bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of β-Lactam/β-Lactamase Inhibitors for Extended-Spectrum-β-Lactamase Infections: Defining the Right Patient Population
Authors: Tamma Pranita D. , Villegas Maria Virginia
Published: June 2017

In a multicenter, multinational observational study that included neutropenic patients with bloodstream infections by extended-spectrum-β-lactamase-producing species, Gudiol et al. (Antimicrob. Agents Chemother. 61:e00164-17, 2017,
https://doi.org/10.1128/AAC.00164-17
) demonstrated that β-lactam/β-lactamase inhibitors are effective treatment options. A review of this work, however, reminds us that some lingering questions remain for specific high-risk subgroups.
PA3225 Is a Transcriptional Repressor of Antibiotic Resistance Mechanisms in Pseudomonas aeruginosa
Authors: Hall Clayton W. , Zhang Li , Mah Thien-Fah
Published: June 2017

The
tssABC1
locus is part of the Hcp secretion island I (HSI-I) type VI secretion system (T6SS) in
Pseudomonas aeruginosa
. Previous work implicated the
tssC1
gene in
P. aeruginosa
biofilm-specific antibiotic resistance, and
tssC1
is preferentially expressed in biofilms compared to planktonic cells. Using a DNA-dependent protein pulldown approach, we discovered that PA3225, an uncharacterized LysR-type transcriptional regulator, specifically bound to the
tssABC1
upstream regulatory region. The deletion of PA3225 led to a 2-fold decrease in
tssA1
expression levels in planktonic cells compared to the wild type, and
tssA1
expression was slightly reduced in ΔPA3225 biofilms compared to wild-type biofilms. Intriguingly, further investigations revealed that the ΔPA3225 mutant was less susceptible to multiple, structurally unrelated antibiotics with various mechanisms of action when grown planktonically. The ΔPA3225 mutant was additionally more resistant to ciprofloxacin when grown in a biofilm. The decreased antibiotic susceptibility of the ΔPA3225 strain was linked to the transcriptional upregulation of the MexAB-OprM efflux pump. By using transcriptome sequencing (RNA-seq), other PA3225-regulated genes were identified, and the products of these genes, such as the putative ABC transporter PA3228, may also contribute to antibiotic resistance.
Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study
Authors: Nayak Seema U. , Griffiss J. McLeod , Blumer Jeffrey , O'Riordan Mary Ann , Gray Wesley , McKenzie Robin , Jurao Robert A. , An Amanda T. , Le Melissa , Bell Stacie J. , Ochsner Urs A. , Jarvis Thale C. , Janjic Nebojsa , Zenilman Jonathan M.
Published: June 2017

Clostridium difficile
causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase and has potent activity against
C. difficile
and aerobic Gram-positive bacteria but little activity against Gram-negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects each received CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC-MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active-treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. The absorbed drug was glucuronidated at reactive amino groups on the molecule, which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for
C. difficile
infections. (This study has been registered at ClinicalTrials.gov under identifier NCT01551004.)
Chlamydia muridarum with Mutations in Chromosomal Genes
tc0237
and/or
tc0668
Is Deficient in Colonizing the Mouse Gastrointestinal Tract
Authors: Shao Lili , Zhang Tianyuan , Liu Quanzhong , Wang Jie , Zhong Guangming
Published: June 2017

Chlamydiae colonize the gastrointestinal tracts of both animals and humans. However, their medical significance remains unknown. We have previously shown that wild-type
Chlamydia muridarum
spreads to and establishes stable colonization of the gastrointestinal tract following intravaginal inoculation. In the present study, we found that
C. muridarum
with mutations in chromosomal genes
tc0237
and/or
tc0668
was defective in spreading to the mouse gastrointestinal tract, which correlated with its attenuated pathogenicity in the upper genital tract. This correlation was more consistent than that of chlamydial pathogenicity with ascending infection in the genital tract, since attenuated
C. muridarum
spread significantly less to the gastrointestinal tract but maintained robust ascending infection of the upper genital tract. Transcervical inoculation further confirmed the correlation between
C. muridarum
spreading to the gastrointestinal tract and its pathogenicity in the upper genital tract. Finally, defective spreading of
C. muridarum
mutants was due to their inability to colonize the gastrointestinal tract since intragastric inoculation did not rescue the mutants' colonization. Thus, promoting
C. muridarum
colonization of the gastrointestinal tract may represent a primary function of the TC0237 and TC0668 proteins. Correlation of chlamydial colonization of the gastrointestinal tract with chlamydial pathogenicity in the upper genital tract suggests a potential role for gastrointestinal chlamydiae in genital tract pathogenicity.
Cyclic AMP-Independent Control of Twitching Motility in Pseudomonas aeruginosa
Authors: Buensuceso Ryan N. C. , Daniel-Ivad Martin , Kilmury Sara L. N. , Leighton Tiffany L. , Harvey Hanjeong , Howell P. Lynne , Burrows Lori L.
Published: June 2017

