015

Ionization radiation (IR) is an integral component of lung cancer treatment. However, disease recurrence represents a significant barrier to effective therapy. One explanation for the difficulties associated with treatment of NSCLC could be the promotion of autophagy, a cytoprotective signaling pathway that controls the degradation and recycling of cellular components. Cytoprotective autophagy may be one of the primary causes for the development of resistance to standard therapies.

In recently published studies (Sharma et al, Autophagy), we showed that the vitamin D analog, EB 1089, leads to conversion of the cytoprotective autophagy induced by radiation alone to a novel ‘cytostatic’ form of autophagy. While pharmacological and genetic inhibition of autophagy increased sensitivity to radiation, interference with autophagy reversed the radio-sensitization by EB 1089 (or Vitamin D3) in H460 and A549 NSCLC cells. These studies demonstrated a switch between the cytoprotective and cytostatic roles of autophagy in response to radiation alone and the combination of EB 1089 (or Vitamin D3) and radiation.

AMPK, an energy sensor, has been shown to be involved in regulating autophagy via the AMPK-mTOR pathway. We observed an increase in phosphorylated AMPK (and ULK-1, which is downstream of AMPK) with the combination treatment of IR and EB 1089. Both pharmacological and genetic inhibition of AMPK, reverted the radio-sensitization effects of EB 1089, implicating AMPK in radio-sensitization. Studies conducted with NSCLC cell lines both wt and mutant or null in p53 indicated that functional p53 was required to radio-sensitize tumor cells with the combination treatment. p53 appears to promote AMPK upregulation via sestrin. Finally, studies to determine the potential involvement of NF-kB in radiation sensitization showed degradation of IKB-α in response to IR alone that was suppressed by EB 1089, indicating NF-kB's involvement in the initiation of cytoprotective autophagy by radiation Overall, these studies suggest that the use of vitamin D or a vitamin D analogue could increase sensitization to radiation treatment for lung cancer.

Citation Format: Khushboo Sharma, Theresa Thekkudan, David Gewirtz, Hisashi Harada, Frank Torti, Suzy Torti. Understanding the molecular pathways underlying radio-sensitization of non-small cell lung cancer (NSCLC) by vitamin D (EB1089). [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 1013. doi:10.1158/1538-7445.AM2015-1013
Abstract 1014: Dihydrotanshione I induces caspase-independent cell death and autophagy in lung cancer cells
Authors: Kim Sung-Hoon , Won Gunho , Jeong Myoung Seok , Yoon Sang Wook , Lee Jihyun , Kim Bonglee , Sohn Eun Jung
Published: August 2015

In the present study the antitumor mechanism of dihydrotanshinone I (DHT) from Salvia miltiorrhiza Bunge was elucidated in lung cancer cells. DHT significantly exerted cytotoxicity and increased the apoptosis by Annexin V assay in NSCLC (A549 and H460 cells) and lung mesothelioma cells (H28, H2452, MSTO). Furthermore, DHT reduced clonogenic ability in A549 cells. Interestingly, DHT increased PARP cleavage, but no activation of caspase-9 and caspase-3, although caspase-8 and, 3 were partially activated. FACS analysis revealed that the pan-caspase inhibitor z-VAD-fmk increased apoptosis induced by DHT. Furthermore, MTT assay showed that z-VAD-fmk treatment did not block cell cytotoxicity induced by DHT. In contrast, DHT induced the features of autophagy, including formation of autophagosomes by immunofluorescence and an increase of LC3II level after DHT exposure. Treatment of 3MA, an inhibitor of autophagy, blocked the expression level of LC3II induced by DHT and induced cytoprotective autophagy in A549 cells. Taken together, our data suggest that DHT induces caspase-independent cell death and autophagy in lung cancer cells as a potent agent for lung cancer treatment.

Citation Format: Sung-Hoon Kim, Gunho Won, Myoung Seok Jeong, Sang Wook Yoon, Jihyun Lee, Bonglee Kim, Eun Jung Sohn. Dihydrotanshione I induces caspase-independent cell death and autophagy in 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 1014. doi:10.1158/1538-7445.AM2015-1014
Abstract 1027: Apoptotic resistance in arsenic transformed cells attributed to decreased SIRT3-FOXO3A signaling
Authors: Roy Ram V. , Shi Xinglin
Published: August 2015

SIRT3 is the primary mitochondrial protein deacetylase that regulates mitochondrial proliferation and DNA integrity. SIRT3 is the only sirtuin whose increased expression was shown to be associated with extended lifespan in humans. Interestingly, very few studies have examined the role of SIRT3 in cancers. Here, we report cellular function of SIRT3 in Beas-2B cells under arsenic stress, and in AT cells. Upon treatment with arsenic, in Beas-2B cells, SIRT3 levels increased and induced apoptosis - nuclear translocation and binding of SIRT3 to FOXO3A - while AT cells exhibited lower levels of SIRT3 which can be attributed to apoptotic resistance, as over-expression of SIRT3 restores sensitivity to apoptosis. In AT cells, lower expression of SIRT3 caused hyperacetylation and aberrant localization of its target protein - FOXO3A. One of the consequences of low SIRT3 levels is absence of SIRT3-FOXO3A interaction in AT cells, which increases the proportion of transcriptionally hyperactive, highly depolarized mitochondria (high ΔΨm) with higher mitochondrial DNA content compared to passage matched parent Beas-2B cells. Conversely, Resveratrol-induced high expression of SIRT3 improves nuclear-mitochondrial crosstalk (increased FOXO3A binding in the D-loop region) and raises sensitivity towards apoptosis. By disconnecting crosstalk between nucleus and mitochondria (SIRT3-FOXO3A interactions), AT cells increase depolarized mitochondrial number, so that the transformed cells maintain low basal ROS and proliferate rapidly. This is the first time that a study has shown functional role of SIRT3-FOXO3A in promoting apoptosis in Beas-2B cells under arsenic stress, and in AT cells.

