bluuebunny/crossref_metadata_2025 huggingface dataset:
Src/Syk-Targeted Anti-Inflammatory Actions of Triterpenoidal Saponins from Gac (Momordica cochinchinensis) Seeds
Authors: Yu Jae Sik , Kim Jun Ho , Lee Seulah , Jung Kiwon , Kim Ki Hyun , Cho Jae Youl
Published: April 2017

Momordica cochinchinensis Spreng (family Cucurbitaceae), also known as gac, or red melon, is an edible Southeast Asian fruit valued for its nutritional and medicinal properties. Specifically, Momordicae Semen, the seeds of the gac fruit, is used in traditional Chinese medicine to treat boils, rheumatic pain, muscle spasm, hemorrhoids, and hemangiomas. In this study, a chemical investigation into a gac seed ethanol (EtOH) extract resulted in the identification of three triterpenoidal saponins (1–3), which were investigated for their anti-inflammatory effects. Among the saponins, momordica saponin I (compound 3) reduced the production of nitric oxide (NO) in LPS-activated RAW264.7 cells without inducing cytotoxicity. The mRNA levels of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 were decreased by momordica saponin I. Additionally, the translocation of p65 and p50 (subunits of the transcription factor NF-[Formula: see text]B) into the nucleus was remarkably inhibited. Furthermore, the phosphorylation levels of inflammatory signaling proteins (I[Formula: see text]B[Formula: see text], Src, and Syk) known to be upstream regulatory molecules of p65 were decreased under momordica saponin I-treated conditions. The molecular targets of momordica saponin I were confirmed in overexpression experiments and through immunoblot analyses with Src and Syk. This study provides evidence that momordica saponin I could be beneficial in treating inflammatory diseases, and should be considered a bioactive immunomodulatory agent with anti-inflammatory properties.
Two-Armed Activation of Bone Mineral Deposition by the Flavones Baicalin and Baicalein, Encapsulated in Polyphosphate Microparticles
Authors: Wang Xiao-Hong , Guo Yue-Wei , Tolba Emad , Kokkinopoulou Maria , Wiens Matthias , Schröder Heinz C. , Müller Werner E.G.
Published: April 2017

In this study, we investigated the effect of the two flavonoids, baicalin (baicalein 7-O-[Formula: see text]- d-glucuronic acid) and its aglycone, baicalein (5,6,7-trihydroxyflavone), after encapsulation into amorphous calcium polyphosphate (Ca-polyP) microparticles on mineralization of primary human osteoblasts (phOSB). Both flavonoids, which come from root extracts of Scutellaria baicalensis Georgi, are used in Traditional Chinese Medicine, and are nontoxic in cells up to a concentration of 3[Formula: see text][Formula: see text]g/ml. The morphogenetically active, energy-rich Ca-polyP particles with a stoichiometric P:Ca ratio of 1:2 are degraded by cellular alkaline phosphatase (ALP) to ortho-phosphate used for bone hydroxyapatite formation. Here we show that the flavone-loaded Ca-polyP microparticles are readily taken up by phOSB, resulting in the accumulation of polyP around the nuclei and the formation of intracellular vesicles containing the ALP. In addition, we demonstrate that baicalin/baicalein causes a rise of the intracellular calcium [Ca[Formula: see text]]ia level which markedly is augmented after encapsulation into Ca-polyP, through activation of the phospholipase C. Moreover, both flavones, either alone or associated with Ca-polyP microparticles, upregulate the expression of the osteoblast calcium efflux channel, the plasma membrane Ca[Formula: see text]-ATPase (PMCA), while the expression of ALP, which promotes bone mineralization, is induced by Ca-polyP and by the flavones only if present in the Ca-polyP-microparticle-associated form. As a result, the extent of bone mineralization is markedly enhanced. Based on the two-armed activating function, new applications of baicalin/baicalein as a component of nutriceuticals for osteoporosis prevention or bone implants can be envisaged.
Life with Salam (1959–1976)
Authors: Delbourgo Robert
Published: April 2017

Having significantly interacted over 17 years with Abdus Salam, as an undergraduate, postgraduate, postdoc, and eventually as an academic colleague, I will try to paint a personal picture of Salam which may convey something about the man, his greatness and his humanity.
Transverse momentum distribution of primary charged particles in p–Pb interactions at forward pseudorapidity at LHC energies
Authors: Ali Y. , Ullah Jan N. , Tabassam U. , Suleymanov M. , Bhatti A. S.
Published: April 2017