FimV is a
Pseudomonas aeruginosa
inner membrane hub protein that modulates levels of the second messenger, cyclic AMP (cAMP), through the activation of adenylate cyclase CyaB. Although type IVa pilus (T4aP)-dependent twitching motility is modulated by cAMP levels, mutants lacking FimV are twitching impaired, even when exogenous cAMP is provided. Here we further define FimV's cAMP-dependent and -independent regulation of twitching. We confirmed that the response regulator of the T4aP-associated Chp chemotaxis system, PilG, requires both FimV and the CyaB regulator, FimL, to activate CyaB. However, in cAMP-replete backgrounds—lacking the cAMP phosphodiesterase CpdA or the CheY-like protein PilH or expressing constitutively active CyaB—
pilG
and
fimV
mutants failed to twitch. Both cytoplasmic and periplasmic domains of FimV were important for its cAMP-dependent and -independent roles, while its septal peptidoglycan-targeting LysM motif was required only for twitching motility. Polar localization of the sensor kinase PilS, a key regulator of transcription of the major pilin, was FimV dependent. However, unlike its homologues in other species that localize flagellar system components, FimV was not required for swimming motility. These data provide further evidence to support FimV's role as a key hub protein that coordinates the polar localization and function of multiple structural and regulatory proteins involved in
P. aeruginosa
twitching motility.

IMPORTANCE
Pseudomonas aeruginosa
is a serious opportunistic pathogen. Type IVa pili (T4aP) are important for its virulence, because they mediate dissemination and invasion via twitching motility and are involved in surface sensing, which modulates pathogenicity via changes in cAMP levels. Here we show that the hub protein FimV and the response regulator of the Chp system, PilG, regulate twitching independently of their roles in the modulation of cAMP synthesis. These functions do not require the putative scaffold protein FimL, proposed to link PilG with FimV. PilG may regulate asymmetric functioning of the T4aP system to allow for directional movement, while FimV appears to localize both structural and regulatory elements—including the PilSR two-component system—to cell poles for optimal function.
Lysinibacillus fusiformis M5 Induces Increased Complexity in Bacillus subtilis 168 Colony Biofilms via Hypoxanthine
Authors: Gallegos-Monterrosa Ramses , Kankel Stefanie , Götze Sebastian , Barnett Robert , Stallforth Pierre , Kovács Ákos T.
Published: June 2017

In recent years, biofilms have become a central subject of research in the fields of microbiology, medicine, agriculture, and systems biology, among others. The sociomicrobiology of multispecies biofilms, however, is still poorly understood. Here, we report a screening system that allowed us to identify soil bacteria which induce architectural changes in biofilm colonies when cocultured with
Bacillus subtilis
. We identified the soil bacterium
Lysinibacillus fusiformis
M5 as an inducer of wrinkle formation in
B. subtilis
colonies mediated by a diffusible signaling molecule. This compound was isolated by bioassay-guided chromatographic fractionation. The elicitor was identified to be the purine hypoxanthine using mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. We show that the induction of wrinkle formation by hypoxanthine is not dependent on signal recognition by the histidine kinases KinA, KinB, KinC, and KinD, which are generally involved in phosphorylation of the master regulator Spo0A. Likewise, we show that hypoxanthine signaling does not induce the expression of biofilm matrix-related operons
epsABCDEFGHIJKLMNO
and
tasA-sipW-tapA
. Finally, we demonstrate that the purine permease PbuO, but not PbuG, is necessary for hypoxanthine to induce an increase in wrinkle formation of
B. subtilis
biofilm colonies. Our results suggest that hypoxanthine-stimulated wrinkle development is not due to a direct induction of biofilm-related gene expression but rather is caused by the excess of hypoxanthine within
B. subtilis
cells, which may lead to cell stress and death.

IMPORTANCE
Biofilms are a bacterial lifestyle with high relevance regarding diverse human activities. Biofilms can be beneficial, for instance, in crop protection. In nature, biofilms are commonly found as multispecies communities displaying complex social behaviors and characteristics. The study of interspecies interactions will thus lead to a better understanding and use of biofilms as they occur outside laboratory conditions. Here, we present a screening method suitable for the identification of multispecies interactions and showcase
L. fusiformis
as a soil bacterium that is able to live alongside
B. subtilis
and modify the architecture of its biofilms.
Trace of nonperturbative charm content of the nucleon on Z + c-jet production
Authors: Rostami S. , Khorramian A.
Published: June 2017

We perform a comparison of the impact of different intrinsic charm (IC) models, based on the prediction of the differential cross-sections of [Formula: see text]-boson and [Formula: see text]-jet production in [Formula: see text] collision. It is shown that regardless of choosing the model, considering nonperturbative intrinsic charm component increases the magnitude of the cross-section when the [Formula: see text] transverse momentum grows or at large rapidity [Formula: see text] of the [Formula: see text]. Moreover, to evaluate the effect of different parton distribution functions (PDFs), we also compare the results of two PDF sets in prediction of production [Formula: see text]-jet in [Formula: see text] at a center-of-mass energy of 13 TeV with taking into account the intrinsic charm contribution in the proton. It is shown that the various PDF sets give some difference in the description of the [Formula: see text]-jet cross-section.
Modeling and Optimization of Multi-Performance Characteristics of Powder-Mixed EDM of Tungsten Carbide Alloy Using Intelligent Decision-Making Tools
Authors: Singh Jagdeep , Sharma Rajiv Kumar
Published: June 2017

