bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring performance of middleware technologies for medical systems
Authors: Rubio-Conde Paloma , Villarán-Molina Diego , García-Valls Marisol
Published: April 2017

After decades of design, development and usage of distributed application technologies, there are numerous communication middleware architectures and implementations in the market that have reached a considerable maturity level. A large number of them are open source initiatives that have shown efficiency and good performance in a broad range of domains, from banking to gaming. These are low cost solutions, easily programmable and of high interest to be explored in areas such as cyber-physical medical systems that have special requirements for safety, availability, communication latency, real-time operation, and fault tolerance. This paper analyzes the suitability of two open source communication middleware technologies, Ice (Internet Communication Engine) and AMQP (Advanced Message Queuing Protocol), as software elements suitable for developing audio transmission and reception systems for low cost medical applications. The paper simulates an audio application with both technologies, made of a server (nurse central) that receives and processes audio media from several clients (patients); communication can be triggered concurrent from multiple patients and in both directions. Stress tests with high load conditions are simulated in the experiments to show the behavior of both technologies mainly with respect to their stability and overhead.
The Relaxed Gradient Based Iterative Algorithm for the Symmetric (Skew Symmetric) Solution of the Sylvester Equation AX + XB = C
Authors: Zhang Xiaodan , Sheng Xingping
Published: April 2017

In this paper, we present two different relaxed gradient based iterative (RGI) algorithms for solving the symmetric and skew symmetric solution of the Sylvester matrix equation AX + XB = C. By using these two iterative methods, it is proved that the iterative solution converges to its true symmetric (skew symmetric) solution under some appropriate assumptions when any initial symmetric (skew symmetric) matrix X0 is taken. Finally, two numerical examples are given to illustrate that the introduced iterative algorithms are more efficient.
The Association of Serum Thrombomodulin with Endothelial Injuring Factors in Abdominal Aortic Aneurysm
Authors: Budzyń Magdalena , Gryszczyńska Bogna , Majewski Wacław , Krasiński Zbigniew , Kasprzak Magdalena Paulina , Formanowicz Dorota , Strzyżewski Krzysztof Wojciech , Iskra Maria
Published: April 2017

Background.The aim of the present study was to evaluate the concentration of serum thrombomodulin (sTM) in the AAA patients and to examine its correlation with various factors which may potentially participate in the endothelial injury.Materials and Methods.Forty-one patients with AAA were involved and divided into subgroups based on different criteria. Concentration of sTM was measured using enzyme-linked-immunosorbent assay (ELISA). The results were compared with those obtained in 30 healthy age- and sex-matched volunteers.Results.The higher concentration of sTM was observed in AAA patients compared with those in controls volunteers [2.37 (1.97–2.82) ng/mL versus 3.93 (2.43–9.20) ng/mL,P< 0.001]. An elevated sTM associated significantly with increased triglycerides (TAG) [P= 0.022], cholesterol [P= 0.029], hsCRP [P= 0.031], and advanced glycation end products (AGEs) [P= 0.033].Conclusions.The elevation of serum sTM level suggests that endothelial damage occurs in AAA pathogenesis. The correlations observed indicate that lipids abnormalities, inflammation, and oxidative stress may be involved in this destructive process.
Melioidosis with Portal Vein Thrombosis
Authors: Direksunthorn Thanyaporn
Published: April 2017

Melioidosis, caused by Burkholderia pseudomallei, is a common infectious disease in tropical regions. The author reports a case of melioidosis with a rare manifestation of portal vein thrombosis and cavernous transformation of the portal vein. Melioidosis should be considered a differential diagnosis in patients with underlying risk factors who present with multiple liver abscesses; moreover, portal vein thrombosis can be a potential complication. Computed tomography is the modality of choice to demonstrate venous thrombosis in various organs.
Attenuation by a Human Body and Trees as well as Material Penetration Loss in 26 and 39 GHz Millimeter Wave Bands
Authors: Wang Qi , Zhao Xiongwen , Li Shu , Wang Mengjun , Sun Shaohui , Hong Wei
Published: April 2017

This paper investigates the attenuation by a human body and trees as well as material penetration loss at 26 and 39 GHz by measurements and theoretical modeling work. The measurements were carried out at a large restaurant and a university campus by using a time domain channel sounder. Meanwhile, the knife-edge (KE) model and one-cylinder and two-cylinder models based on uniform theory of diffraction (UTD) are applied to model the shape of a human body and predict its attenuation in theory. The ITU (International Telecommunication Union) and its modified models are used to predict the attenuation by trees. The results show that the upper bound of the KE model is better to predict the attenuation by a human body compared with UTD one-cylinder and two-cylinder models at both 26 and 39 GHz. ITU model overestimates the attenuation by willow trees, and a modified attenuation model by trees is proposed based on our measurements at 26 GHz. Penetration loss for materials such as wood and glass with different types and thicknesses is measured as well. The measurement and modeling results in this paper are significant and necessary for simulation and planning of fifth-generation (5G) mm-wave radio systems in ITU recommended frequency bands at 26 and 39 GHz.
U-Statistic for Multivariate Stable Distributions
Authors: Teimouri Mahdi , Rezakhah Saeid , Mohammadpour Adel
Published: April 2017