Transverse momentum distributions of primary charged particles have been studied using simulated data from the HIJING 1.0 event generator in the minimum bias p–Pb collisions at [Formula: see text] = 0.9, 1.8, 2.76 and 5.02[Formula: see text], in the two forward pseudorapidity ([Formula: see text]) regions: [Formula: see text] and [Formula: see text] and in the transverse momentum range of [Formula: see text]. The simulated data in the pseudorapidity region of [Formula: see text] at 5.02[Formula: see text] depicts some differences in the region of [Formula: see text] [Formula: see text] 2[Formula: see text] when compared with CMS data. Model shows systematically higher values than the experimental measurements pointing out absorption effect for the experimental data. It is also observed that with increasing rapidity interval from [Formula: see text] to [Formula: see text] observed differences for the behavior of the transverse momentum distributions are shifted to high transverse momentum region. The nuclear modification factor as a function of transverse momentum is constructed using the HIJING 1.0 code. With incident energy, the values of nuclear modification factor increase, for 0.9 and 1.8 [Formula: see text], the distributions seem to increase, but for 2.76 and 5.02 [Formula: see text], the distributions look flat. Numerically, the value of nuclear modification factor increases with the increase in the number of jets. This result shows that for the considered more forward pseudorapidiry area, the influence of the incident energy dominates and this is the reason that main results in the areas are connected with the leading particles.
Quantum image processing: A review of advances in its security technologies
Authors: Yan Fei , Iliyasu Abdullah M. , Le Phuc Q.
Published: April 2017

In this review, we present an overview of the advances made in quantum image processing (QIP) comprising of the image representations, the operations realizable on them, and the likely protocols and algorithms for their applications. In particular, we focus on recent progresses on QIP-based security technologies including quantum watermarking, quantum image encryption, and quantum image steganography. This review is aimed at providing readers with a succinct, yet adequate compendium of the progresses made in the QIP sub-area. Hopefully, this effort will stimulate further interest aimed at the pursuit of more advanced algorithms and experimental validations for available technologies and extensions to other domains.
Application of TQM for Innovation: An Exploratory Research of Japanese, Indian and Thailand Companies
Authors: Taddese Fasil
Published: April 2017

Total quality management (TQM) and innovation have long been discussed as major contributors to organizational success. TQM has been discussed with regard to management practices while innovation is discussed with regard to technological change. However, a vague relationship has been established between these two due to the challenge to establish statistical relationship. The main purpose of this research is to empirically study the application of TQM for innovation. Fourteen companies from Japan, India and Thailand are considered in an empirical exploratory research to uncover the relationship between TQM and innovation. Three factors of TQM (human factor, technology factor and information factor) are considered to see the effect on process innovation and product innovation. The research findings indicate that TQM facilitates the development of innovation capabilities in organizations through harmonized management practices in a sequence of inter-related incremental innovation initiatives. Moreover, this research indicates that the innovation speed achieved by TQM is found to be dramatic as compared to traditional innovation. However, it was not only the speediness of the innovation achieved using TQM that surprises, but also its response to different market needs.
WITH A LITTLE HELP FROM MY CUSTOMERS: THE INFLUENCE OF CUSTOMER EMPOWERMENT ON CONSUMERS’ PERCEPTIONS OF WELL-ESTABLISHED BRANDS
Authors: MEIßNER MARTIN , HAURAND MICHELLE D. , STUMMER CHRISTIAN
Published: April 2017

Labelling product innovations as designed and/or selected by customers can positively affect non-participating consumers’ self-stated behavioural intentions, that is, it can increase the probability of purchasing that product. Most previous studies have used fictitious brands to test the aforementioned effect, raising concerns about the degree to which these findings are relevant for marketing practice. Brand managers thus might wonder whether labelling product innovations as user-designed and/or user-selected might indeed increase sales for their well-established brands. This paper addresses this research gap by investigating the possible effects of three alternative strategies for labelling innovations (i.e., empowerment-to-select, empowerment-to-create, and full empowerment) for two well-established technology brands. For all three strategies and both brands, we find that involving customers significantly increases the perceived innovation ability, which then positively mediates the effect on behavioural intentions. However, due to a negative direct effect, only labelling products as selected by customers has an overall positive effect.
Spam Mobile Apps
Authors: Seneviratne Suranga , Seneviratne Aruna , Kaafar Mohamed Ali , Mahanti Anirban , Mohapatra Prasant
Published: April 2017

