bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of Nrf2 in Ocular Diseases
Authors: Batliwala Shehzad , Xavier Christy , Liu Yang , Wu Hongli , Pang Iok-Hou
Published: April 2017

The human body harbors within it an intricate and delicate balance between oxidants and antioxidants. Any disruption in this checks‐and‐balances system can lead to harmful consequences in various organs and tissues, such as the eye. This review focuses on the effects of oxidative stress and the role of a particular antioxidant system—the Keap1‐Nrf2‐ARE pathway—on ocular diseases, specifically age‐related macular degeneration, cataracts, diabetic retinopathy, and glaucoma. Together, they are the major causes of blindness in the world.
Toeplitz Operators, Pseudo-Homogeneous Symbols, and Moment Maps on the Complex Projective Space
Authors: Morales-Ramos Miguel Antonio , Quiroga-Barranco Raul , Sanchez-Nungaray Armando
Published: April 2017

Following previous works for the unit ball due to Nikolai Vasilevski, we define quasi-radial pseudo-homogeneous symbols on the projective space and obtain the corresponding commutativity results for Toeplitz operators. A geometric interpretation of these symbols in terms of moment maps is developed. This leads us to the introduction of a new family of symbols, extended pseudo-homogeneous, that provide larger commutative Banach algebras generated by Toeplitz operators. This family of symbols provides new commutative Banach algebras generated by Toeplitz operators on the unit ball.
HO‐1 Is Essential for Tetrahydroxystilbene Glucoside Mediated Mitochondrial Biogenesis and Anti‐Inflammation Process in LPS‐Treated RAW264.7 Macrophages
Authors: Yu Weihua , Zhang Xiaodi , Wu Hao , Zhou Qingbiao , Wang Zhao , Liu Rui , Liu Jiangzheng , Wang Xin , Hai Chunxu
Published: April 2017

2,3,5,4′‐Tetrahydroxystilbene‐2‐O‐β‐D‐glucoside (TSG), an important monomer extracted from Polygonum multiflorum, can prevent a number of inflammation associated chronic diseases. However, the mechanism involved in TSG inducing anti‐inflammatory role remains unclear. As an inducible antioxidant enzyme, Heme oxygenase‐1 (HO‐1), is crucial for protecting the mammalian cells against adverse stimuli. Here, we found that the TSG treatment strongly induces the expression of HO‐1 in an NRF2‐depended manner. Meanwhile, TSG increased the mitochondrial mass through upregulation of the mitochondrial biogenesis activators (PGC‐1α, NRF1, and TFAM) as well as the mitochondrial complex IV. Furthermore, TSG attenuated Lipopolysaccharide (LPS) mediated RAW264.7 cells activation and secretion of proinflammatory cytokines, including interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNF‐α). Zinc Protoporphyrin (ZnPP), a selective inhibitor of HO‐1 activity, was able to attenuate TSG mediated mitochondrial biogenesis and anti‐inflammatory process. Finally, we observed that LPS induced obvious mtDNA depletion and ATP deficiency, which indicated a severe damage of mitochondria. TSG restored the LPS induced mitochondrial dysfunction via activation of the mitochondrial biogenesis. ZnPP treatment markedly reversed the inhibitory effects of TSG on mitochondrial damage and oxidative stress in LPS stimulated macrophages. Taken together, these findings suggest that TSG enhances mitochondrial biogenesis and function mainly via activation the HO‐1. TSG can be developed as a potential drug for treatment of inflammatory diseases.
Grassmannian Constellation Based on Antipodal Points and Orthogonal Design and Its Simplified Detecting Algorithm
Authors: Peng Li , Hu Dacong , Zhang Lin , Qin Zhen
Published: April 2017

This study presents a framework of the unitary space time modulation (USTM) constellation based on antipodal points over Grassmannian manifold. The antipodal constellation enables an intrinsic simplified ML detecting algorithm. The algebraic orthogonal USTM constellation is also an antipodal constellation which, apart from being adaptive to the antipodal simplified ML detector, also has another simplified ML detector based on its self-indexing features, and the latter is simpler because of getting rid of the matrix operation. A searching orthogonal USTM constellation based on the grid search algorithm is obtained under the presented framework and its minimum Frobenius chordal distance and simulation performance are be superior to those of the algebraic orthogonal USTM constellation.
miR-155 Inhibits Mouse Osteoblast Differentiation by Suppressing SMAD5 Expression
Authors: Gu Yue , Ma Lianjun , Song Lei , Li Xiaoping , Chen Dong , Bai Xiaoxue
Published: April 2017