A U-statistic for the tail index of a multivariate stable random vector is given as an extension of the univariate case introduced by Fan (2006). Asymptotic normality and consistency of the proposed U-statistic for the tail index are proved theoretically. The proposed estimator is used to estimate the spectral measure. The performance of both introduced tail index and spectral measure estimators is compared with the known estimators by comprehensive simulations and real datasets.
A Meta-Analysis of the Association between DNMT1 Polymorphisms and Cancer Risk
Authors: Li Hao , Liu Jing-wei , Sun Li-ping , Yuan Yuan
Published: April 2017

Previous studies have examined the associations of DNA methyltransferase 1 (DNMT1) polymorphisms, including single nucleotide polymorphisms rs16999593 (T/C), rs2228611 (G/A), and rs2228612 (A/G), with cancer risk. However, the results are inconclusive. The aim of this meta-analysis is to elucidate the associations between DNMT1 polymorphisms and cancer susceptibility. The PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure databases were searched systematically to identify potentially eligible reports. Odd ratios and 95% confidence intervals were used to evaluate the strength of association between three DNMT1 polymorphisms and cancer risk. A total of 16 studies were finally included in the meta-analysis, namely, nine studies of 3378 cases and 4244 controls for rs16999593, 11 studies of 3643 cases and 3866 controls for rs2228611, and three studies of 1343 cases and 1309 controls for rs2228612. The DNMT1 rs2228612 (A/G) polymorphism was significantly related to cancer risk in the recessive model. The meta-analysis also suggested that DNMT1 rs16999593 (T/C) may be associated with gastric cancer, while rs2228611 (G/A) may be associated with breast cancer. In future research, large-scale and well-designed studies are required to verify these findings.
Dihydropyridine Derivatives as Cell Growth Modulators In Vitro
Authors: Bruvere Imanta , Bisenieks Egils , Poikans Janis , Uldrikis Janis , Plotniece Aiva , Pajuste Karlis , Rucins Martins , Vigante Brigita , Kalme Zenta , Gosteva Marina , Domracheva Ilona , Velena Astrida , Vukovic Tea , Milkovic Lidija , Duburs Gunars , Zarkovic Neven
Published: April 2017

The effects of eleven 1,4‐dihydropyridine derivatives (DHPs) used alone or together with prooxidant anticancer drug doxorubicin were examined on two cancer (HOS, HeLa) and two nonmalignant cell lines (HMEC, L929). Their effects on the cell growth (3H‐thymidine incorporation) were compared with their antiradical activities (DPPH assay), using well‐known DHP antioxidant diludine as a reference. Thus, tested DHPs belong to three groups: (1) antioxidant diludine; (2) derivatives with pyridinium moieties at position 4 of the 1,4‐DHP ring; (3) DHPs containing cationic methylene onium (pyridinium, trialkylammonium) moieties at positions 2 and 6 of the 1,4‐DHP ring. Diludine and DHPs of group 3 exerted antiradical activities, unlike compounds of group 2. However, novel DHPs had cell type and concentration dependent effects on 3H‐thymidine incorporation, while diludine did not. Hence, IB‐32 (group 2) suppressed the growth of HOS and HeLa, enhancing growth of L929 cells, while K‐2‐11 (group 3) enhanced growth of every cell line tested, even in the presence of doxorubicin. Therefore, growth regulating and antiradical activity principles of novel DHPs should be further studied to find if DHPs of group 2 could selectively suppress cancer growth and if those of group 3 promote wound healing.
Vitamin D and Parathyroid Hormone Status in Female Garment Workers: A Case-Control Study in Bangladesh
Authors: Mahmood Shakil , Rahman Matiur , Biswas Subrata Kumar , Saqueeb Shaikh Nazmus , Zaman Shiblee , Manirujjaman M. , Perveen Rasheda , Ali Nurshad
Published: April 2017

Despite the abundant sunlight, vitamin D deficiency is prevalent in South Asian countries including Bangladesh. Information on vitamin D level is insufficient in adults particularly in female garment workers in Bangladesh. This study was designed to evaluate the status of vitamin D, parathormone (PTH), calcium, and alkaline phosphatase (ALP) among the female garment workers in Bangladesh. Blood samples were collected from female garment workers (n=40, case group) and general female workers (n=40, control group) in Dhaka. Serum vitamin D, PTH, calcium, and ALP were measured by chemiluminescence microparticle immunoassay. The mean level of vitamin D was significantly (p<0.001) lower in case (14.2±2.6 ng/mL) than in the control (22.4±2.4 ng/mL) group. No significant difference was found at mean of PTH and calcium between case (33.9±17.2 pg/mL;9.1±0.6 mg/dL, resp.) and control (35.9±16.3 pg/mL;9.3±0.6 mg/dL, resp.) group. The mean ALP in case (117.2±14.4 U/L) group was significantly (p<0.001) higher than the control group (80.5±30.6 U/L). Overall, PTH level did not show significant correlation with vitamin D. However, calcium and ALP levels showed a significant positive (p<0.05) and negative (p<0.001) correlation with vitamin D, respectively. This study indicates a high prevalence of vitamin D deficiency in the female garment workers in Bangladesh.
Three-Input Single-Output Voltage-Mode Multifunction Filter with Electronic Controllability Based on Single Commercially Available IC
Authors: Klungtong Supachai , Thanapatay Dusit , Jaikla Winai
Published: April 2017