The main aim of this work is to propose a hybrid framework, which makes use of intelligent decision-making tools, that are gray, fuzzy, and ANFIS, to optimize the multi-performance characteristics (MPCs) of powder-mixed electrical discharge machining (PM-EDM) of tungsten carbide (WC). To perform the experimentation, four input parameters: (i) pulse-on time, (ii) current, (iii) powder concentration, and (iv) powder grain size are considered to investigate the MPCs such as material removal rate, tool wear rate, surface roughness, and micro-hardness. The proposed framework uses response surface methodology (RSM) with gray, gray-fuzzy, and gray-ANFIS approaches to obtain optimal solution and also to handle the element of uncertainty or fuzziness associated with the uncertain, multi-input, and discrete data. This method helps to generate the values of gray relational grade (GRG), gray-fuzzy reasoning grade (GFRG), and gray adaptive neuro-fuzzy inference system grade (G-ANFISG) for all the 30 experiments. Analysis of variance (ANOVA) is performed on GRG, GFRG, and G-ANFISG to identify the major contributing input parameters which may affect the MPCs. Finally, the theoretical prediction is done to verify the improvement in the performance characteristics obtained through the proposed approaches. Both the experimental and statistical results clearly demonstrate the success of proposed framework for the optimization of PM-EDM of WC alloy.
Numerical Investigation on the Water Entry of Convex Objects Using a Multiphase Smoothed Particle Hydrodynamics Model
Authors: Zou L. , Zhu G. X. , Chen Z. , Pei Y. G. , Zong Z.
Published: June 2017

In this paper, the hydrodynamic behaviors of a typical convex object during water entry are numerically investigated using a meshfree particle method, smoothed particle hydrodynamics (SPH). In order to consider the practical air-cushion effects during water–entry process, a multiphase model with interface force is incorporated to the SPH method to maintain sharp water–air interface. Three numerical examples including bubble rising, water impact on a flate plate and water entry of a wedge are firstly simulated to validate the effectiveness of the multiphase SPH method in predicting the slamming forces and trajectories of falling objects. Water entry of free falling convex objects with different shapes and sizes is then simulated using the validated numerical method for comparative studies. Two slamming processes, including the convex slamming and the structure slamming, are observed in simulations, with double-jetting pattern occurring after the structure slamming. The air-cushion effects are well captured with slamming-induced vortexes clearly shown in the simulation snapshots. Quantitatively, significant drop in pressure peak value is observed when the dimensionless width of the convex is larger than 0.2. Among various shapes of convexes, the square shaped convex experiences the minimal local pressure peak value.
High-intensity interval training and calorie restriction promote remodeling of glucose and lipid metabolism in diet-induced obesity
Authors: Davis Rachel A. H. , Halbrooks Jacob E. , Watkins Emily E. , Fisher Gordon , Hunter Gary R. , Nagy Tim R. , Plaisance Eric P.
Published: June 2017

Calorie restriction (CR) decreases adiposity, but the magnitude and defense of weight loss is less than predicted due to reductions in total daily energy expenditure (TEE). The purpose of the current investigation was to determine whether high-intensity interval training (HIIT) would increase markers of sympathetic activation in white adipose tissue (WAT) and rescue CR-mediated reductions in EE to a greater extent than moderate-intensity aerobic exercise training (MIT). Thirty-two 5-wk-old male C57BL/6J mice were placed on ad libitum HFD for 11 wk, followed by randomization to one of four groups ( n = 8/group) for an additional 15 wk: 1) CON (remain on HFD), 2) CR (25% lower energy intake), 3) CR + HIIT (25% energy deficit created by 12.5% CR and 12.5% EE through HIIT), and 4) CR + MIT (25% energy deficit created by 12.5% CR and 12.5% EE through MIT). Markers of adipose thermogenesis ( Ucp1, Prdm16, Dio2, and Fgf21) were unchanged in either exercise group in inguinal or epididymal WAT, whereas CR + HIIT decreased Ucp1 expression in retroperitoneal WAT and brown adipose tissue. HIIT rescued CR-mediated reductions in lean body mass (LBM) and resting energy expenditure (REE), and both were associated with improvements in glucose/insulin tolerance. Improvements in glucose metabolism in the CR + HIIT group appear to be linked to a molecular signature that enhances glucose and lipid storage in skeletal muscle. Exercise performed at either moderate or high intensity does not increase markers of adipose thermogenesis when performed in the presence of CR but remodels skeletal muscle metabolic and thermogenic capacity.
Silver Nanoparticles Obtained by Semicontinuous Chemical Reduction Using Carboxymethyl Cellulose as a Stabilizing Agent and Its Antibacterial Capacity
Authors: Pedroza-Toscano M. A. , López-Cuenca S. , Rabelero-Velasco M. , Moreno-Medrano E. D. , Mendizabal-Ruiz A. P. , Salazar-Peña R.
Published: June 2017