Osteogenesis from preosteoblasts is important for bone tissue engineering. MicroRNAs are a class of endogenous small RNA molecules that potentially modulate osteogenesis. In this study, we found that miR-155 expression was downregulated in a time-dependent manner in cells of the preosteoblast cell line MC3T3-E1 after osteogenic induction using bone morphogenetic protein 2 (BMP2). Transfection with miR-155 decreased alkaline phosphatase (ALP) activity, ALP expression, and the staining intensity of Alizarin Red in MC3T3-E1 cells treated with BMP2, whereas treatment with miR-155 inhibitor promoted BMP2-induced osteoblast differentiation. The luciferase assay confirmed that miR-155 can bind to the 3′ untranslated region of SMAD5 mRNA. miR-155 transfection significantly decreased the expression of SMAD5 protein and mRNA in MC3T3-E1 cells under control media and the p-SMAD5 protein level during osteogenesis. After transfecting cells with the SMAD5 overexpression plasmids, the inhibitory effect of miR-155 on osteogenesis was significantly attenuated. In conclusion, miR-155 inhibited osteoblast differentiation by downregulating the translation of SMAD5 in mouse preosteoblast cells. Inhibition of miR-155 promoted osteogenic potential and thus it can be used as a potential target in the treatment of bone defects.
Preparation and Photocatalytic Performance of Ti3C2/TiO2/CuO Ternary Nanocomposites
Authors: Lu Yang , Yao Meihuan , Zhou Aiguo , Hu Qianku , Wang Libo
Published: April 2017

Ti3C2/TiO2/CuO nanocomposites were synthesized via the decomposition of a mixture of Ti3C2 (a novel two-dimensional carbide) and cupric nitrate under an argon atmosphere. The morphology and structures of the obtained samples were characterized. X-ray diffraction and energy dispersive spectrometer analysis indicate that the sample is composed of Ti3C2, anatase-TiO2, and CuO. Scanning electron microscopy images show that CuO and TiO2 nanoparticles were evenly distributed on the surface of Ti3C2. The particles size increased with an increase in the cupric nitrate content. Photocatalytic degradation of methyl orange shows that the Ti3C2/TiO2/CuO nanocomposite has good photocatalytic degradation efficiency. A possible photocatalytic mechanism of the Ti3C2/TiO2/CuO nanocomposites was proposed. The data indicated that CuO and Ti3C2 effectively promote the separation of photoelectrons from vacancies.
Multiple Failure Modes Reliability Modeling and Analysis in Crack Growth Life Based on JC Method
Authors: Sun YuanTao , Liu Chao , Zhang Qing , Qin XianRong
Published: April 2017

The fatigue crack growth (FCG) phenomenon generally exists in large mechanical structures. Due to the influences of varied kinds of random factors, the safety evaluation of structure in FCG is under great uncertainty. In this paper, based on the reliability theory, the limit state equations of fracture failure and static strength failure were derived firstly, and the parameters in those equations were regarded as random variables that follow the normal distribution or log‐normal distribution. According to the limit state equations, the JC method (equivalent normalizing method) was used to calculate the reliability indexes under the different failure modes of structure in every stress cycle. Based on the reliability indexes and correlation of the two failure modes, the joint failure probability was obtained. In the end, a specific computation example was given, and the curve of joint failure probability in multiple failure modes was used for comparison with the result of single failure mode. The results indicated that the reliability analysis based on multiple failure modes was more reasonable, and the evaluation of reliability could be obtained in fatigue crack growth process.
Epidemic of Vitamin D Deficiency and Its Management: Awareness among Indian Medical Undergraduates
Authors: Lhamo Yangshen , Chugh Preeta Kaur , Gautam Sandhya R. , Tripathi C. D.
Published: April 2017

Vitamin D deficiency is prevalent across all age groups in epidemic proportions. The purpose of this study was to acquire a baseline assessment and create awareness among medical students regarding vitamin D. A cross-sectional, voluntary survey was conducted among undergraduate medical students. Data were collected using a questionnaire which assessed the level of knowledge students had with regard to where vitamin D comes from, what it does for health, how much is recommended, factors that affect its levels, and deficiency management. Majority of students were unaware that vitamin D deficiency has attained epidemic proportions. Though bone and skeletal disorders as a complication of vitamin D deficiency were known, a large number were unaware of systemic consequences (diabetes mellitus, cardiovascular diseases, and cancers). Only one-third of respondents were aware of duration and timing of sun exposure required for adequate serum vitamin D levels. However, we observed lack of awareness among students regarding the various biochemical forms, dose, and duration of vitamin D supplementation for treatment of nutritional deficiency. Our study highlighted a lack of knowledge about the importance of vitamin D, worldwide prevalence of vitamin D deficiency, and its management among medical students. Promoting vitamin D health awareness, if replicated across populations, could lead to positive health outcomes globally.
Simultaneous Determination of Preservatives in Dairy Products by HPLC and Chemometric Analysis
Authors: Zamani Mazdeh Fatemeh , Sasanfar Sima , Chalipour Anita , Pirhadi Elham , Yahyapour Ghazal , Mohammadi Armin , Rostami Akram , Amini Mohsen , Hajimahmoodi Mannan
Published: April 2017