This paper presents a second-order voltage-mode filter with three inputs and single-output voltage using single commercially available IC, one resistor, and two capacitors. The used commercially available IC, called LT1228, is manufactured by Linear Technology Corporation. The proposed filter is based on parallel RLC circuit. The filter provides five output filter responses, namely, band-pass (BP), band-reject (BR), low-pass (LP), high-pass (HP), and all-pass (AP) functions. The selection of each filter response can be done without the requirement of active and passive component matching condition. Furthermore, the natural frequency and quality factor are electronically controlled. Besides, the nonideal case is also investigated. The output voltage node exhibits low impedance. The experimental results can validate the theoretical analyses.
Stable Isotope Ratio and Elemental Profile Combined with Support Vector Machine for Provenance Discrimination of Oolong Tea (Wuyi-Rock Tea)
Authors: Lou Yun-xiao , Fu Xian-shu , Yu Xiao-ping , Ye Zi-hong , Cui Hai-feng , Zhang Ya-fen
Published: April 2017

This paper focused on an effective method to discriminate the geographical origin of Wuyi-Rock tea by the stable isotope ratio (SIR) and metallic element profiling (MEP) combined with support vector machine (SVM) analysis. Wuyi-Rock tea (n=99) collected from nine producing areas and non-Wuyi-Rock tea (n=33) from eleven nonproducing areas were analysed for SIR and MEP by established methods. The SVM model based on coupled data produced the best prediction accuracy (0.9773). This prediction shows that instrumental methods combined with a classification model can provide an effective and stable tool for provenance discrimination. Moreover, every feature variable in stable isotope and metallic element data was ranked by its contribution to the model. The results show thatδ2H,δ18O, Cs, Cu, Ca, and Rb contents are significant indications for provenance discrimination and not all of the metallic elements improve the prediction accuracy of the SVM model.
Quantum Self-Frictional Relativistic Nucleoseed Spinor-Type Tensor Field Theory of Nature
Authors: Guseinov I. I.
Published: April 2017

For study of quantum self-frictional (SF) relativistic nucleoseed spinor-type tensor (NSST) field theory of nature (SF-NSST atomic-molecular-nuclear and cosmic-universe systems) we use the complete orthogonal basis sets of22s+1-component column-matrices type SFΨnljmjδ⁎s-relativistic NSST orbitals (Ψδ⁎s-RNSSTO) and SFXnljmjs-relativistic Slater NSST orbitals (Xs-RSNSSTO) through theψnlmlδ⁎-nonrelativistic scalar orbitals (ψδ⁎-NSO) andχnlml-nonrelativistic Slater type orbitals (χ-NSTO), respectively. Hereδ⁎=pl⁎orδ⁎=α⁎andpl⁎=2l+2-α⁎,  α⁎are the integer(α⁎=α, -∞<α≤2) or noninteger(α⁎≠α, -∞<α⁎<3) SF quantum numbers, wheres=0,1/2,1,3/2,2,…. We notice that the nonrelativisticψδ⁎-NSO andχ-NSTO orbitals themselves are obtained from the relativisticΨδ⁎s-RNSSTO andXs-RSNSSTO functions fors=0, respectively. The column-matrices-type SFY1jmjls-RNSST harmonics (Y1ls-RNSSTH) andY2jmjls-modified NSSTH (Y2ls-MNSSTH) functions for arbitrary spinsintroduced by the author in the previous papers are also used. The one- and two-center one-range addition theorems forψδ⁎-NSO and nonintegern  χ-NSTO orbitals are presented. The quantum SF relativistic nonperturbative theory forVnljmjδ⁎-RNSST potentials (Vδ⁎-RNSSTP) and their derivatives is also suggested. To study the transportations of mass and momentum in nature the quantum SF relativistic NSST gravitational photon (gph) withs=1is introduced.
TiO2 (Nano)Particles Extracted from Sugar-Coated Confectionery
Authors: Lorenzetti Martina , Drame Anja , Šturm Sašo , Novak Saša
Published: April 2017

As the debate about TiO2 food additive safety is still open, the present study focuses on the extraction and characterisation of TiO2 (nano)particles added as a whitening agent to confectionary products, that is, chewing gum pellets. The aim was to (1) determine the colloidal properties of suspensions mutually containing TiO2 and all other chewing gum ingredients in biologically relevant media (preingestion conditions); (2) characterise the TiO2 (nano)particles extracted from the chewing gum coating (after ingestion); and (3) verify their potential photocatalysis. The particle size distribution, in agreement with the zeta potential results, indicated that a small but significant portion of the particle population retained mean dimensions close to the nanosize range, even in conditions of moderate stability, and in presence of all other ingredients. The dispersibility was enhanced by proteins (i.e., albumin), which acted as surfactants and reduced particle size. The particle extraction methods involved conventional techniques and no harmful chemicals. The presence of TiO2 particles embedded in the sugar-based coating was confirmed, including 17–30% fraction in the nanorange (<100 nm). The decomposition of organics under UV irradiation proved the photocatalytic activity of the extracted (nano)particles. Surprisingly, photocatalysis occurred even in presence of an amorphous SiO2 layer surrounding the TiO2 particles.
iBGP: A Bipartite Graph Propagation Approach for Mobile Advertising Fraud Detection
Authors: Hu Jinlong , Liang Junjie , Dong Shoubin
Published: April 2017