The increased popularity of smartphones has attracted a large number of developers to offer various applications for the different smartphone platforms via the respective app markets. One consequence of this popularity is that the app markets are also becoming populated with spam apps. These spam apps reduce the users’ quality of experience and increase the workload of app market operators to identify these apps and remove them. Spam apps can come in many forms such as apps not having a specific functionality, those having unrelated app descriptions or unrelated keywords, or similar apps being made available several times and across diverse categories. Market operators maintain antispam policies and apps are removed through continuous monitoring. Through a systematic crawl of a popular app market and by identifying apps that were removed over a period of time, we propose a method to detect spam apps solely using app metadata available at the time of publication. We first propose a methodology to manually label a sample of removed apps, according to a set of checkpoint heuristics that reveal the reasons behind removal. This analysis suggests that approximately 35% of the apps being removed are very likely to be spam apps. We then map the identified heuristics to several quantifiable features and show how distinguishing these features are for spam apps. We build an
Adaptive Boost
classifier for early identification of spam apps using only the metadata of the apps. Our classifier achieves an accuracy of over 95% with precision varying between 85% and 95% and recall varying between 38% and 98%. We further show that a limited number of features, in the range of 10--30, generated from app metadata is sufficient to achieve a satisfactory level of performance. On a set of 180,627 apps that were present at the app market during our crawl, our classifier predicts 2.7% of the apps as potential spam. Finally, we perform additional manual verification and show that human reviewers agree with 82% of our classifier predictions.
Low-Power Clock Tree Synthesis for 3D-ICs
Authors: Lu Tiantao , Srivastava Ankur
Published: April 2017

We propose efficient algorithms to construct a low-power clock tree for through-silicon-via (TSV)-based 3D-ICs. We use shutdown gates to save clock trees’ dynamic power, which selectively turn off certain clock tree branches to avoid unnecessary clock activities when the modules in these tree branches are inactive. While this clock gating technique has been extensively studied in 2D circuits, its application in 3D-ICs is unclear. In 3D-ICs, a shutdown gate is connected to a control signal unit through
control
TSVs, which may cause placement conflicts with existing
clock
TSVs in the layout due to TSV’s large physical dimension. We develop a two-phase clock tree synthesis design flow for 3D-ICs: (1) 3D abstract clock tree generation based on K-means clustering and (2) clock tree embedding with simultaneous shutdown gates’ insertion based on simulated annealing (SA) and a force-directed TSV placer. Experimental results indicate that (1) the K-means clustering heuristic significantly reduces the clock power by clustering modules with similar switching behavior and close proximity, and (2) the SA algorithm effectively inserts the shutdown gates to a 3D clock tree, while considering
control
TSV’s placement. Compared with previous 3D clock tree synthesis techniques, our K-means clustering-based approach achieves larger reduction in clock tree power consumption while ensuring zero clock skew.
The glorious promise of the post-truth world
Authors: Odlyzko Andrew
Published: April 2017

"Post-truth"---an adjective designated the 2016 Word of the Year by the Oxford English Dictionaries, and the related term "truthiness," have received much public attention recently, and have inspired heated discussions of "fake news" and "alternative facts."

In this article (spoof/parody/satire/dystopia/…, depending on how you read it), the author argues that the essential role of truthiness in human life is underestimated, and that it "is safer to embrace the inevitable and march into the brave new post-truth world."
Automated closed-loop model checking of implantable pacemakers using abstraction trees
Authors: Jiang Zhihao , Abbas Houssam , Mosterman Pieter J. , Mangharam Rahul
Published: April 2017

Autonomous medical devices such as implantable cardiac pacemakers are capable of diagnosing the patient condition and delivering therapy without human intervention. Their ability to autonomously affect the physiological state of the patient makes them safety-critical. Sufficient evidence for the safety and efficacy of the device software, which makes these autonomous decisions, should be provided before these devices can be released on the market. Formal methods like model checking can provide safety evidence that the devices can safely operate under a large variety of physiological conditions. The challenge is to develop physiological models that are general enough to cover the large variability of human physiology, and also expressive enough to provide physiological contexts to counter-examples returned by the model checker. In this paper, the authors develop a set of physiological abstraction rules that introduce physiological constraints to heart models. By applying these abstraction rules to a initial set of heart models, an abstraction tree is created. The root model covers all possible inputs to a pacemaker and derived models cover inputs from different heart conditions. If a counter-example is returned by the model checker, the abstraction tree is traversed so that the most concrete counter-example(s) with physiological contexts can be returned to the domain experts for validity check. The abstraction tree framework replaces the manual abstraction and refinement framework, which reduced the amount of domain knowledge required to perform closed-loop model checking. It encourages the use of model checking during the development of autonomous medical devices, and identifies safety risks earlier in the design process.
1
Model-based falsification of an artificial pancreas control system
Authors: Sankaranarayanan Sriram , Kumar Suhas Akshar , Cameron Faye , Bequette B. Wayne , Fainekos Georgios , Maahs David M.
Published: April 2017

We present a model-based falsification scheme for artificial pancreas controllers. Our approach performs a closed-loop simulation of the control software using models of the human insulin-glucose regulatory system. Our work focuses on testing properties of an overnight control system for hypoglycemia/hyperglycemia minimization in patients with type-1 diabetes. This control system is currently the subject of extensive phase II clinical trials.