Preparation of silver nanoparticles was carried out by semicontinuous reduction of Ag+ ions at low temperatures. Silver nitrate was used as the Ag0 precursor, the carboxymethyl cellulose (CMC) as stabilizer and primary reducing agent, and sodium borohydride as reducing agent. Weight ratios of 1 : 1 and 1 : 2 of AgNO3 : CMC were used for carrying out the reactions. Silver nanoparticles were characterized by UV-VIS spectroscopy, transmission electronic microscopy (TEM), and X-ray diffraction (XRD). The formation of silver nanoparticles was confirmed by XRD spectroscopy and by the presence of an absorption peak around 400 nm in the UV-visible spectrum. Unimodal size distributions of spheroidal nanoparticles were observed by TEM. Greater productivities than those reported by other authors were obtained with the advantage of using a lower temperature and minor reaction times. By using a higher CMC/AgNO3 weight ratio or a higher concentration of AgNO3, AgNPs with larger average size were produced. Antibacterial activity of AgNPs against S. aureus and E. coli was determined by the agar disk diffusion method. The higher the AgNPs concentration, the larger the inhibition zone. The minimum inhibitory concentration (MIC) of AgNPs against S. aureus and E. coli was 5 μg/disk.
New Methods of Finite‐Time Synchronization for a Class of Fractional‐Order Delayed Neural Networks
Authors: Zhang Weiwei , Cao Jinde , Alsaedi Ahmed , Alsaadi Fuad E.
Published: June 2017

Finite‐time synchronization for a class of fractional‐order delayed neural networks with fractional order α, 0 < α ≤ 1/2 and 1/2 < α < 1, is investigated in this paper. Through the use of Hölder inequality, generalized Bernoulli inequality, and inequality skills, two sufficient conditions are considered to ensure synchronization of fractional‐order delayed neural networks in a finite‐time interval. Numerical example is given to verify the feasibility of the theoretical results.
Preparation and Characterization of Emamectin Benzoate Solid Nanodispersion
Authors: Yang Dongsheng , Cui Bo , Wang Chunxin , Zhao Xiang , Zeng Zhanghua , Wang Yan , Sun Changjiao , Liu Guoqiang , Cui Haixin
Published: June 2017

The solid nanodispersion of 15% emamectin benzoate was prepared by the method of solidifying nanoemulsion. The mean particle size and polydispersity index of the solid nanodispersions were 96.6±1.7 nm and 0.352±0.041, respectively. The high zeta potential value of 31.3±0.5 mV and stable crystalline state of the nanoparticles suggested the excellent physical and chemical stabilities. The contact angle and retention compared with microemulsions and water dispersible granules on rice, cabbage, and cucumber leaves indicated its improved wettability and adhesion properties. The bioassay compared with microemulsions and water dispersible granules against diamondback moths and green peach aphids provided an evidence of its enhanced biological activity. This formulation composition could avoid organic solvents and obviously reduce surfactants. It is perspective in raising bioavailability and reducing residual pollution of pesticides and further improving agricultural production and environmental safety.
The Japanese Version of the Massachusetts General Hospital Acupuncture Sensation Scale: A Validation Study
Authors: Nishiwaki Masako , Takayama Miho , Yajima Hiroyoshi , Nasu Morihiro , Kong Jian , Takakura Nobuari
Published: June 2017

Acupuncture sensations are considered essential in producing the treatment effect of acupuncture. The Massachusetts General Hospital Acupuncture Sensation Scale (MASS) is a frequently used scale in acupuncture research to measure acupuncture sensations. We translated the MASS into Japanese (Japanese MASS) based on Beaton’s guidelines. 30 acupuncturists evaluated the relevancy and meaning of the 12 descriptors included in the Japanese MASS. The content validity ratios for 10 of the 12 descriptors were 0.33 or greater. 42 healthy subjects then evaluated acupuncture sensations evoked by manual acupuncture at LI4 using the Japanese MASS. Cronbach’s alpha was 0.86. The correlation coefficient of total MASS scores and total Short Form McGill Pain Questionnaire scores and MASS indices and sensory visual analogue scores were 0.78 and 0.80, respectively. Factor analysis loaded the 12 descriptors onto two meaningful factors. This study demonstrated that the Japanese MASS has good reliability, content validity, criterion‐related validity, and construct validity. Therefore, the Japanese MASS is a valid and reliable instrument for use with Japanese populations.
On the Emergence of the Coulomb Forces in Quantum Electrodynamics
Authors: Naudts Jan
Published: June 2017

A simple transformation of field variables eliminates Coulomb forces from the theory of quantum electrodynamics. This suggests that Coulomb forces may be an emergent phenomenon rather than being fundamental. This possibility is investigated in the context of reducible quantum electrodynamics. It is shown that states exist which bind free photon and free electron fields. The binding energy peaks in the long-wavelength limit. This makes it plausible that Coulomb forces result from the interaction of the electron/positron field with long-wavelength transversely polarized photons.
Random Harmonic Detection and Compensation Based on Synchronous Reference Frame
Authors: Che Yanbo , Yin Zhaojing , Yu Shuyan , Sun Qiang
Published: June 2017