Online mobile advertising plays a vital financial role in supporting free mobile apps, but detecting malicious apps publishers who generate fraudulent actions on the advertisements hosted on their apps is difficult, since fraudulent traffic often mimics behaviors of legitimate users and evolves rapidly. In this paper, we propose a novel bipartite graph-based propagation approach, iBGP, for mobile apps advertising fraud detection in large advertising system. We exploit the characteristics of mobile advertising user’s behavior and identify two persistent patterns: power law distribution and pertinence and propose an automatic initial score learning algorithm to formulate both concepts to learn the initial scores of non-seed nodes. We propose a weighted graph propagation algorithm to propagate the scores of all nodes in the user-app bipartite graphs until convergence. To extend our approach for large-scale settings, we decompose the objective function of the initial score learning model into separate one-dimensional problems and parallelize the whole approach on an Apache Spark cluster. iBGP was applied on a large synthetic dataset and a large real-world mobile advertising dataset; experiment results demonstrate that iBGP significantly outperforms other popular graph-based propagation methods.
Unintended Sunburn: A Potential Target for Sun Protection Messages
Authors: McLeod Geraldine F. H. , Reeder Anthony I. , Gray Andrew R. , McGee Rob
Published: April 2017

New Zealand (NZ) has the highest melanoma incidence rate in the world. Primary prevention efforts focus on reducing sunburn incidence and increasing sun protective practices in the population. However, sunburn from excessive ultraviolet radiation (UVR) remains common. To reduce sunburn incidence, it is important to examine those individuals who experience unintended sunburn. This study aims to use data from the NZ Triennial Sun Protection Survey to describe respondents who were not intending to tan but were sunburnt after outdoor UVR exposure. Information on sociodemographics, concurrent weather conditions, sun protection attitudes and knowledge, and outdoor behaviour was also collected. The results showed 13.5% of respondents’ experienced unintended sunburn during the survey weekend but had not attempted to obtain a tan that summer. Respondents who reported unintended sunburn were more likely than others to have been near water and in unshaded areas, used sunscreen, had higher SunSmart knowledge scores, had lower positive attitudes towards tanning, and were outdoors for a longer duration with less body coverage. As sunburn was unintended these respondents’ outdoor sun protective behaviours may be amenable to change. Future public health initiatives should focus on increasing sun protection (clothing and shade) and reducing potential barriers to sun protection.
The Complexity of Pain Management in Children Affected by Mucopolysaccharidoses
Authors: Congedi Sabrina , Di Pede Chiara , Scarpa Maurizio , Rampazzo Angelica , Benini Franca
Published: April 2017

Mucopolysaccharidoses (MPSs) are a group of rare, genetic lysosomal storage disorders. They are caused by deficiencies of the lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Pain is a common feature in mucopolysaccharidoses. However, the pathophysiology of pain in this group of diseases is still unclear and genesis of pain is multifactorial. Currently, poor data about pain management in these patients are available. Here, we present our clinical experience in complex pain management in three children with MPS.
Hematochezia: An Uncommon Presentation of Colonic Tuberculosis
Authors: Ayoub Fares , Khullar Vikas , Powers Harry , Pham Angela , Islam Shehla , Suman Amitabh
Published: April 2017

Abdominal tuberculosis (TB) is an uncommon entity in the United States. Colonic TB is reported in 2-3% of patients with abdominal TB. It is frequently misdiagnosed as Crohn’s disease or carcinoma of the colon due to their shared clinical, radiographic, and endoscopic presentations. We present a case of a 72-year-old male with colonic tuberculosis presenting as hematochezia. Our patient presented with shortness of breath and weight loss. Chest X-ray demonstrated ill-defined bilateral parenchymal opacities in the perihilar, mid, and lower lung zones. The patient was diagnosed and treated for community acquired pneumonia, with no improvement. Hematochezia complicated by symptomatic hypotension developed later in the course of admission. Colonoscopy revealed multiple ulcers at the anus and transverse and ascending colon as well as the cecum with stigmata of bleeding. Biopsy of a sigmoid ulcer was consistent with colonic tuberculosis. Antitubercular therapy was initiated, but the patient passed away secondary to multiorgan failure 29 days into admission.
Ischiospinal Dysostosis in a Child with Pierre-Robin Syndrome
Authors: Almasri Mahmoud , Kishta Waleed , Abduljabbar Fahad H. , Arlet Vincent , Saran Neil , Oullet Jean
Published: April 2017

Ischiospinal Dysostosis (ISD) is a complex and very rare medical entity. It is associated with kyphoscoliosis, dysplasia or aplasia of the ischial rami, segmental anomalies of the bony vertebrae, and peculiar facial morphologies. In this case report, we present a child with Ischiospinal Dysostosis and Pierre-Robin Syndrome. This case report is unique as we followed the patient for 13 years in which he had multiple spinal procedures to treat his kyphoscoliosis. In this paper, we elucidated the number of case reports with documented follow-up regarding spinal cord injury or other complications of ISD and its management.
Dynamic Modal Correlation of an Automotive Rear Subframe, with Particular Reference to the Modelling of Welded Joints
Authors: Rotondella Vincenzo , Merulla Andrea , Baldini Andrea , Mantovani Sara
Published: April 2017