Cheese and yogurt are two kinds of nutritious dairy products that are used worldwide. The major preservatives in dairy products are sodium benzoate, potassium sorbate, and natamycin. The maximum permitted levels for these additives in cheese and yogurt are established according to Iranian national standards. In this study, we developed a method to detect these preservatives in dairy products by reversed phase chromatography with UV detection in 220 nm, simultaneously. This method was performed on C18 column with ammonium acetate buffer (pH=5) and acetonitrile (73 : 27 v/v) as mobile phase. The method was carried out on 195 samples in 5 kinds of commercial cheeses and yogurts. The results demonstrated insufficient separation where limit of detection (LOD) and limit of quantitation (LOQ) ranged from 0.326 to 0.520 mg/kg and 0.989 to 1.575 mg/kg in benzoate and sorbate, respectively. The correlation coefficient of each calibration curve was mostly higher than 0.997. All samples contained sodium benzoate in various ranges. Natamycin and sorbate were detected in a remarkable amount of samples, while, according to Iranian national standard, only sorbate is permitted to be added in processed cheeses as a preservative. In order to control the quality of dairy products, determination of preservatives is necessary.
Evolution of Bounded Confidence Opinion in Social Networks
Authors: Xie Hui , Li Guangjian , Yan Yongjie , Shu Sihui
Published: April 2017

We investigate opinion dynamics as a stochastic process in social networks. We introduce the stubborn agent in order to determine the impact of network structure on the emergence of consensus. Depending on the fraction of undirected long-range connections, we observe fascinatingly rich dynamical behavior and transitions from disordered to ordered states. In general, we find that the stubborn agent promotes the emergence of consensus due to the so-called “group effect” that facilitates coalescence between separated network components. Agents are also behaviorally constrained Shannon information entropy in networks. However, since agents want to evolve their opinion with Brownian motion, which may in turn impede full consensus, sufficiently frequent long-range links are in such situations crucial for the network to converge into an absorbing phase. Our experimental findings indicate that, for a large range of control parameters, our model yields stable and fluctuating polarized states.
Preparation of a Leaf-Like BiVO4-Reduced Graphene Oxide Composite and Its Photocatalytic Activity
Authors: Xiong Shimin , Wu Tianhui , Fan Zihong , Zhao Deqiang , Du Mao , Xu Xuan
Published: April 2017

We prepared a unique leaf-like BiVO4-reduced graphene oxide (BiVO4-rGO) composite with prominent adsorption performance and photocatalytic ability by a single-step method. Multiple characterization results showed that the leaf-like BiVO4with average diameter of about 5 um was well dispersed on the reduced graphene oxide sheet, which enhanced the transportation of photogenerated electrons into BiVO4, thereby leading to efficient separation of photogenerated carriers in the coupled graphene-nanocomposite system. The characterization and experiment results also indicated that the outstanding adsorption ability of such composite was closely associated with the rough surface of the leaf-like BiVO4and doped rGO. The surface photocurrent spectroscopy and transient photocurrent density measurement results demonstrated that the doped rGO enhanced separation efficiency and transfer rate of photogenerated charges. As a result, the BiVO4-rGO exhibited higher photocatalytic capacity toward the degradation of rhodamine B dye under visible-light irradiation compared with pure BiVO4and P25.
Fuzzy Based Advanced Hybrid Intrusion Detection System to Detect Malicious Nodes in Wireless Sensor Networks
Authors: Singh Rupinder , Singh Jatinder , Singh Ravinder
Published: April 2017

In this paper, an Advanced Hybrid Intrusion Detection System (AHIDS) that automatically detects the WSNs attacks is proposed. AHIDS makes use of cluster-based architecture with enhanced LEACH protocol that intends to reduce the level of energy consumption by the sensor nodes. AHIDS uses anomaly detection and misuse detection based on fuzzy rule sets along with the Multilayer Perceptron Neural Network. The Feed Forward Neural Network along with the Backpropagation Neural Network are utilized to integrate the detection results and indicate the different types of attackers (i.e., Sybil attack, wormhole attack, and hello flood attack). For detection of Sybil attack, Advanced Sybil Attack Detection Algorithm is developed while the detection of wormhole attack is done by Wormhole Resistant Hybrid Technique. The detection of hello flood attack is done by using signal strength and distance. An experimental analysis is carried out in a set of nodes; 13.33% of the nodes are determined as misbehaving nodes, which classified attackers along with a detection rate of the true positive rate and false positive rate. Sybil attack is detected at a rate of 99,40%; hello flood attack has a detection rate of 98, 20%; and wormhole attack has a detection rate of 99, 20%.
Stevens-Johnson Syndrome following Failure of Genetic Screening prior to Carbamazepine Prescription
Authors: Nasir Suraya Ahmad , Tan Huann Lan , Tan Hui Jan , Hussaini Haizal Mohd , Ramli Roszalina
Published: April 2017

Failure to screen susceptible individuals for human leucocyte allele B∗1502 leads to the onset of Stevens-Johnson syndrome (SJS). We report a case of a 27-year-old Malay female who was treated with carbamazepine following the diagnosis of trigeminal neuralgia without a genetic screening. She was prescribed 150 mg of carbamazepine initially and the dose was increased to 300 mg following the initial dose. A sudden development of skin and mucous membrane ulcers was observed and this warranted immediate hospitalization. A diagnosis of SJS was made and she was treated immediately with intravenous corticosteroids. Genetic screening prior to carbamazepine prescription is essential especially in susceptible populations.
Characterization of Polymer Surfaces by the Use of Different Wetting Theories Regarding Acid-Base Properties
Authors: Kraus Eduard , Orf Lukas , Heilig Michael , Baudrit Benjamin , Starostina Irina , Stoyanov Oleg
Published: April 2017