Algorithms for harmonic detection and compensation are important guarantees for an active power filter (APF) to achieve the harmonic control function and directly determine the overall performance. Existing algorithms usually need a large amount of computation, and the compensation effect of specified order harmonic is also limited. DC side capacitor voltage at sudden change of load is affected by the algorithm as well. This paper proposes a new algorithm for harmonic detection and compensation based on synchronous reference frame (SRF), in which a band-pass filter with center frequency of 6kth harmonic is designed in fundamental frequency SRF to extract random harmonic current with two different frequencies of (6k±1)th harmonic in stationary reference frame. This new algorithm can rapidly detect any specified harmonic, and it can adjust the power factor to compensate reactive power. Meanwhile, it has few impacts on DC side capacitor voltage under complicated operating conditions such as sudden change of load. The correctness and effectiveness of this new algorithm are verified by simulation and experiment.
The Acupuncture Effect on Median Nerve Morphology in Patients with Carpal Tunnel Syndrome: An Ultrasonographic Study
Authors: Ural Fatma Gülçin , Öztürk Gökhan Tuna
Published: June 2017

Introduction. The aim of this study was to explore the acupuncture effect on the cross‐sectional area (CSA) of the median nerve at the wrist in patients with carpal tunnel syndrome (CTS) and, additionally, to identify whether clinical, electrophysiological, and ultrasonographic changes show any association. Methods. Forty‐five limbs of 27 female patients were randomly divided into two groups (acupuncture and control). All patients used night wrist splint. The patients in the acupuncture group received additional acupuncture therapy. Visual analog scale (VAS), Duruöz Hand Index (DHI), Quick Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores, electrophysiologic measurements, and median nerve CSAs were noted before and after the treatment in both groups. Results. VAS, DHI, Quick DASH scores, and electrophysiological measurements were improved in both groups. The median nerve CSA significantly decreased in the acupuncture group, whereas there was no change in the control group. Conclusion. After acupuncture therapy, the patients with CTS might have both clinical and morphological improvement.
Experimental Investigation and Discrete Element Modelling of Composite Hollow Spheres Subjected to Dynamic Fracture
Authors: Coré Arthur , Kopp Jean-Benoît , Viot Philippe , Charles Jean-Luc , Dau Fréderic
Published: June 2017

This paper deals with the characterization and the numerical modelling of the collapse of composite hollow spherical structures developed to absorb energy during high velocity impacts. The structure is composed of hollow spheres (ϕ=2–30 mm) made of epoxy resin and mineral powder. First of all, quasi-static and dynamic (v=5 mm·min−1 to v=2 m·s−1) compression tests are conducted at room temperature on a single sphere to study energy dissipation mechanisms. Fracture of the material appears to be predominant. A numerical model based on the discrete element method is investigated to simulate the single sphere crushing. The stress-strain-time relationship of the material based on the Ree-Eyring law is numerically implemented. The DEM modelling takes naturally into account the dynamic fracture and the crack path computed is close to the one observed experimentally in uniaxial compression. Eventually, high velocity impacts (v>100 m·s−1) of a hollow sphere on a rigid surface are conducted with an air cannon. The numerical results are in good agreement with the experimental data and demonstrate the ability of the present model to correctly describe the mechanical behavior of brittle materials at high strain rate.
Numerical and Experimental Investigation of Wrinkling Pattern for Aerospace Laminated Membrane Structures
Authors: Hong Yihong , Yao Wenjuan , Xu Yan
Published: June 2017

Al-polymer laminated membranes are widely used in large aerospace structures. When the laminated membranes are pressurized, wrinkles emerge, which have an important effect on the performance of the structures during operation. This paper describes the numerical simulation and experimental investigation of wrinkles in laminated membranes. The nonlinear postbuckling analysis method, based on laminated thin-shell elements, was used to simulate the onset, growth, and final configuration of wrinkles when laminated membranes are subjected to external loads. The simulations are conducted with the ANSYS finite element package. Changing regularities of number, wavelength, and range for the wrinkles during the onset and growth processes are investigated. The wrinkles of laminated membranes with different design parameters such as material selection, ply number, ply angle, and ply mode are predicted. Devices that can be used to clamp and load laminated membranes in several load cases were designed and developed. A 3D photogrammetry system was constructed to characterize wrinkling patterns of laminated membranes subjected to shear displacement loads. By comparing the results of numerical analysis and experimental results, the accuracy of the numerical analysis method was verified. This study work is expected to inform wrinkling simulation and shape control of aerospace laminated membrane structures.
The Best Anticoagulation Strategy for Cirrhotic Patients who Underwent Splenectomy: A Network Meta-Analysis
Authors: Gong Cheng , Qin Xian , Yang Jian , Guo Tao
Published: June 2017

Objective.To determine the best anticoagulation strategy for the patients who underwent splenectomy with cirrhosis through network meta-analysis.Methods.We conducted a systematic review of the literature in PubMed, Embase, and the Cochrane Library database. We extracted data on incidence of Portal vein system thrombosis (PVST) from studies that compared various anticoagulation strategies for use with patients who underwent splenectomy with cirrhosis. Network meta-analysis was conducted in ADDIS by evaluating the different incidence of PVST. Consistency and inconsistency models were developed to identify differences among the therapeutic strategies. Cumulative probability was utilized to rank the strategies under examination. Results. A total of 11 studies containing 1153 patients were included in the network meta-analysis. The results revealed that the application of Antithrombin III was the best anticoagulation option for patients who underwent splenectomy with cirrhosis (P=0.59). The data of consistency and inconsistency models exhibited basically consistent and showed good convergence.Conclusions.Application of Antithrombin III seemed to be the best anticoagulation strategy for cirrhotic patients who underwent splenectomy and should be considered a first-choice clinical reference.
Prevalence of Virulence Genes Associated with Diarrheagenic Pathotypes ofEscherichia coliIsolates from Water, Sediment, Fish, and Crab in Aby Lagoon, Côte d’Ivoire
Authors: Kambire Ollo , Adingra Ama Antoinette , Yao Konan Mathurin , Koffi-Nevry Rose
Published: June 2017