This paper presents a comparison between the experimental investigation and the Finite Element (FE) modal analysis of an automotive rear subframe. A modal correlation between the experimental data and the forecasts is performed. The present numerical model constitutes a predictive methodology able to forecast the experimental dynamic behaviour of the structure. The actual structure is excited with impact hammers and the modal response of the subframe is collected and evaluated by the PolyMAX algorithm. Both the FE model and the structural performance of the subframe are defined according to the Ferrari S.p.A. internal regulations. In addition, a novel modelling technique for welded joints is proposed that represents an extension of ACM2 approach, formulated for spot weld joints in dynamic analysis. Therefore, the Modal Assurance Criterion (MAC) is considered the optimal comparison index for the numerical-experimental correlation. In conclusion, a good numerical-experimental agreement from 50 Hz up to 500 Hz has been achieved by monitoring various dynamic parameters such as the natural frequencies, the mode shapes, and frequency response functions (FRFs) of the structure that represent a validation of this FE model for structural dynamic applications.
Enc-DNS-HTTP: Utilising DNS Infrastructure to Secure Web Browsing
Authors: Hussain Mohammed Abdulridha , Jin Hai , Hussien Zaid Alaa , Abduljabbar Zaid Ameen , Abbdal Salah H. , Ibrahim Ayad
Published: April 2017

Online information security is a major concern for both users and companies, since data transferred via the Internet is becoming increasingly sensitive. The World Wide Web uses Hypertext Transfer Protocol (HTTP) to transfer information and Secure Sockets Layer (SSL) to secure the connection between clients and servers. However, Hypertext Transfer Protocol Secure (HTTPS) is vulnerable to attacks that threaten the privacy of information sent between clients and servers. In this paper, we propose Enc-DNS-HTTP for securing client requests, protecting server responses, and withstanding HTTPS attacks. Enc-DNS-HTTP is based on the distribution of a web server public key, which is transferred via a secure communication between client and a Domain Name System (DNS) server. This key is used to encrypt client-server communication. The scheme is implemented in the C programming language and tested on a Linux platform. In comparison with Apache HTTPS, this scheme is shown to have more effective resistance to attacks and improved performance since it does not involve a high number of time-consuming operations.
Salvia miltiorrhizaRoots against Cardiovascular Disease: Consideration of Herb-Drug Interactions
Authors: Chen Feng , Li Li , Tian Dan-Dan
Published: April 2017

Salvia miltiorrhizaroot (Danshen) is widely used in Asia for its cardiovascular benefits and contains both hydrophilic phenolic acids and lipophilic tanshinones, which are believed to be responsible for its therapeutic efficacy. This review summarized the effects of these bioactive components fromS. miltiorrhizaroots on pharmacokinetics of comedicated drugs with mechanic insights regarding alterations of protein binding, enzyme activity, and transporter activity based on the published data stemming from bothin vitroandin vivohuman studies.In vitrostudies indicated that cytochrome P450 (CYP450), carboxylesterase enzyme, catechol-O-methyltransferase, organic anion transporter 1 (OAT1) and OAT3, and P-glycoprotein were the major targets involved inS. miltiorrhiza-drug interactions. Lipophilic tanshinones had much more potent inhibitory effects towards CYPs activities compared to hydrophilic phenolic acids, evidenced by much lowerKivalues of the former. ClinicalS. miltiorrhiza-drug interaction studies were mainly conducted using CYP1A2 and CYP3A4 probe substrates. In addition, the effects of coexisting components on the pharmacokinetic behaviors of those noted bioactive compounds were also included herein.
Telomere Length and Neighborhood Circumstances: Evaluating Biological Response to Unfavorable Exposures
Authors: Lynch Shannon M. , Mitra Nandita , Ravichandran Krithika , Mitchell Jonathan , Spangler Elaine , Zhou Wenting , Paskett Electra D. , Gehlert Sarah , DeGraffinreid Cecilia , Stowe Raymond , Dubowitz Tamara , Riethman Harold , Branas Charles C. , Peek M.K. , Rebbeck Timothy R.
Published: April 2017

Background: Multilevel frameworks suggest neighborhood circumstances influence biology; however, this relationship is not well studied. Telomere length (TL) shortening has been associated with individual-level and neighborhood-level exposures and disease and may provide insights into underlying biologic mechanisms linking neighborhood with biology. To support neighborhood–biology investigations, we sought to determine the independent effect of neighborhood exposures on TL using standard multilevel linear regression models and quantile regression, a nonlinear, social science method applicable for testing the biologic hypothesis that extremes of the TL distribution are related to poor outcomes.

Methods: In a multicenter, cross-sectional study, blood TL was measured in 1,488 individuals from 127 census tracts in three U.S. regions using terminal restriction fragment assays. Multilevel linear and quantile regression models were adjusted for individual-level race, education, perceived stress, and depression. Neighborhood exposures included population density, urban/residential crowding, residential stability/mobility, and socioeconomic status.

Results: TL was not associated with any neighborhood variable using linear models, but quantile regression revealed inverse associations between population density and urban crowding at the lower tails of the TL distribution [5th (population density P = 0.03; urban crowding P = 0.002), 50th (both P < 0.001), 75th percentiles (both P < 0.001)]. TL was related to residential stability at the upper tail (95th percentile P = 0.006).

Conclusions: Findings support the use of nonlinear statistical methods in TL research and suggest that neighborhood exposures can result in biological effects.

Impact: TL may serve as an underlying example of a biologic mechanism that can link neighborhood with biology, thus supporting multilevel investigations in future studies. Cancer Epidemiol Biomarkers Prev; 26(4); 553–60. ©2017 AACR.