The existing wetting methods for the determination of acid-base properties on solid surfaces are discussed. Striving for a better understanding of the adhesive polymer interactions in adhesively joined polymers, the methods of Berger and van Oss-Chaudhury-Good were found as the most suitable methods for the investigation of wetting on solid polymer surfaces. Methods of nonlinear systems by Della Volpe and Siboni were adapted and evaluated on plastic surfaces. In the context of these investigations various data of the surface free energy as well as its components have been identified for a number of polymer surfaces by application of spatial equation solutions.
A Robust PCR Protocol for HIV Drug Resistance Testing on Low-Level Viremia Samples
Authors: Gupta Shivani , Taylor Tracy , Patterson Aileen , Liang Binhua , Bullard Jared , Sandstrom Paul , Van Domselaar Gary , Ji Hezhao
Published: April 2017

The prevalence of drug resistance (DR) mutations in people with HIV-1 infection, particularly those with low-level viremia (LLV), supports the need to improve the sensitivity of amplification methods for HIV DR genotyping in order to optimize antiretroviral regimen and facilitate HIV-1 DR surveillance and relevant research. Here we report on a fully validated PCR-based protocol that achieves consistent amplification of the protease (PR) and reverse transcriptase (RT) regions of HIV-1 pol gene across many HIV-1 subtypes from LLV plasma samples. HIV-spiked plasma samples from the External Quality Assurance Program Oversight Laboratory (EQAPOL), covering various HIV-1 subtypes, as well as clinical specimens were used to optimize and validate the protocol. Our results demonstrate that this protocol has a broad HIV-1 subtype coverage and viral load span with high sensitivity and reproducibility. Moreover, the protocol is robust even when plasma sample volumes are limited, the HIV viral load is unknown, and/or the HIV subtype is undetermined. Thus, the protocol is applicable for the initial amplification of the HIV-1 PR and RT genes required for subsequent genotypic DR assays.
Inverse Analysis of UHPFRC Beams with a Notch to Evaluate Tensile Behavior
Authors: Lee Seong-Cheol , Kim Han-Byeol , Joh Changbin
Published: April 2017

Recently, ultra high performance fiber reinforced concrete (UHPFRC) has been developed to attain considerably increased compressive cracking strength and ductile tensile behavior with high tensile strength through adding straight steel fibers in concrete mixture. Although benefits with UHPFRC were investigated through experimental program, it is difficult to predict structural behavior of UHPFRC members since theoretical approaches are limited. In this paper, inverse analysis procedure has been proposed for a three-point bending test with notched UHPFRC beams so that tensile behavior of UHPFRC could be rationally evaluated. On the inverse analysis procedure, failure mode of the UHPFRC beam was simplified and the simplified diverse embedment model (SDEM) was employed. To verify the proposed inverse analysis procedure, UHPFRC beams with a notch were analyzed with the tensile behavior of UHPFRC evaluated through the inverse analysis procedure. The analytical predictions showed good agreement with the load-crack mouth opening displacement (CMOD) responses measured through the three-point bending test. Consequently, it can be concluded that UHPFRC tensile behavior can be rationally evaluated through the proposed inverse analysis procedure. The proposed inverse analysis procedure can be useful in relevant research areas such as development of advanced design approaches or computational methods for UHPFRC members.
In Vitro Evaluation of Manual Torque Values Applied to Implant-Abutment Complex by Different Clinicians and Abutment Screw Loosening
Authors: Dincer Kose Onur , Karataslı Burcin , Demircan Sabit , Kose Taha Emre , Cene Erhan , Aya Serhan Aydın , Erdem Mehmet Ali , Cankaya Abdulkadir Burak
Published: April 2017

Preload is applied to screws manually or using a torque wrench in dental implant systems, and the preload applied must be appropriate for the purpose. The aim of this study was to assess screw loosening and bending/torsional moments applied by clinicians of various specialties following application of manual tightening torque to combinations of implants and abutments. Ten-millimeter implants of 3.7 and 4.1 mm diameters and standard or solid abutments were used. Each group contained five implant-abutment combinations. The control and experimental groups comprised 20 and 160 specimens, respectively. Implants in the experimental group were tightened by dentists of different specialties. Torsional and bending moments during tightening were measured using a strain gauge. Control group and implants with preload values close to the ideal preload were subjected to a dynamic loading test at 150 N, 15 Hz, and 85,000 cycles. The implants that deformed in this test were examined using an optical microscope to assess deformities. Manual tightening did not yield the manufacturer-recommended preload values. Dynamic loading testing suggested early screw loosening/fracture in samples with insufficient preload.
Multiparameter Monitoring and Prevention of Fault-Slip Rock Burst
Authors: Hu Shan-chao , Tan Yun-liang , Ning Jian-guo , Guo Wei-Yao , Liu Xue-sheng
Published: April 2017