This study was conducted to characterize virulence genes ofEscherichia coliisolates from water, sediment, fish, and crab in Aby Lagoon. Serogrouping was performed by EPEC antisera in 113E. colistrains. The presence of diarrhea-associated genes(eae, stx, AggR, elt,andest)was assessed by multiplex PCR using specific primers. Based on the multiplex PCR, sixty-two isolates (42 from water, 19 from sediment, and 1 from crab) were positive for virulence genes, including 34 positive forelt(ETEC), 46 positive forest(ETEC),24 positive for botheltandest,6 positive forstx(EHEC), 1 positive for bothstx+est, and 1 positive for bothstx+elt.Geneseae(EPEC) andAggR(EAEC) were not detected. Nine serogroups (O114, O127, O55, O111, O86, O119, O126, O128, and O142) were identified. This study revealed the presence of diarrheagenic and nondiarrheagenicE. coliand potential public health risks if fishery products are not appropriately cooked.
Nature and Nurture: What Determines Tumor Metabolic Phenotypes?
Authors: Mayers Jared R. , Vander Heiden Matthew G.
Published: June 2017

Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy. Cancer Res; 77(12); 3131–4. ©2017 AACR.
PPARδ Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC
Authors: Kim Mi-Jin , Choi Yeon-Kyung , Park Soo Young , Jang Se Young , Lee Jung Yi , Ham Hye Jin , Kim Byung-Gyu , Jeon Hui-Jeon , Kim Ji-Hyun , Kim Jung-Guk , Lee In-Kyu , Park Keun-Gyu
Published: June 2017

The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here, we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator–activated receptor-δ (PPARδ), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose-derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress. These glutamine-dependent metabolic alterations were attributed to PPARδ, which was upregulated in sorafenib-resistant HCC cells and human HCC tissues. Furthermore, PPARδ contributed to increased proliferative capacity and redox homeostasis in sorafenib-resistant HCC cells. Accordingly, inhibiting PPARδ activity reversed compensatory metabolic reprogramming in sorafenib-resistant HCC cells and sensitized them to sorafenib. Therefore, targeting compensatory metabolic reprogramming of glutamine metabolism in sorafenib-resistant HCC by inhibiting PPARδ constitutes a potential therapeutic strategy for overcoming sorafenib-resistance in HCC.

Implications: This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPARδ in advanced hepatocellular carcinoma. Mol Cancer Res; 15(9); 1230–42. ©2017 AACR.
Abstract AP01: HE4 IS A BIOMARKER FOR NEWLY DIAGNOSED AND RECURRENT HIGH–GRADE SEROUS OVARIAN CANCERS WITH NORMAL CA–125 VALUES
Authors: LaVigne Katherine , Dao Fanny , Abu–Rustum Nadeem , Jelinic Petar , Ramanathan Lakshmi V. , Fleisher Martin , Levine Douglas A.
Published: June 2017

PURPOSE: CA125 is widely used for the diagnosis and monitoring of women with epithelial ovarian cancer. However, CA125 will not be elevated in ~20% of patients. Human epididymis protein 4 (HE4) was approved by the FDA in 2008 to monitor ovarian cancer. The objective of this study was to evaluate whether HE4 would serve as a useful biomarker in patients with a normal CA125 at either the time of diagnosis or at the time of recurrence.

METHODS: Twenty–one patients with high–grade serous ovarian cancer and CA125 values <50U/ml at the time of diagnosis were identified from a bank of serum specimens collected between 2006–2012. Twenty patients with high–grade serous ovarian cancer and CA125 values >1000U/ml served as positive controls and 11 patients without disease served as negative controls. Fourteen patients with an elevated CA125 at diagnosis (>50 U/ml) and a normal CA125 at the time of recurrence were also identified. HE4 was measured using the Abbott Architect i2000 assay and validation was performed using the Fujirebio HE4 ELISA assay. Normal age–based HE4 values were obtained from the published literature (Urban N, et al.; PMID: 22962406). Data was compared between groups using standard two–sided statistical tests.

RESULTS: At the time of diagnosis, the mean HE4 was 1082±437.9 in the positive control patients with elevated CA125, the mean HE4 was 50.96±11.43 in the patients without disease, and 214.4±236.9 in patients with a normal CA–125 (P = <.0001 compared to normal controls; Student's t–test). At the time of recurrence, the mean HE4 was 102.7±83.29 in patients with normal CA125 levels. For 12 of 14 (86%) patients, the HE4 value was greater than the expected normal age–based reference.

CONCLUSIONS: These preliminary data suggest that HE4 values are elevated in newly diagnosed ovarian cancer patients with a normal CA125 value. HE4 also appears to be a potentially useful biomarker for detecting recurrent disease in patients with an elevated CA125 at the time of diagnosis who have a normal CA125 level at the time of recurrence.