We describe how the overall closed loop simulator is constructed, and formulate properties to be tested. Significantly, the closed loop simulation incorporates the control software, as is, without any abstractions. Next, we demonstrate the use of a simulation-based falsification approach to find potential property violations in the resulting control system. We formulate a series of properties about the controller behavior and examine the violations obtained. Using these violations, we propose modifications to the controller software to improve its performance under these adverse (corner-case) scenarios. We also illustrate the effectiveness of robustness as a metric for identifying interesting property violations. Finally, we identify important open problems for future work.
Support for safety case generation via model transformation
Authors: Lin Chung-Ling , Shen Wuwei , Hawkins Richard
Published: April 2017

Assessing the safety of complex safety- or mission-critical systems under ever tightening time constraints with any degree of confidence is a growing challenge for industry and regulators alike. One method of helping to address this situation is through the use of assurance cases. Challenges abound here as well; too little or too much abstraction or poorly constructed arguments can affect confidence that a system will perform as intended. The automatic generation of a (safety) assurance case not only can expedite a development process but also leverage the ability to perform compliance checking. In this paper, we propose a novel framework which weaves a safety case pattern, guidance metamodel, and a development process metamodel together to generate a safety assurance case, which facilitates checking the conformance of the system to the guidance. As a case study, we use the GPCA infusion pump project as a subject to illustrate how this framework can aid in compliance checking using the infusion pump guidance published by FDA as a reference oracle.
Vertical Vibration Characteristics of a Variable Impedance Pile Embedded in Layered Soil
Authors: Wu Wenbing , Xu Xuelian , Liu Hao , Fang Changliang , Dou Bin , Liang Rongzhu
Published: April 2017

In engineering applications, various defects such as bulging, necking, slurry crappy, and weak concrete are always observed during pile integrity testing. To provide more reasonable basis for assessing the above defects, this paper proposed simple and computationally efficient solutions to investigate the vertical vibration characteristics of a variable impedance pile embedded in layered soil. The governing equations of pile‐soil system undergoing a vertical dynamic loading are built based on the plane strain model and fictitious soil pile model. By employing the Laplace transform method and impedance function transfer method, the analytical solution of the velocity response at the pile head is derived in the frequency domain. Then, the corresponding semianalytical solution in the time domain for the velocity response of a pile subjected to a semisinusoidal force applied at the pile head is obtained by adopting inverse Fourier transform and convolution theorem. Based on the presented solutions, a parametric study is conducted to study the vertical vibration characteristics of variable cross‐section pile and variable modulus pile. The study gives an important insight into the evaluation of the construction quality of pile.
Artificial Neural Networks in Image Processing for Early Detection of Breast Cancer
Authors: Mehdy M. M. , Ng P. Y. , Shair E. F. , Saleh N. I. Md , Gomes C.
Published: April 2017

Medical imaging techniques have widely been in use in the diagnosis and detection of breast cancer. The drawback of applying these techniques is the large time consumption in the manual diagnosis of each image pattern by a professional radiologist. Automated classifiers could substantially upgrade the diagnosis process, in terms of both accuracy and time requirement by distinguishing benign and malignant patterns automatically. Neural network (NN) plays an important role in this respect, especially in the application of breast cancer detection. Despite the large number of publications that describe the utilization of NN in various medical techniques, only a few reviews are available that guide the development of these algorithms to enhance the detection techniques with respect to specificity and sensitivity. The purpose of this review is to analyze the contents of recently published literature with special attention to techniques and states of the art of NN in medical imaging. We discuss the usage of NN in four different medical imaging applications to show that NN is not restricted to few areas of medicine. Types of NN used, along with the various types of feeding data, have been reviewed. We also address hybrid NN adaptation in breast cancer detection.
Microglia-Synapse Pathways: Promising Therapeutic Strategy for Alzheimer’s Disease
Authors: Xie Jingdun , Wang Haitao , Lin Ting , Bi Bingtian
Published: April 2017