Fault-slip rock burst is one type of the tectonic rock burst during mining. A detailed understanding of the precursory information of fault-slip rock burst and implementation of monitoring and early warning systems, as well as pressure relief measures, are essential to safety production in deep mines. This paper first establishes a mechanical model of stick-slip instability in fault-slip rock bursts and then reveals the failure characteristics of the instability. Then, change rule of mining-induced stress and microseismic signals before the occurrence of fault-slip rock burst are proposed, and multiparameter integrated early warning methods including mining-induced stress and energy are established. Finally, pressure relief methods targeting large-diameter boreholes and coal seam infusion are presented in accordance with the occurrence mechanism of fault-slip rock burst. The research results have been successfully applied in working faces 2310 of the Suncun Coal Mine, and the safety of the mine has been enhanced. These research results improve the theory of fault-slip rock burst mechanisms and provide the basis for prediction and forecasting, as well as pressure relief, of fault-slip rock bursts.
Influence of Nanolime and Curing Period on Unconfined Compressive Strength of Soil
Authors: Govindasamy Panbarasi , Taha Mohd Raihan , Alsharef Jamal , Ramalingam Kowstubaa
Published: April 2017

This paper presents the improvement of the unconfined compressive strength (UCS) of soil by mixing different percentages of nanolime and 5% lime with soil. The UCS of treated soil increased significantly over curing time with increasing percentage of nanolime. The optimum results were reached at only 0.5% nanolime admixtures which were much higher than 5% lime admixture. This may be due to higher ability of nanolime to flocculate and agglomerate the soil particles compared with the lime. In addition, the lime could fill only the micropores while nanolime could fill the micro- and nanopores as well. The strength gain is inversely proportional to the remolded moisture content and curing period. However, when the content of nanolime used is larger than 0.5%, nanolime particles are not uniformly dispersed. Therefore, a weak area in the form of voids is created, consequently the homogeneous hydrated microstructure cannot be formed, and finally the strength will decrease.
A Novel Fusion Framework Based on Adaptive PCNN in NSCT Domain for Whole-Body PET and CT Images
Authors: Song Zhiying , Jiang Huiyan , Li Siqi
Published: April 2017

The PET and CT fusion images, combining the anatomical and functional information, have important clinical meaning. This paper proposes a novel fusion framework based on adaptive pulse-coupled neural networks (PCNNs) in nonsubsampled contourlet transform (NSCT) domain for fusing whole-body PET and CT images. Firstly, the gradient average of each pixel is chosen as the linking strength of PCNN model to implement self-adaptability. Secondly, to improve the fusion performance, the novel sum-modified Laplacian (NSML) and energy of edge (EOE) are extracted as the external inputs of the PCNN models for low- and high-pass subbands, respectively. Lastly, the rule of max region energy is adopted as the fusion rule and different energy templates are employed in the low- and high-pass subbands. The experimental results on whole-body PET and CT data (239 slices contained by each modality) show that the proposed framework outperforms the other six methods in terms of the seven commonly used fusion performance metrics.
Influence of Oral Appliances for Mandibular Advancement on Dentitions Using a Strain Gauge Analysis: A Pilot Study
Authors: Ueda Hiroshi , Matsumura Yu , Horihata Atsushi , Concepcion Cynthia , Iwai Koji , Tanimoto Kotaro
Published: April 2017

Introduction. This study aimed to evaluate the influence of oral appliances (OAs) on dentition using a strain gauge analysis.Materials/Methods. Eight volunteers, who were mild snorers, participated in this study. OAs were individually constructed, and advancement was defined as two-thirds of the maximum mandibular advancement. Strain gauges were mounted on the right first molar and central incisor of both the upper and lower arches. After OA use, two measurement sessions (short- and long-term) were performed.Results. Compressive strain on the labial surface was significantly larger than the stretching strain on the lingual surface on U1. On L1, the stretching strain on the labial surface was significantly larger than the compressive strain on the lingual surface. Comparing the upper and lower teeth, the stretching strain was significantly greater on L1 than on U1 in both test sessions. Moreover, the stretching strain was significantly larger on U6 than on L6.Conclusion. OA side effects, such as forcing on the incisors, might be repeated every night. In this way, permanent occlusal changes, such as labial tipping of L1, may occur, followed by lingual tipping of U1 and buccal and lingual movements of the U6 and L6, respectively.
Activation of AMPK by Buddleja officinalis Maxim. Flower Extract Contributes to Protecting Hepatocytes from Oxidative Stress
Authors: Jung Ji Yun , Lee Chul Won , Park Sang Mi , Jegal Kyung Hwan , Kim Jae Kwang , Park Chung A. , Cho Il Je , Jung Dae Hwa , An Won G. , Ku Sae Kwang , Zhao Rongjie , Kim Sang Chan
Published: April 2017