See all the articles in this CEBP Focus section, “Geospatial Approaches to Cancer Control and Population Sciences.”
Pancreatic Cancer: “A Riddle Wrapped in a Mystery inside an Enigma”
Authors: Borazanci Erkut , Dang Chi V. , Robey Robert W. , Bates Susan E. , Chabot John A. , Von Hoff Daniel D.
Published: April 2017

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology—systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes are KRAS, CDKN2A, TP53, and SMAD4/DPC4. Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer. Recent studies suggest that epigenetics may play a larger role than previously recognized. A major new understanding is the recognition that PDAC should be considered a composite of tumor cells, as well as pancreatic stellate cells, immune cells, and extracellular matrix. The individual components contribute to metabolic aberration, immune dysfunction, and chemotherapy resistance, and therapeutic innovations may be needed to address them individually. It has also been recognized that metastatic seeding from PDAC occurs very early in the disease course—in an estimated 73% of cases, once the tumor reaches 2 cm. The implication of this is that therapies directed toward micrometastatic disease and increasing fractional cell kill are most needed. Neoadjuvant approaches have been taken to increase resectability and improve outcome. So much work remains, and most critical is the need to understand how this tumor originates and develops. Clin Cancer Res; 23(7); 1629–37. ©2017 AACR.

See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale
Authors: Salgia Ravi
Published: April 2017

MET or hepatocyte growth factor (HGF) receptor pathway signaling mediates wound healing and hepatic regeneration, with pivotal roles in embryonic, neuronal, and muscle development. However, dysregulation of MET signaling mediates proliferation, apoptosis, and migration and is implicated in a number of malignancies. In non–small cell lung cancer (NSCLC), aberrant MET signaling can occur through a number of mechanisms that collectively represent a significant proportion of patients. These include MET or HGF protein overexpression, MET gene amplification, MET gene mutation or fusion/rearrangement, or aberrations in downstream signaling or regulatory components. Responses to MET tyrosine kinase inhibitors have been documented in clinical trials in patients with MET-amplified or MET-overexpressing NSCLC, and case studies or case series have shown that MET mutation/deletion is a biomarker that is also predictive of response to these agents. However, other recent clinical data have highlighted an urgent need to elucidate optimal biomarkers based on genetic and/or protein diagnostics to correctly identify patients most likely to benefit in ongoing clinical trials of an array of MET-targeted therapies of differing class. The latest advances in the development of MET biomarkers in NSCLC have been reviewed, toward establishing appropriate MET biomarker selection based on a scientific rationale. Mol Cancer Ther; 16(4); 555–65. ©2017 AACR.
Abstract A07: The RAD51 paralog complex SWS1-SWSAP1 is critical for homologous recombination in the mouse
Authors: Prakash Rohit , Abreu Carla Manuela , Keeney Scott , Jasin Maria
Published: April 2017

Homologous recombination (HR), also termed homology-directed repair, is a major pathway for the repair of DNA double-strand breaks (DSBs) generated by DNA damaging agents, replication fork collapse and during meiosis. Failure to repair DSBs correctly causes genomic instability, leading to mutagenesis, and developmental defects. Moreover, defects in HR impact the response to many therapeutics. Components of the HR machinery include BRCA2 and five RAD51 paralogs, which are critical for RAD51 assembly onto single-stranded DNA, an important intermediate for homologous strand invasion. Disruption of these HR genes in mice results in embryonic lethality (pre-implantation to mid-gestation defects), developmental defects (e.g., sterility), and tumorigenesis. Recently, the Shu complex, composed of SWS1 and SWSAP1 subunits, was identified in human cells as a potential RAD51 paralog complex, since it functions with RAD51 to promote mitotic HR like its ortholog in yeast. Here, we show that the mouse Shu complex interacts with the ubiquitously expressed RAD51 recombinase and also with the meiosis-specific DMC1 recombinase. Knockout mice lacking one or both Shu complex subunits are viable and show no obvious developmental defects, except in gonads of both female and male mice, which are infertile. Analyses in males demonstrate that Shu complex is required for proper homologous synapsis and for the formation of RAD51 and DMC1 foci very early in meiotic prophase I. Our preliminary results indicate that the mouse Shu complex is also important for mitotic HR. Therefore, we propose that Shu complex ensures the assembly of RAD51 and DMC1 proteins into nucleoprotein filaments on resected DSBs to promote successful homology search and strand invasion, for completion of meiotic and mitotic recombination.

Citation Format: Rohit Prakash, Carla Manuela Abreu, Scott Keeney, Maria Jasin. The RAD51 paralog complex SWS1-SWSAP1 is critical for homologous recombination in the mouse [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 A07.
Abstract A12: CTCF facilitates DNA double-strand break repair by homologous recombination
Authors: Hilmi Khalid , Zhang Chenxi , Yu Zhenbao , Saad Amine , Richard Stephane , McCaffrey Luke , Alaoui-Jamali Moulay A. , Witcher Michael
Published: April 2017

The repair of DNA double strand breaks (DSB) is mediated via two major pathways, non-homologous end joining (NHEJ) or homologous recombination repair (HRR). Such repair is critical for cell survival and genome stability. Here, we report a new role for the multifunctional protein CTCF in facilitating the repair of DSB via the HRR pathway. CTCF is recruited to DSB through its zinc finger domain independently of poly(ADP-ribose) polymers catalyzed by PARP-1. CTCF ensures proper DSB repair kinetics in response to gamma-irradiation, and potentiates activation of the G2/M checkpoint. We find that CTCF regulates HRR through facilitating the recruitment of BRCA2, which is dependent on CTCF PARylation. In contrast, CTCF does not influence the recruitment, or retention, of the NHEJ protein 53BP1 to DSB. We also see that loss of CTCF is associated with hypersensitivity to DNA damaging inducing agents and inhibitors of PARP-1. Taken together, our findings establish for the first time that CTCF is an important regulator of the HRR pathway and indicate that tumors harboring hypo-PARylated CTCF may show elevated sensitivity to PARP inhibition.