The main hallmarks of Alzheimer’s disease (AD) are extracellular deposits of amyloid plaques and intracellular accumulation of hyperphosphorylated neurofibrillary tangles (tau). However, the mechanisms underlying these neuropathological changes remain largely unclear. To date, plenty of studies have shown that microglia-mediated neuroinflammation contributes to the pathogenesis of AD, and the microglia-synapse pathways have been repeatedly identified as the crucial factor in the disease process. In this review, evidences from microglia and synapse studies are presented, and the role of microglia in the pathogenesis of AD, the contributing factors to synapse dysfunction, and the role and mechanisms of microglia-synapse pathways will be discussed.
DKA-Induced Takotsubo Cardiomyopathy in Patient with Known HOCM
Authors: Gordon Ayla , LaCapra Gina , Roberti Roberto
Published: April 2017

The first published case of Diabetic Ketoacidosis-induced Takotsubo cardiomyopathy was in 2009. Our patient is the 1st reported case of Diabetic Ketoacidosis- (DKA-) induced Takotsubo cardiomyopathy (TC) in a patient with known hypertrophic cardiomyopathy (HOCM) in the United States. In the literature, there are only two examples linking DKA to TC; however, this report focuses on the biochemical and physiological causes of TC in a patient with known HOCM and new-onset DKA. TC in previously diagnosed HOCM poses particular complications. With the above patient’s baseline outflow tract obstruction due to septal hypertrophy, the acute reduction in EF due to TC resulted in transient drop in brain perfusion and, therefore, syncope.
Increase of Short-Term Heart Rate Variability Induced by Blood Pressure Measurements during Ambulatory Blood Pressure Monitoring
Authors: Frigy Attila , Magdás Annamária , Moga Victor-Dan , Coteț Ioana Georgiana , Kozlovszky Miklós , Szilágyi László
Published: April 2017

Objective.The possible effect of blood pressure measurements per se on heart rate variability (HRV) was studied in the setting of concomitant ambulatory blood pressure monitoring (ABPM) and Holter ECG monitoring (HM).Methods.In 25 hypertensive patients (14 women and 11 men, mean age: 58.1 years), 24-hour combined ABPM and HM were performed. For every blood pressure measurement, 2-minute ECG segments (before, during, and after measurement) were analyzed to obtain time domain parameters of HRV: SDNN and rMSSD. Mean of normal RR intervals (MNN), SDNN/MNN, and rMSSD/MNN were calculated, too. Parameter variations related to blood pressure measurements were analyzed using one-way ANOVA with multiple comparisons.Results.2281 measurements (1518 during the day and 763 during the night) were included in the analysis. Both SDNN and SDNN/MNN had a constant (the same for 24-hour, daytime, and nighttime values) and significant change related to blood pressure measurements: an increase during measurements and a decrease after them (p<0.01for any variation).Conclusion.In the setting of combined ABPM and HM, the blood pressure measurement itself produces an increase in short-term heart rate variability. Clarifying the physiological basis and the possible clinical value of this phenomenon needs further studies.
Surgical Fixation of Bilateral Simultaneous Avulsion Fractures of the Proximal Tibia in a 12-Year-Old with History of Conservatively Managed Unilateral Tibial Avulsion Fracture
Authors: Newman Christopher , Musiienko Dharsh , Law Samuel
Published: April 2017

Fractures of the proximal tibial epiphysis are rare, representing less than 3% of all epiphyseal and 1% of all physeal injuries in adolescents. Bilateral injuries are extremely rare. The specific anatomical and histological features of the proximal tibial epiphysis make it vulnerable to a specific fracture pattern that occurs when the tensile force of the quadriceps is greater than the fibrocartilaginous tissue underlying the tibial tuberosity. We report the first case to our knowledge of a 12-year-old boy who sustained simultaneous bilateral tibial avulsion fractures on the background of a previous conservatively managed unilateral tibial tuberosity avulsion fracture. We report this case for its uniqueness and as an educational review of the anatomy, the mechanism of injury, and the development of classifying these fractures and discussion of the stages of the growing physis that determine the treatment approach.
Enterocutaneous Fistula Secondary to Stump Appendicitis
Authors: Agostinho Nelson , Bains Harinder K. , Sardelic Franko
Published: April 2017

The management of appendicitis with appendicectomy is very common in surgical practice. A recognised complication of appendicitis and appendicectomy is the formation of an enterocutaneous fistula. We present the case of a seventy-five-year-old woman who presented with an appendicocutaneous fistula on the background of an open appendicectomy performed sixty years prior to presentation.
Energy Efficient Fault Tolerant Coverage in Wireless Sensor Networks
Authors: Henna Shagufta
Published: April 2017