The Buddleja officinalis Maxim. flower is used in traditional Chinese and Korean medicine to treat inflammation, vascular diseases, headache, and stroke, as well as enhance liver function. This research investigated the effects of B. officinalis Maxim. flower extract (BFE) on hepatotoxicity. The cytoprotective effects and mechanism of BFE against severe mitochondrial dysfunction and H2O2 production in hepatotoxicity induced by coadministration of arachidonic acid (AA) and iron were observed in the HepG2 cell line. In addition, we performed blood biochemical, histopathological, and histomorphometric analyses of mice with carbon tetrachloride‐ (CCl4‐) induced acute liver damage. BFE inhibited the AA + iron‐mediated hepatotoxicity of HepG2 cells. Moreover, it inhibited mitochondrial dysfunction, H2O2 production, and glutathione depletion mediated by AA + iron in the same cells. Meanwhile, the cytoprotective effects of BFE against oxidative stress were associated with the activation of AMP‐activated protein kinase (AMPK). In particular, based on the histopathological observations, BFE (30 and 100 mg/kg) showed clear hepatoprotective effects against CCl4‐induced acute hepatic damage. Furthermore, it inhibited 4‐hydroxynonenal and nitrotyrosine immunoreactivity in hepatocytes. These results provide evidence that BFE has beneficial hepatoprotective effects against hepatic damage via the activation of AMPK pathway. Accordingly, BFE may have therapeutic potential for diverse liver disorders.
Rapid Biosynthesis of Silver Nanoparticles Based on Flocculation and Reduction of an Exopolysaccharide from Arthrobacter sp. B4: Its Antimicrobial Activity and Phytotoxicity
Authors: Yumei Li , Yamei Li , Qiang Li , Jie Bao
Published: April 2017

Silver nanoparticles (AgNPs) were rapidly synthesized using an exopolysaccharide from Arthrobacter sp. B4 (B4-EPS). The optimum condition for AgNPs synthesis was under the concentration of 5 g/L B4-EPS and 1 mM AgNO3 at 80°C between pH 7.0 and 8.0. The resulting AgNPs displayed a face-centred-cubic structure with the size range from 9 nm to 72 nm. Further analysis showed that flocculation and reduction of B4-EPS played a pivotal role in the formation of AgNPs. Furthermore, these nanoparticles exhibited great stability, excellent antimicrobial activity, and low phytotoxicity. The aforementioned data provide a feasible and efficient approach for green synthesis of AgNPs using microbial polysaccharides with flocculation and reduction activity, which will be promising in medical filed.
Strategies for Increasing Pancreatic Tumor Immunogenicity
Authors: Johnson Burles A. , Yarchoan Mark , Lee Valerie , Laheru Daniel A. , Jaffee Elizabeth M.
Published: April 2017

Immunotherapy has changed the standard of care for multiple deadly cancers, including lung, head and neck, gastric, and some colorectal cancers. However, single-agent immunotherapy has had little effect in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single-agent immunotherapies. In this review, we discuss differences between immunotherapy-sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor-infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are druggable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes. Clin Cancer Res; 23(7); 1656–69. ©2017 AACR.

See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
Current and Emerging Therapies in Metastatic Pancreatic Cancer
Authors: Manji Gulam Abbas , Olive Kenneth P. , Saenger Yvonne M. , Oberstein Paul
Published: April 2017

Targeted therapies and immunotherapy have changed the face of multiple solid malignancies, including metastatic melanoma and lung cancer, but no such therapies exist for pancreatic ductal adenocarcinoma (PDAC) despite the knowledge of key mutations and an increasing understanding of the tumor microenvironment. Until now, most clinical studies have not been biomarker driven in this highly immunosuppressive and heterogeneous cancer. Ongoing basic and translational studies are better classifying the disease in hopes of identifying critical pathways that distinguish the unique PDAC subtypes, which will lead to personalized therapies. In this review, we discuss the current treatment options for metastatic pancreatic cancer and highlight current ongoing clinical trials, which aim to target the stroma and the immune microenvironment either alone or in combination with standard chemotherapy. Identifying biomarkers and key resistance pathways and targeting these pathways in a personalized manner in combination with chemotherapy are likely to yield a more immediate and durable clinical benefit. Clin Cancer Res; 23(7); 1670–8. ©2017 AACR.

See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
Abstract A10: The impact of cancer-associated RAD51C mutations in homologous recombination
Authors: Sullivan Meghan R. , Prakash Rohit , Jasin Maria , Bernstein Kara A.
Published: April 2017

Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks (DSBs). Loss of function of key HR repair proteins have been linked to diseases characterized by genomic instability including cancers and Fanconi anemia. Regulation of RAD51 filaments is critical during HR repair and is mediated by several factors including the RAD51 paralogs, a group of proteins that share sequence homology with RAD51. The RAD51 paralog family consists of five proteins in humans, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. The RAD51 paralog, RAD51C, has recently become a key protein of interest as RAD51C mutations have been linked to familial breast and ovarian cancers. However, the specific functions of RAD51C have remained enigmatic as mouse and non-tumorigenic knockout models are inviable. Given these limitations, we have identified RAD51C point mutations from breast and ovarian cancer patients to study the phenotypes of these RAD51C mutants and how they impair homologous recombination. We have found that RAD51C mutations can disrupt interactions with RAD51 paralog binding partners, RAD51B and XRCC3, required for RAD51C stability. Through yeast-two/three-hybrid and co-immunoprecipitation experiments, we isolated RAD51C mutations that disrupt interactions within RAD51 paralog complexes. These complexes have important roles in the repair of classical DSBs induced by ionizing radiation or chemotherapeutic reagents as well as in replication fork protection such as after replication stress induced by hydroxyurea. Using RAD51C mutants to complement a conditional knockout model, we investigated how the roles of RAD51C were impacted by point mutations in response to these diverse substrates to ultimately understand how tumors with RAD51C mutations can be best targeted for treatment.