Citation Format: Katherine LaVigne, MD, Fanny Dao, MS, Nadeem Abu–Rustum, MD, Petar Jelinic, PhD, Lakshmi V. Ramanathan, PhD, Martin Fleisher, PhD, Douglas A. Levine, MD. HE4 IS A BIOMARKER FOR NEWLY DIAGNOSED AND RECURRENT HIGH–GRADE SEROUS OVARIAN CANCERS WITH NORMAL CA–125 VALUES [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP01.
Abstract AP07: USE OF COMMON MEDICATIONS AND SURVIVAL AFTER OVARIAN CANCER DIAGNOSIS
Authors: Merritt Melissa A. , Rice Megan S. , Tworoger Shelley S. , Poole Elizabeth M.
Published: June 2017

BACKGROUND: Ovarian cancer is the 5th deadliest cancer among US women. Although clinical characteristics (e.g., disease stage and histology) and treatment (e.g., optimal debulking) predict outcomes, little is known about whether modifiable factors contribute to prognosis. Inflammation and chronic stress have both been implicated in ovarian cancer progression. Therefore, we evaluated whether use of analgesics (aspirin; other non–steroidal anti–inflammatory drugs [NSAIDs], or acetaminophen) or beta–blockers (a common medication for hypertension that targets stress signaling pathways) is associated with ovarian cancer prognosis.

METHODS: The Nurses' Health Study is a prospective study of 121,700 US nurses who have completed biennial questionnaires on lifestyle, medications, and disease diagnosis since 1976. Regular aspirin use (> 2 times/week over the prior year) was queried on every questionnaire since 1980; regular use of other NSAIDs or acetaminophen was queried since 1990; and use of beta–blockers was queried since 1988. We used Cox proportional hazards regression to calculate relative risks (RRs) and 95% confidence intervals (CI), adjusting for tumor and personal characteristics. Women diagnosed with stage IV ovarian cancer were excluded from the analysis.

RESULTS: Available case numbers ranged from 427–779, depending on the medication. Women who regularly used aspirin after diagnosis had a 45% lower risk of dying due to ovarian cancer (RR: 0.55; 95% CI: 0.35–0.86). Post–diagnosis use of other NSAIDs was associated with a suggestive decreased risk of ovarian cancer death (RR: 0.89; 95% CI: 0.60–1.32). There was no association of pre–diagnosis use of any of the analgesic medications with prognosis, nor was there an association of post–diagnosis acetaminophen use with survival. Similarly, there was no association with either pre–diagnosis (RR: 0.92; 95% CI: 0.69–1.23) or post–diagnosis (RR: 0.93; 95% CI: 0.62–1.40) use of beta blockers.

CONCLUSIONS: In this study of analgesic and beta blocker use among ovarian cancer patients, regular use of aspirin after diagnosis appeared to improve survival. Power was limited for some analysis, particularly current use of non–aspirin NSAIDS as there were relatively few current users available for analysis (114 women were current users; 49 of whom died of ovarian cancer during follow–up). Overall, our results suggest that reducing inflammation after diagnosis may be beneficial for improving survival. Future analyses will consider other hypertension medications and well as other modifiable lifestyle factors.

Citation Format: Melissa A. Merritt, Megan S. Rice, Shelley S. Tworoger, Elizabeth M. Poole. USE OF COMMON MEDICATIONS AND SURVIVAL AFTER OVARIAN CANCER DIAGNOSIS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP07.
Abstract AP09: GENOMIC ALTERATIONS IN ENDOMETRIOSIS
Authors: Anglesio Michael S. , Nazeran Tayyebeh M. , Horlings Hugo M. , Lac Vivian , Lum Amy , Senz Janine , Ho Julie , Wang Amy , Wong Fontayne , Allaire Catherine , Williams Christina , Gilks C. Blake , Yong Paul J. , Huntsman David G.
Published: June 2017

BACKGROUND: Endometriosis affects ~10% of reproductive–aged women and is characterized by extra–uterine biphasic growth of uterine endometrial epithelium and stroma. Endometriosis is widely considered to be a hormonally–dependent inflammatory condition and is classified into three anatomically defined types: deep infiltrating endometriosis that locally invades pelvic organs; ovarian endometriotic cysts, and superficial peritoneal endometriosis. A clonal “precursor–cancer” link to co–occurring clear cell and endometrioid ovarian cancers has been established and somatic mutations occur in these cancer–associated endometriotic cysts, including distant benign–appearing lesions. The spectrum of genetic alteration in non–cancer associated endometriosis is not known.

METHODS: We screened a pilot series of 10 deep–infiltrating [pelvic] endometriosis lesions, without co–occurrence or history of cancer, for somatic alterations using laser captured endometrial stroma and epithelium. Two overlapping amplicon panels and digital PCR were used to validate mutations.

RESULTS: In four of ten cases we validated the presence of activating codon 12 KRAS mutations. Mutations were restricted to the epithelium and no evidence of any alterations was found in the stromal fraction.