Citation Format: Khalid Hilmi, Chenxi Zhang, Zhenbao Yu, Amine Saad, Stephane Richard, Luke McCaffrey, Moulay A. Alaoui-Jamali, Michael Witcher. CTCF facilitates DNA double-strand break repair by 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 A12.
Abstract A24: A genome-wide RNAi screen identifies synthetic lethality of CX-5461 with homologous recombination repair deficiency in ovarian cancer
Authors: Yan Shunfei , Chan Keefe T. , Simpson Kaylene J. , Sanij Elaine , Sheppard Karen E. , Hannan Katherine M. , Hannan Ross D. , Pearson Richard B.
Published: April 2017

Cancer is characterized by deregulated cell growth and proliferation, both of which are associated with hyperactivation of ribosome biogenesis. Inhibition of ribosome biogenesis using CX-5461, a specific inhibitor of RNA polymerase I-dependent transcription, has shown therapeutic efficacy in a MYC driven B-cell lymphoma mouse model, which is enhanced when used in combination with the mTORC1 inhibitor Everolimus. However, the therapeutic potential of CX-5461 in solid cancers is yet to be determined.

Our preliminary data utilizing a panel of 36 ovarian cancer (OVCA) cell lines suggest that acute CX-5461 treatment results in cell cycle arrest and does not induce apoptosis. We hypothesize that the identification of genes that can be targeted to cooperate with CX-5461 will define novel drug combinations for the improved treatment of OVCA. Therefore, we performed a genome-wide RNAi screen to identify synthetic lethal genes with CX-5461 in the high-grade serous ovarian cancer (HGSOC) cell line OVCAR4. Pathway enrichment analysis of the candidate hits showed significant enrichment in the homologous recombination DNA repair (HR) pathway. Synergy with CX-5461 was validated in multiple HGSOC cell lines by both genetic and pharmacological inhibition of HR pathway components. We are currently investigating the mechanism of this synergy and will further assess efficacy in vivo.

As HR deficiency is observed in 20% of OVCA patients, we suggest that future application of our studies will lead to new therapeutic options to improve the survival of this cohort of patients.

Citation Format: Shunfei Yan, Keefe T. Chan, Kaylene J. Simpson, Elaine Sanij, Karen E. Sheppard, Katherine M. Hannan, Ross D. Hannan, Richard B. Pearson. A genome-wide RNAi screen identifies synthetic lethality of CX-5461 with homologous recombination repair deficiency in ovarian 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 A24.
Abstract A32: Exploring the interplay between nucleotide excision repair and DNA replicative stress
Authors: Drobetsky Elliot , Bélanger François , Angers Jean-Philippe , Fortier Émile , Costantino Santiago , Wurtele Hugo
Published: April 2017

Ultraviolet (UV) light causes highly genotoxic DNA lesions that are removed by nucleotide excision repair (NER), and NER is critical for preventing UV-associated skin cancers. UV-induced DNA lesions block the progression of DNA polymerases, leading to replicative stress and genomic instability. Upon UV, the ataxia-telangectasia and rad3 related (ATR) kinase is rapidly activated, leading to cell-cycle arrest, inhibition of replication origin firing, and stabilization of blocked replication forks. Intriguingly, previous data indicated that reduced ATR activity causes profound NER defects specifically in S phase cells. Moreover many model cancer cell lines, including a majority of melanoma lines, present striking S phase-specific NER defects.

We used the yeast S. cerevisiae as model to investigate NER activity during S phase. We optimized a novel flow cytometry-based assay to quantify NER as a function of cell cycle in this organism. Using this assay we demonstrate that, as for human cells, deletion of the yeast ATR homolog Mec1 causes NER defects uniquely in S, and that initiation of DNA replication is prerequisite for manifestation of this defect. S phase-specific NER was perturbed by mutations in various genes encoding key DNA damage response factors that regulate, e.g. cell cycle checkpoints, chromatin remodeling, and homologous recombination. Our data also reveal a strong correlation between S phase-specific NER defects and elevated RPA focus formation in mutants that are sensitive to replicative stress. Finally we demonstrate that modulation of RPA levels strongly influences NER activity specifically during S in human cancer cell lines. Overall, our data indicate that mutations in a multitude of DNA damage response pathways cause inordinate sequestration of RPA at stalled replication forks, thereby reducing the availability of this factor to perform its essential role in NER. This has important implications for our understanding of UV-induced skin cancer development in humans.