Citation Format: Meghan R. Sullivan, Rohit Prakash, Maria Jasin, Kara A. Bernstein. The impact of cancer-associated RAD51C mutations in homologous recombination [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A10.
Abstract A26: High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway
Authors: Hakkert Anne , Ebus Marli E. , Versteeg Rogier , Huib Caron N. , Koster Jan , Molenaar Jan J.
Published: April 2017

Background: Somatic mutations can be grouped into 96 tri-nucleotide patterns, termed mutational signatures. These signatures can provide insights into underlying processes that fuel the evolution of tumor cells, and may expose therapeutic intervention avenues. Here we investigated the mutational signature of 84 whole genome sequenced neuroblastoma cases.

Results: Mutational signature analysis revealed an extreme bias towards Cytosine to Adenine (CtoA) mutations in a majority of neuroblastoma tumors. This seems to be a unique feature of neuroblastoma. CtoA mutations are primarily found in high stage tumors and are therefore associated with a poor prognosis. Oxidative stress is known to be a source for such mutations, which can accumulate due to defects in the 8-Oxo-Guanine repair pathway genes OGG1, MUTYH and MTH1. We could show a strong correlation between CtoA mutations and chromosomal loss of MTH1, OGG1 and MUTYH. Besides copy number losses, sequencing also revealed a tumor with a homozygous mutation in OGG1 and this tumor showed a very strong bias towards CtoA mutations. Modified alkaline comet assays were performed for quantification of 8-Oxo-Guanine content present in the DNA of neuroblastoma cell lines. These comet assays showed that neuroblastoma cell lines with loss of either OGG1 or MUTYH, had higher 8-Oxo-Guanine content than cell lines without these losses. 8-Oxo-Guanine content is correlated with CtoA mutation frequency in short term cultured neuroblastoma organoids. Overexpression of OGG1 or MUTYH in neuroblastoma cell lines with losses of OGG1 or MUTYH respectively leads to rescue of the phenotype and a decrease in the amount of 8-Oxo-Guanine in the DNA. We are currently performing a compound screen to test the efficacy of 352 compounds functioning in the DNA damage repair in cell lines with and without MUTYH expression, and were testing compounds that further interfere in this specific branch of DNA damage repair including the newly developed MTH1 inhibitors.

Conclusion: We identified a subset of neuroblastoma tumors with a high CtoA mutation frequency, which correlates with losses of glycosylases involved in the repair of CtoA mutations. 8-Oxo-Guanine levels are elevated in cell lines with loss of OGG1 or MUTYH, which can be rescued by overexpression of OGG1 or MUTYH respectively.

Citation Format: Anne Hakkert, Marli E. Ebus, Rogier Versteeg, Caron N. Huib, Jan Koster, Jan J. Molenaar. High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A26.
Abstract A44: The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer
Authors: Timoteo Ana Rafaela de Souza , Souza Jorge Estefano Santana de , Lajus Tirzah Braz Petta
Published: April 2017

Hereditary breast cancer corresponds to 10-15% of all diagnosed cases of breast cancer in the world. The majority germline mutations are identified in BRCA1/2 genes, however the application of multigene panels has increased the number of pathogenic variations detected in DNA repair genes. According to the current version of NCCN Guideline, mutations in BRCA1/2, TP53 and PTEN confers high risk to develop breast cancer, and mutations in CDH1, CHEK2, PALB2, ATM and BRIP can increases over than 20% this risk. We analyzed 157 individuals from Northeastern region of Brazil with personal and/or familial breast cancer history. Genomic DNA was isolated from peripheral blood through saline-based extraction and samples were analyzed using next-generation sequencing (NGS). We identified 15 pathogenic variants and 4 VUS (Variants of Uncertain Significance) in 27 individuals (27/157; 17%), in which three are asymptomatic. Six novel variants in 4 genes were identified: BRCA1_c.3409A>G; BRCA2_c.5800C>T; BRCA2_c.5228G>A; BRCA2_c.5305delG; ATM_c.634delT and ATR_c.3043C>T. Sixty-eight percent (13/19; 68%) of variants was detected in BRCA1/2 genes, while 32% (6/19) were identified in moderate risk genes ATM (2/19); ATR (1/19); CDH1 (1/19); MLH1 (1/19) and MSH6 (1/19). The individuals were separated in two groups for comparative analysis: high-risk genes and moderate risk genes. Among three asymptomatic individuals, two present variants in moderate risk genes ATM and MLH1. Among breast cancer individuals, eighteen patients (18/24; 75%) presents mutations in high-risk genes, while six (6/24; 25%) harbors mutations in moderate risk genes. Both groups had a high incidence of early-onset breast cancer, 83%. The group of individuals harboring variants in high-risk genes presented a greater occurrence of high-grade tumors (83% vs. 67%, P= 0.0090). In the group of individuals harboring mutation in moderate risk genes, tumors presented a more aggressive phenotype with bilateral cancer (33% vs. 11%, P= 0.0002), occurrence of metastasis (33% vs. 5.6%, P<0.0001) and incidence of deaths (33% vs. 5.6%, P<0.0001). Altogether, 1/3 of variants were identified in moderate risk genes in patients presenting a more aggressive phenotype. These results reinforce the importance of applying multigene analysis in individuals at-risk for breast cancer, especially in a heterogeneous population as Brazilian.