Citation Format: Ram V. Roy, Xinglin Shi. Apoptotic resistance in arsenic transformed cells attributed to decreased SIRT3-FOXO3A signaling. [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 1027. doi:10.1158/1538-7445.AM2015-1027
Abstract 1045: A snapshot of pan-cellular PTM in response to Sorafenib-mediated multikinase inhibition
Authors: Loch Christian M.
Published: August 2015

More fundamentally than regulating specific functions or cascades, PTM affords proteins the mechanical complexity necessary to make human cells function. We believe that specifically modified forms of proteins are what conduct the cells business, and that by monitoring these “proteoforms” we can gain unique insight into cellular physiology. To test this, we treated HepG2 hepatocellular carcinoma cells with the multi-kinase inhibitor Sorafenib, and observed pharmacodynamic changes to PTM across the cellular proteome. Our novel approach, referred to as Snapshot Proteomics, revealed changes in phosphorylation to known targets of this drug. Intriquingly, we also observed changes to proteins whose roles make them strong candidates for mediating the clinical side effects of Sorafenib treatment. We also observed that the changes mediating the therapeutic response were far from the most dramatic ones observed, suggesting other, unexpected proteins as better putative pharmacodynamic biomarkers. Finally, we found that manipulating cellular phosphorylation pharmacologically had dramatic and interesting effects on other PTM pathways as well, ubiquitin in particular. This confirmed the already established crosstalk between these pathways, and supports our contention that no PTM occurs in a vacuum.

Citation Format: Christian M. Loch. A snapshot of pan-cellular PTM in response to Sorafenib-mediated multikinase inhibition. [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 1045. doi:10.1158/1538-7445.AM2015-1045
Abstract 1048: Chromatin remodelers are frequently disrupted by epigenetic and genetic alterations at an early stage of carcinogenesis
Authors: Takeshima Hideyuki , Niwa Tohru , Takahashi Takamasa , Ando Takayuki , Taniguchi Hirokazu , Katai Hitoshi , Sugiyama Toshiro , Ushijima Toshikazu
Published: August 2015

Chromatin remodeling factors (chromatin remodelers), such as SWI/SNF and ISWI complexes, regulate gene transcription by modulating chromatin accessibility. Genes encoding subunits of chromatin remodelers are frequently disrupted by loss of function mutations in various types of cancers. In contrast, inactivation of chromatin remodelers by epigenetic alterations, such as aberrant DNA methylation, is unknown. In this study, we aimed to clarify 1) whether or not chromatin remodelers are inactivated by aberrant DNA methylation, and 2) the timing of this occurrence.

DNA methylation statuses of 16 genes encoding chromatin remodelers with promoter CpG islands were analyzed in non-cancerous tissues of male gastric cancer patients using an Infinium HumanMethylation450 BeadChip array. Among the 16 genes, two genes, ACTL6B and SMARCA1, were frequently methylated in non-cancerous gastric tissues. Among these genes, SMARCA1 was expressed at high levels in normal gastric tissues, but ACTL6B was not. In four of 50 primary gastric cancers, SMARCA1 was aberrantly methylated. It was re-expressed after treatment with a DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), in gastric cancer cell lines, AGS and GC2. Somatic mutations of 18 genes encoding chromatin remodelers were analyzed using a next-generation personal sequencer in the 50 primary gastric cancers. Nine genes, ARID1A, ARID1B, ARID2, SMARCA1, SMARCA2, SMARCA4, SMARCB1, PBRM1, and PHF10, were mutated in one or more of the 50 gastric cancers. The mutant allele frequency was close to the cancer cell content in cancer samples with a specific mutation of a chromatin remodeler. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, by shRNAs in cancer cell lines promoted their growth.

These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis (Takeshima et al., Cancer Letters, in press).

Citation Format: Hideyuki Takeshima, Tohru Niwa, Takamasa Takahashi, Takayuki Ando, Hirokazu Taniguchi, Hitoshi Katai, Toshiro Sugiyama, Toshikazu Ushijima. Chromatin remodelers are frequently disrupted by epigenetic and genetic alterations at an early stage of carcinogenesis. [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 1048. doi:10.1158/1538-7445.AM2015-1048
Abstract 1054: Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer
Authors: Ichimura Norihisa , Shinjo Keiko , Ohka Fumiharu , Katsushima Keisuke , Hatanaka Akira , Tojo Masayuki , Shimizu Yasuhiro , Yamamoto Eiichiro , Suzuki Hiromu , Kondo Yutaka
Published: August 2015

Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer (CRC). The relationship between TET inactivation and CIMP in CRCs is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) CRCs. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in CRCs, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of CRCs as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (24/55, 44%) than CIMP-N (3/113, 3%, P<0.0001) CRCs. This trend was also observed in colon polyps (CIMP-P, 18/40, 45%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P CRCs. CRCs with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and P = 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in CRC.

Citation Format: Norihisa Ichimura, Keiko Shinjo, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Masayuki Tojo, Yasuhiro Shimizu, Eiichiro Yamamoto, Hiromu Suzuki, Yutaka Kondo. Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal 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 1054. doi:10.1158/1538-7445.AM2015-1054