Energy efficiency and fault tolerance are two of the major concerns in wireless sensor networks (WSNs) for the target coverage. Design of target coverage algorithms for a large scale WSNs should incorporate both the energy efficiency and fault tolerance. In this paper, we study the coverage problem where the main objective is to construct two disjoint cover sets in randomly deployed WSNs based on relay energy (Erelay). Further, we present an approximation algorithm called Energy Efficient Maximum Disjoint Coverage (EMDC) with provable approximation ratios. We analyze the performance of EMDC theoretically and also perform extensive simulations to demonstrate the effectiveness of EMDC in terms of fault tolerance and energy efficiency.
Apolipoproteins A-I, B, and C-III and Obesity in Young Adult Cherokee
Authors: Wang Wenyu , Blackett Piers , Khan Sohail , Lee Elisa
Published: April 2017

Since young adult Cherokee are at increased risk for both diabetes and cardiovascular disease, we assessed association of apolipoproteins (A-I, B, and C-III in non-HDL and HDL) with obesity and related risk factors. Obese participants (BMI ≥ 30) aged 20–40 years (n=476) were studied. Metabolically healthy obese (MHO) individuals were defined as not having any of four components of the ATP-III metabolic syndrome after exclusion of waist circumference, and obese participants not being MHO were defined as metabolically abnormal obese (MAO). Associations were evaluated by correlation and regression modeling. Obesity measures, blood pressure, insulin resistance, lipids, and apolipoproteins were significantly different between groups except for total cholesterol, LDL-C, and HDL-apoC-III. Apolipoproteins were not correlated with obesity measures with the exception of apoA-I with waist and the waist : height ratio. In a logistic regression model apoA-I and the apoB : apoA-I ratio were significantly selected for identifying those being MHO, and the result (C-statistic = 0.902) indicated that apoA-I and the apoB : apoA-I ratio can be used to identify a subgroup of obese individuals with a significantly less atherogenic lipid and apolipoprotein profile, particularly in obese Cherokee men in whom MHO is more likely.
Age and Sex Effects on the Active Stiffness of Vastus Intermedius under Isometric Contraction
Authors: Wang Cong-Zhi , Guo Jing-Yi , Li Tian-Jie , Zhou Yongjin , Shi Wenxiu , Zheng Yong-Ping
Published: April 2017

Previously, a novel technique was proposed to quantify the relationship between the muscle stiffness and its nonfatigue contraction intensity. The method extended the measured range of isometric contraction to 100% maximum voluntary contraction (MVC) using an ultrasonic shear wave measurement setup. Yet, it has not been revealed how this relationship could be affected by factors like age or sex. To clarify these questions, vastus intermedius (VI) stiffness of 40 healthy subjects was assessed under 11 step levels of isometric contraction. The subjects were divided into four groups: young males, young females, elderly males, and elderly females (n=10for each). In a relaxed state, no significant difference was observed between the male and female subjects (p=0.156) nor between the young and elderly subjects (p=0.221). However, when performing isometric contraction, the VI stiffness of males was found to be significantly higher than that of females at the same level (p<0.001), and that of the young was higher than the elderly (p<0.001). Meanwhile, for two knee joint angles used, the stiffness measured at a 90° knee joint angle was always significantly larger than that measured at 60° (p<0.001). Recognizing the active muscle stiffness of VI contributes to body stability, and these results may provide insight into the age and sex bias in musculoskeletal studies, such as those on fall risks.
Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development
Authors: Dreyer Stephan B. , Chang David K. , Bailey Peter , Biankin Andrew V.
Published: April 2017

Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development. Clin Cancer Res; 23(7); 1638–46. ©2017 AACR.

See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked
Authors: Evan Gerard I. , Hah Nasun , Littlewood Trevor D. , Sodir Nicole M. , Campos Tania , Downes Michael , Evans Ronald M.
Published: April 2017

The “hallmarks” of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity, and maintenance. Hence, interfering with such super enhancer–driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extraterminal motif proteins, have shown the feasibility of disrupting super enhancer–dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanisms suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease. Clin Cancer Res; 23(7); 1647–55. ©2017 AACR.

See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
Abstract A06: Regulation of homologous recombination by the SUMO ligase NSMCE2
Authors: Pond Kelvin W. , DeRenty Christelle , Yagle Mary , Ellis Nathan
Published: April 2017

Introduction: The purpose of this study is to determine the role of the E3 SUMO ligase NSMCE2 in BLM regulation and homologous recombination (HR).