Citation Format: Ana Rafaela de Souza Timoteo, Jorge Estefano Santana de Souza, Tirzah Braz Petta Lajus. The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A44.
Abstract B24: Genomic prediction of response to PARP inhibition in breast cancer
Authors: Hassan Saima , Esch Amanda , Heiser Laura M. , Gray Joe W.
Published: April 2017

Efficacy of PARP inhibition has been demonstrated in several cancer types including prostate, ovarian, and breast. Most recently, anti-PARP therapy was shown to be effective in combination with carboplatin in triple-negative breast cancer patients in the neoadjuvant setting. However, it is not yet well known which subset of triple-negative breast cancers will benefit from single-agent anti-PARP therapy. We determined the therapeutic efficacy of three PARP inhibitors: veliparib, olaparib, and BMN 673, in a panel of eight triple-negative breast cancer cell lines. We used a 10-day in-vitro assay, after which we fixed the cells and determined 53BP1 expression using immunofluorescence and high-content imaging. We used cell counts to derive IC50 values and enumerated 53BP1 foci per cell to determine EC50 values. We used pre-treatment whole-transcriptome data to identify genes associated with 53BP1 response using gene set enrichment and pathway enrichment analysis. We determined the prevalence of these genes in a dataset of triple-negative breast cancer patients, and performed survival analysis. We found PARP inhibition to be effective in both BRCA-mutant and BRCA wild-type breast cancer cell lines. BMN 673 was the most potent PARP inhibitor, with the lowest concentrations required for DNA damage (measured by 53BP1 expression) and cell kill (measured by cell count), followed by olaparib, and then veliparib. We found a strong correlation between the IC50 values for cell count and the EC50 values for 53BP1 response. We identified a gene set associated with 53BP1 response, which was involved with three major pathways: DNA repair, cell cycle, and programmed cell death. These genes were found to be downregulated in triple-negative breast cancer patients. Patients with aberrations in these genes demonstrated poorer overall survival (P = 0.03). In conclusion, we identified a gene set involved with DNA repair, cell-cycle, and programmed cell death, which was associated with poor outcomes in triple-negative breast cancer patients that could potentially benefit from anti-PARP therapy.

Citation Format: Saima Hassan, Amanda Esch, Laura M. Heiser, Joe W. Gray. Genomic prediction of response to PARP inhibition in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B24.
Abstract IA11: Signatures of mutational processes in human cancer
Authors: Alexandrov Ludmil B.
Published: April 2017

All cancers are caused by somatic mutations. These mutations may be the consequence of the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA, or defective DNA repair. In some cancer types, a substantial proportion of somatic mutations are known to be generated by exogenous arcinogens, for example, tobacco smoking in lung cancers and ultraviolet light in skin cancers, or by abnormalities of DNA maintenance, for example, defective DNA mismatch repair in some colorectal cancers.

Each biological process causing mutations leaves a characteristic imprint on the genome of a cancer cell, termed, mutational signature. In this talk, I will present mutational signatures analyses encompassing 12,023 cancer genomes across 40 distinct types of human cancer revealing more than 30 different signatures of mutational processes. Some signatures are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer etiology, prevention and therapy.

Citation Format: Ludmil B. Alexandrov. Signatures of mutational processes in human cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA11.
Abstract IA14: Mechanisms of the ATR-dependent replication stress response
Authors: Cortez David
Published: April 2017

Replication stress can be caused by DNA damage, difficult to replicate DNA sequences, collisions between replication and transcriptional machineries, and aberrations in the replication timing or other regulatory mechanisms. Cancer cells often have elevated levels of replication stress driven by oncogenes. Replication stress response pathways are important in these contexts to allow cells to complete replication, maintain genome stability, and remain viable. Drugs that increase the replication stress burden or inactivate components of the replication stress response pathway can be useful as cancer therapeutics. For example, inhibitors of the replication checkpoint kinase ATR are currently being tested in clinical trials. To better understand how replication stress response pathways operate, we have taken both genetic and proteomic approaches. These approaches include purifying active and stressed replication fork proteomes using isolation of proteins on nascent DNA (iPOND). iPOND can monitor changes in the replication fork proteome and when combined with mass spectrometry provides an unbiased analysis. These approaches have allowed us characterize the consequences of replication stress and functions of ATR. For example, we found that ATR does not regulate the stability of the replisome itself in response to stress, but it does direct the action of a number of fork remodeling enzymes including SMARCAL1 that act to protect and repair damaged forks. In addition, iPOND identified new replication stress response proteins including ETAA1—a new regulator of the ATR checkpoint kinase. I will present our latest data on the replication stress response emphasizing the results from iPOND proteomic analyses.

Citation Format: David Cortez. Mechanisms of the ATR-dependent replication stress response [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA14.