CONCLUSIONS: We provide incontrovertible evidence of activating KRAS mutations in 40% of deep infiltrating endometriosis. This frequency of KRAS mutations is substantially higher than what has been observed in clear cell (CCOC) or endometrioid (ENOC) ovarian cancers and the occurrence of non–ovarian primary CCOC/ENOC is largely anecdotal. Our evidence suggests that these mutations represent core features of endometriosis itself, rather than a risk of malignant transformation. Overall we propose this as an opportunity to fundamentally shift the study of endometriosis to a spectrum of neoplasms. This may lead to the generation of a molecularly informed classification system and ultimately to improved prognostication and treatment.

Citation Format: Michael S. Anglesio, Tayyebeh M. Nazeran, Hugo M. Horlings, Vivian Lac, Amy Lum, Janine Senz, Julie Ho, Amy Wang, Fontayne Wong, Catherine Allaire, Christina Williams, C. Blake Gilks, Paul J. Yong, and David G. Huntsman. GENOMIC ALTERATIONS IN ENDOMETRIOSIS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP09.
Abstract AP15: MODULATION OF OXIDATIVE STRESS AND SUBSEQUENT INDUCTION OF APOPTOSIS AND ENDOPLASMIC RETICULUM STRESS ALLOWS CITRAL TO DECREASE CANCER CELL PROLIFERATION
Authors: Kapur Arvinder , Felder Mildred , Fass Lucas , Kaur Justanjot , Czarnecki Austin , Rathi Kavya , Zeng San , Osowski Kathryn Kalady , Howell Colin , Xiong May P. , Whelan Rebecca J. , Patankar Manish S.
Published: June 2017

The monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5, and phospho-eIF2α. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA, and NOXA expression. Inhibition of p53 by pifithrin-α, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of gluthatione synthesis by L-buthionine sulfoxamine increased potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent, and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors.

Citation Format: Arvinder Kapur, Mildred Felder, Lucas Fass, Justanjot Kaur, Austin Czarnecki, Kavya Rathi, San Zeng, Kathryn Kalady Osowski, Colin Howell, May P. Xiong, Rebecca J. Whelan, Manish S. Patankar. MODULATION OF OXIDATIVE STRESS AND SUBSEQUENT INDUCTION OF APOPTOSIS AND ENDOPLASMIC RETICULUM STRESS ALLOWS CITRAL TO DECREASE CANCER CELL PROLIFERATION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP15.
Abstract AP25: INHIBITION OF HDAC ACTIVITY SELECTIVELY INHIBITS ARID1A–MUTATED OVARIAN CLEAR CELL CARCINOMA THROUGH A NOVEL P53 REGULATORY MECHANISM
Authors: Bitler Benjamin G. , Park Pyoung Hwa , Hai Yang , Aird Katherine M. , Wang Yemin , Huntsman David G. , Cho Kathleen R. , Christianson David W. , Zhang Rugang
Published: June 2017

PURPOSE OF THE STUDY: ARID1A is mutated ~50% and 30% of clear cell (OCCC) and endometrioid (OEC) ovarian cancers, respectively. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression. In several cancers including OCCC, ARID1A and p53 mutations are often mutually exclusive. OCCC carries a worse prognosis compared to the other histosubtypes of ovarian cancer. Thus, there is an urgent clinical need for improved therapeutic strategies.

EXPERIMENTAL PROCEDURE: To investigate the role of specific HDACs in the context of ARID1A expression, we examined the effect of knocking down HDACs in an isogenic OCCC cell line with and without ARID1A expression. Utilizing a panel of ARID1A-mutated and wildtype OCCC cell lines, we evaluated the effect of HDAC knockdown and inhibition through a variety of 2D and 3D assays. We also examined the consequence of HDAC inhibition on tumor growth, survival, and dissemination in an in vivo mouse model of ovarian cancer.

SUMMARY OF THE DATA: We have discovered that ARID1A is involved in the repression of HDACs, and ARID1A-inactivation promotes aberrant transcriptional regulation of HDACs. Importantly, we uncovered a novel HDAC-dependent regulatory mechanism of p53. Several HDAC inhibitors are currently in clinical trials. We found HDAC inhibitors were more selective in ARID1A-mutated OCCC cell lines compared to ARID1A-wildtype cells. We observed that HDAC inhibition led to a significant increase in apoptosis in ARID1A-mutated cells. In an orthotopic intra-bursal xenograft model using ARID1A wildtype and deficient cells, the HDAC inhibitor suppressed primary tumor growth and inhibited tumor cell dissemination only in the ARID1A-mutated tumors. Significantly, HDAC inhibition significantly improved the survival of mice bearing ARID1A-mutated tumors.

CONCLUSIONS: These findings imply that HDAC inhibition represents a novel therapeutic strategy for ARID1A-deficient cancers. This study further elucidates the observed mutual exclusivity of ARID1A and p53. Importantly, we have uncovered a novel regulatory mechanism of p53 mediated through ARID1A and HDACs. Clinically, this study describes a precision medicine approach to the treatment of ARID1A-mutated OCCC.

Citation Format: Benjamin G. Bitler, Pyoung Hwa Park, Yang Hai, Katherine M. Aird, Yemin Wang, David G. Huntsman, Kathleen R. Cho, David W. Christianson, Rugang Zhang. INHIBITION OF HDAC ACTIVITY SELECTIVELY INHIBITS ARID1A–MUTATED OVARIAN CLEAR CELL CARCINOMA THROUGH A NOVEL P53 REGULATORY MECHANISM [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP25.