Background: DNA damage generated during replication is a major source of mutations and failure to repair this damage can cause genomic instability. HR is a high-fidelity DNA repair pathway activated primarily by replication-associated DNA damage. Numerous HR proteins are regulated by sumoylation, but the mechanisms that control sumoylation and their roles in HR are poorly understood. Cells deficient in the SUMO E3 ligase NSMCE2 are sensitive to DNA damaging agents and have defects in HR. Our preliminary data indicated that BLM sumoylation is dependent on NSMCE2. Because BLM sumolyation is required to recruit RAD51 to stalled forks, we hypothesized that NSMCE2-deficient cells are deficient in HR due to a defect in BLM-dependent RAD51 recruitment.

Results: To test this hypothesis, we transfected HeLa cells with siRNAs specific to NSMCE2 and tested whether cells could recruit RAD51 to replication forks stalled with hydroxyurea (HU). Contrary to our hypothesis, we found that the amount of RAD51 protein that accumulated at stalled forks was greater in HU-treated NSMCE2-deficient cells compared to HU-treated control cells. To our surprise, the amount of single-stranded DNA binding protein RPA was diminished by half in HU-treated NSMCE2-deficient cells and DNA damage signaling was similarly diminished as evidenced by the lower levels of γ-H2AX. Consistent with the low levels of γ-H2AX, the double-strand breaks (DSB) that normally form after extended treatment with HU were also greatly diminished in NSMCE2-deficient cells. Consistent with previous reports, we found that the levels of HU-induced sister chromatid exchange were also low. These data indicated that despite the over-accumulation of RAD51 to sites of stalled replication forks, cells are unable to perform HR repair efficiently, indicating that RAD51 is unable to complete its function there.

Conclusions: The hyper-accumulation of RAD51 at stalled forks we observed in NSMCE2-deficient cells suggests the sumoylation of one or more substrates by NSMCE2 is required for the remodeling of stalled forks that normally leads to unloading of RAD51 at the fork, strand breakage, and repair by HR. We suggest that the RAD51 accumulation that is observed in a substantial fraction of cancers may not be sufficient to demonstrate that the cells are HR proficient. Based on our data, RPA staining combined with RAD51 may be able to distinguish HR-proficient and deficient cells.

Citation Format: Kelvin W. Pond, Christelle DeRenty, Mary Yagle, Nathan Ellis. Regulation of homologous recombination by the SUMO ligase NSMCE2 [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 A06.
Abstract A11: RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1
Authors: Vélez-Cruz Renier , Manickavinayaham Swarnalatha , Biswas Anup K. , Clary Regina W. , Johnson David G.
Published: April 2017

The retinoblastoma (RB) tumor suppressor is widely recognized as a master regulator of the transcriptional program that controls entry into the S phase of the cell cycle. Its loss, which is a hallmark of cancer, leads to uncontrolled cell proliferation. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers and remodelers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double strand breaks (DSBs) dependent on E2F1 and ATM kinase activity. RB promotes DNA end resection and DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1 and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability and renders mice hypersensitive to IR. Importantly, depletion of either RB or BRG1 in osteosarcoma and breast cancer cell lines results in sensitivity to DNA damaging agents, thus underscoring the importance of these factors in DNA repair. We uncover a novel, non-transcriptional function for RB in HR, which could contribute to genome instability associated with RB loss.

Citation Format: Renier Vélez-Cruz, Swarnalatha Manickavinayaham, Anup K. Biswas, Regina W. Clary, David G. Johnson. RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 [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 A11.
Abstract A39: Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetorchore-microtubule attachments
Authors: Yu Lan , Shang Zeng-Fu , Chen Benjamin P. C. , Saha Debabrata
Published: April 2017

The DAB2IP tumor suppressor protein is a member of the Ras GTPase-activating protein family and is often downregulated by epigenetic silencing in many advanced cancer types. Current literature indicates that DAB2IP plays a crucial role in suppression of the PI3K-Akt pathway and epithelial-mesenchymal transition. Loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is associated with increased androgen receptor signaling and poor patient prognosis. Here we report that loss of DAB2IP is also resulted in chromosomal instability due to defects in kinetochore-microtubule (KT-MT) attachment and the spindle assembly checkpoint (SAC) during mitotic cell cycle transition. Chromosomal instability is one of the key hallmarks of carcinogenesis and has been linked to metastasis, poor prognosis, and therapy resistance in cancer. Our results further indicate that DAB2IP directly interacts with Plk1, and its loss attenuates Plk1 kinase activity and Plk1-dependent BubR1 phosphorylation which is required for BubR1 localization at the kinetochore during mitosis and SAC regulation. Consequently, loss of DAB2IP leads to increased resistance of PCa cells toward microtubule stabilizing drugs (paclitaxel, docetaxel) and Plk1 inhibitor (BI2536). Our findings demonstrate a novel function of DAB2IP in the maintenance of KT-MT structure and proper SAC regulation during mitosis to promote chromosomal stability and genome integrity.