Citation Format: Elliot Drobetsky, François Bélanger, Jean-Philippe Angers, Émile Fortier, Santiago Costantino, Hugo Wurtele. Exploring the interplay between nucleotide excision repair and DNA replicative stress [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 A32.
Abstract A33: Defect in S phase cell cycle checkpoint renders tumours vulnerable to CHK1 inhibitor single-agent treatment in vitro and in vivo
Authors: Oo Zay Yar , Stevenson Alexander , Lanagan Catherine , Spoerri Loredana , Larsen Jill , Gabrielli Brian
Published: April 2017

CHK1 inhibitors are being investigated as chemosensitizing agents with agents that increase replication stress. Here we have investigated the molecular basis of sensitivity to CHK1 inhibitors as single agents in melanoma and lung cancer. We have found that sensitivity in vitro and in vivo to single agent CHK1 inhibitor is loss of the S phase cell cycle checkpoint response. This is through a number of mechanisms including the uncoupling of CHK1 activation with the destabilization of CDC25A. Loss of checkpoint by over-expressing components of the checkpoint or inhibition of Wee1, covert CHK1 inhibitor insensitive cells to sensitive, and similarly depletion of CDC25A reduces CHK1 inhibitor sensitivity in sensitive lines. Loss of the S phase checkpoint provides cells with an adaptive advantage through introduction of moderate levels of genomic instability. The increased DNA damage found with CHK1 inhibitor treatment is not sufficient to induce cell death, but also involves a mechanism that is dependent in part on DNA-PK activity. Loss of S phase checkpoint function is predicted for <25% of melanomas and non-small cell lung squamous cell cancers. This is independent of other known risk factors, suggesting a significant proportion of melanoma and lung cancer patients could benefit from treatment with these drugs.

Note: This abstract was not presented at the conference.

Citation Format: Zay Yar Oo, Alexander Stevenson, Catherine Lanagan, Loredana Spoerri, Jill Larsen, Brian Gabrielli. Defect in S phase cell cycle checkpoint renders tumours vulnerable to CHK1 inhibitor single-agent treatment in vitro and in vivo [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 A33.
Abstract A37: Development of screening methods to identify Translesion DNA Synthesis inhibitors
Authors: Villafañez Florencia , García Alejandra Iris , Pansa María Florencia , Carbajosa Sofía , Bocco José Luis , Soria Gastón
Published: April 2017

Translesion DNA synthesis (TLS) is a DNA damage tolerance process that employs specialized polymerases to bypass DNA damage during replication. Recent evidence indicates that TLS is a key process that promotes the development of resistance to cancer treatments that induce DNA damage (i.e. Cisplatin). Thus, the inhibition of TLS emerges as a promising strategy for cancer therapy. However, to date, specific chemical inhibitors of TLS are not available.

The main goal of our project is to identify specific inhibitors of TLS that can be used as a proof of concept in cancer therapy by developing cell-based assays that explore TLS markers. Our rational is that since TLS polymerases recruitment to sites of DNA damage is a key step for TLS success, we can indirectly monitor TLS efficiency in a given context by studying two key markers of TLS polymerases recruitment: 1) The mono-ubiquitylation of the replication auxiliary factor PCNA and 2) the accumulation of a TLS polymerase into replication foci. We thus developed two screening methods that allow us to promptly identify inhibitors of PCNA ubiquitylation and TLS polymerases recruitment into DNA damage sites. The first marker, PCNA mono-ubiquitylation, is assessed through a western-Blot-based platform where the identification of unmodified PCNA and mono-ubiquitylated PCNA are achieved by two different antibodies coupled to fluorescent infrared detection using a fluorescence scanner. For the second marker, TLS polymerase recruitment to damage sites, we developed stable cell lines expressing TLS polymerases fused to fluorescent proteins and we analyze polymerases recruitment through an imaging-based assay.

In this poster we describe the results of a pilot screening using an open source library of kinase inhibitors from GlaxoSmithKline (known as PKIS2), and the early validation of the identified hits.

Citation Format: Florencia Villafañez, Alejandra Iris García, María Florencia Pansa, Sofía Carbajosa, José Luis Bocco, Gastón Soria. Development of screening methods to identify Translesion DNA Synthesis inhibitors [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 A37.
Abstract A42: Identification of glutamate and aspartate ADP-ribosylation sites onto histones by mass mass spectrometry
Authors: Gagné Jean-Philippe , Roux-Dalvai Florence , Defoy Daniel , Droit Arnaud , Michael Hendzel J. , Poirier Guy G.
Published: April 2017

Chromatin structure and function is regulated by histone post-translational modifications. Histone proteins are subject to a variety of post-translational modifications that can work combinatorially to alter the transcriptional state or the repair of DNA damage. The landscape of histone modifications includes mono- and poly(ADP-ribosylation), which can directly alter nucleosome structure and DNA accessibility. ADP-ribosylation occuring on glutamate and aspartate residues was the most intensively studied histone ADP-ribosylation modification in the past, primarily because these carboxylester-type ADP-ribose–protein bonds were the most susceptible to hydroxylamine hydrolysis, a particularly fast and efficient method of protein de-ADP-ribosylation. Taking advantage of hydroxylamine-based developments in the identification of ADP-ribosylated residues by liquid-chromatography tandem mass spectrometry (LC-MS/MS), we generated a repertoire of glutamate- and aspartate-specific ADP-ribosylation sites onto histones. In our study, high confidence MS/MS-assigned ADP-ribosylation site identification onto a combination of in vitro and in vivo ADP-ribosylated histones revealed that all five major classes of histones are targets for D/E ADP-ribosylation. We found that the histone tails are not the sole location of the sites of ADP-ribosylation. Significant ADP-ribosylation sites were located in central globular regions of histones adding to the complexity of the histone modification landscape.

Citation Format: Jean-Philippe Gagné, Florence Roux-Dalvai, Daniel Defoy, Arnaud Droit, Hendzel J. Michael, Guy G. Poirier. Identification of glutamate and aspartate ADP-ribosylation sites onto histones by mass mass spectrometry [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 A42.