Citation Format: Lan Yu, Zeng-Fu Shang, Benjamin P. C. Chen, Debabrata Saha. Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetorchore-microtubule attachments [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 A39.
Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Authors: Burgenske Danielle , Mladek Ann , Sarkaria Jann
Published: April 2017

Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both established and primary GBM cell lines. Moreover, combined treatment with TMZ demonstrated therapeutic responses that, following regression analysis, were deemed synergistic (p<0.001). Validation studies using siRNA confirmed ATR as a central mediator of TMZ sensitivity as knockdown of ATM elicited no added benefit when tested in combination. VX-970 also enhanced radiation effects in neurosphere formation assays to suggest it may also be used as a radiosensitizer. While the specific mechanism responsible for these observations has yet to be determined, VX-970 treatment was found to exert anti-proliferative effects in a dose-dependent manner. This collection of work suggests that ATR inhibition may represent a worthwhile treatment strategy in GBM.

Citation Format: Danielle Burgenske, Ann Mladek, Jann Sarkaria. The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma [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 B21.
Abstract B37: PARP inhibitor olaparib induces genomic instability in normal mammalian cells
Authors: Vanoli Fabio , Ito Shuhei , Frock Richard L. , Alt Frederick W. , Moynahan Mary Ellen , Jasin Maria
Published: April 2017

Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA damage response pathways to be targeted by specific inhibitors for clinical benefit. Tumors with defects in homologous recombination (HR) are hypersensitive to PARP inhibitors (PARPi), and early phase clinical trials have been promising in patients with advanced BRCA1 and BRCA2-associated breast, ovary and prostate cancer. Unlike HR-defective cells, HR-proficient cells manifest low cytotoxicity when exposed to PARPi. Nonetheless, they mount a DNA damage response and show a genomic instability phenotype as demonstrated by an increased frequency of sister chromatid exchange. To study molecular mechanisms underlying PARPi-generated genomic instability, we took advantage of olaparib an agent in clinical use. Our results in mouse embryonic stem cells show that olaparib increases HR leading to copy number alterations and induces a mutator phenotype. Further, using a genome wide approach we finally demonstrate that PARPi treatment increases DNA double-strand breaks genome-wide which can lead to translocations and other genome aberrations. Our findings have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration in prevention strategies or for non-oncologic indications.

Citation Format: Fabio Vanoli, Shuhei Ito, Richard L. Frock, Frederick W. Alt, Mary Ellen Moynahan, Maria Jasin. PARP inhibitor olaparib induces genomic instability in normal mammalian cells [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 B37.
Abstract B45: A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection
Authors: Young Jordan , Bashkurov Mikhail , McEwan Andrea , Sun Thomas , Datti Alessandro , Durocher Daniel
Published: April 2017

Homologous recombination (HR) is an essential DNA double-strand break (DSB) repair pathway that is of critical importance during the S and G2 phases of the mammalian cell cycle. The limiting step in the HR pathway is the generation of single-stranded DNA (ssDNA) by resection of DNA ends at the DSB site. We have established a high-throughput immunofluorescence-based assay that monitors DNA end resection by plate-based laser scanning cytometry. Employing this assay we screened a genome-scale siRNA library that targeted approximately 18,500 genes. Remarkably, the top hits in our screen were known regulators of resection including CtIP and all three subunits of the MRN complex. I will present ongoing work on one of the hits from the screen, the zinc finger protein ZNF335. The ZNF335 gene was recently found to be mutated in a syndrome that causes some of the worst cases of neonatal microcephaly ever observed. Numerous genome instability syndromes have been documented to display microcephaly as a clinical feature, including Seckel syndrome, which can be caused by mutations in the known resection genes CtIP and DNA2. We first validated the results of the screen by demonstrating that ZNF335 promotes resection and repair by HR. We determined that the four C-terminal zinc finger domains of ZNF335 are necessary and sufficient for its function in resection. Depletion of ZNF335 inhibits phosphorylation of CHK1 at a characterized ATR consensus site, suggesting that ZNF335 is needed for activation of ATR following a DSB. We examined the recruitment of known resection factors to DSB sites and determined that the localization of CtIP and BLM were impaired in cells depleted of ZNF335. Our data suggests that ZNF335 plays an important role in promoting resection and ATR activation in response to DSBs.

Citation Format: Jordan Young, Mikhail Bashkurov, Andrea McEwan, Thomas Sun, Alessandro Datti, Daniel Durocher. A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection [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 B45.