bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamical Analysis and Circuit Simulation of a New Fractional-Order Hyperchaotic System and Its Discretization
Authors: El-Sayed A. M. A. , Elsonbaty A. , Elsadany A. A. , Matouk A. E.
Published: December 2016

This paper presents an analytical framework to investigate the dynamical behavior of a new fractional-order hyperchaotic circuit system. A sufficient condition for existence, uniqueness and continuous dependence on initial conditions of the solution of the proposed system is derived. The local stability of all the system’s equilibrium points are discussed using fractional Routh–Hurwitz test. Then the analytical conditions for the existence of a pitchfork bifurcation in this system with fractional-order parameter less than 1/3 are provided. Conditions for the existence of Hopf bifurcation in this system are also investigated. The dynamics of discretized form of our fractional-order hyperchaotic system are explored. Chaos control is also achieved in discretized system using delay feedback control technique. The numerical simulation are presented to confirm our theoretical analysis via phase portraits, bifurcation diagrams and Lyapunov exponents. A text encryption algorithm is presented based on the proposed fractional-order system. The results show that the new system exhibits a rich variety of dynamical behaviors such as limit cycles, chaos and transient phenomena where fractional-order derivative represents a key parameter in determining system qualitative behavior.
Periodic Orbits in a Second-Order Discontinuous System with an Elliptic Boundary
Authors: Li Liping , Luo Albert C. J.
Published: December 2016

This paper develops the analytical conditions for the onset and disappearance of motion passability and sliding along an elliptic boundary in a second-order discontinuous system. A periodically forced system, described by two different linear subsystems, is considered mainly to demonstrate the methodology. The passable, sliding and grazing conditions of a flow to the elliptic boundary in the discontinuous dynamical system are provided through the analysis of the corresponding vector fields and [Formula: see text]-functions. Moreover, by constructing appropriate generic mappings, periodic orbits in such a discontinuous system are predicted analytically. Finally, three different cases are discussed to illustrate the existence of periodic orbits with passable and/or sliding flows. The results obtained in this paper can be applied to the sliding mode control in discontinuous dynamical systems.
LRS Bianchi type I magnetized cosmological model with perfect fluid and with quintessence, Chaplygin gas dark energy in bimetric theory of gravitation
Authors: Borkar M. S. , Gayakwad P. V.
Published: December 2016

We studied the LRS Bianchi type I cosmological models with perfect fluid, quintessence and standard Chaplygin gas dark energy in the presence as well as in the absence of magnetic field [Formula: see text], in bimetric theory of gravitation. It is realized that the magnetic field controlled the whole behavior of the models. In the absence of magnetic field, these models exists and the model never exists in the presence of magnetic field. The geometry of quintessence model for [Formula: see text] and standard Chaplygin gas model coincide and their physical behavior are same in the absence of magnetic field. Some geometrical and physical properties of each of the model are explored. The model have also been studied in regard with the singularities and it is pointed out that the model is singular in the presence of magnetic field and nonsingular in the absence of magnetic field.
The influence of an equation-of-state during radiative collapse
Authors: Govender M. , Bogadi R. S. , Maharaj S. D.
Published: December 2016

We study the role played by an equation-of-state during gravitational collapse of a radiating star. Starting from an initially static matter configuration obeying a linear equation-of-state, the star loses hydrostatic equilibrium and undergoes dissipative collapse in the form of a radial heat flux. We show that the equation-of-state parameter plays an important role in determining the temperature profiles of the collapsing body.
DIMENSION ANALYSIS OF CONTINUOUS FUNCTIONS WITH UNBOUNDED VARIATION
Authors: WANG JUN , YAO KUI
Published: December 2016

In this paper, we mainly discuss fractal dimensions of continuous functions with unbounded variation. First, we prove that Hausdorff dimension, Packing dimension and Modified Box-counting dimension of continuous functions containing one UV point are [Formula: see text]. The above conclusion still holds for continuous functions containing finite UV points. More generally, we show the result that Hausdorff dimension of continuous functions containing countable UV points is [Formula: see text] also. Finally, Box dimension of continuous functions containing countable UV points has been proved to be [Formula: see text] when [Formula: see text] is self-similar.
A Numerical Homogenization Scheme for Glass Particle-Toughened Polymers Under Dynamic Loading
Authors: Karamnejad Amin , Ahmed Awais , Sluys Lambertus Johannes
Published: December 2016

A numerical homogenization scheme is presented to model glass particle-toughened polymer materials under dynamic loading. A constitutive law is developed for the polymer material and validated by comparing the results to experimental test data. A similar constitutive law as that of the polymer material with unknown material parameters is assumed for the glass particle-toughened polymer. A homogenization scheme is used to determine the unknown material parameters from the boundary value problem (BVP) of a representative volume element. Unlike the standard computational homogenization scheme, the proposed numerical homogenization scheme can be used after localization occurs in the material. The proposed multiscale model is then verified against direct numerical simulation.
Monotone homotopies and contracting discs on Riemannian surfaces
Authors: Chambers Gregory R. , Rotman Regina
Published: December 2016

A monotone homotopy is a homotopy composed of simple closed curves which are also pairwise disjoint. In this paper, we prove a “gluing” theorem for monotone homotopies; we show that two monotone homotopies which have appropriate overlap can be replaced by a single monotone homotopy. The ideas used to prove this theorem are used in [G. R. Chambers and Y. Liokumovich, Existence of minimal hypersurfaces in complete manifolds of finite volume, arXiv:1609.04058] to prove an analogous result for cycles, which forms a critical step in their proof of the existence of minimal surfaces in complete non-compact manifolds of finite volume.

We also show that, if monotone homotopies exist, then fixed point contractions through short curves exist. In particular, suppose that [Formula: see text] is a simple closed curve of a Riemannian surface, and that there exists a monotone contraction which covers a disc which [Formula: see text] bounds consisting of curves of length [Formula: see text]. If [Formula: see text] and [Formula: see text], then there exists a homotopy that contracts [Formula: see text] to [Formula: see text] over loops that are based at [Formula: see text] and have length bounded by [Formula: see text], where [Formula: see text] is the diameter of the surface. If the surface is a disc, and if [Formula: see text] is the boundary of this disc, then this bound can be improved to [Formula: see text].
Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes
Authors: Škrtić Marko , Lytvyn Yuliya , Bjornstad Petter , Reich Heather N. , Scholey James W. , Yip Paul , Sochett Etienne B. , Perkins Bruce , Cherney David Z. I.
Published: December 2016

The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration—an early hemodynamic abnormality associated with diabetic nephropathy—would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC ( n = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [ n = 36, T1D-N, glomerular filtration rate (GFR) 90–134 ml·min−1·1.73 m2] or hyperfiltration ( n = 32, T1D-H, GFR ≥ 135 ml·min−1·1.73 m2) during euglycemic conditions (4–6 mmol/l). Gomez’s equations were used to derive efferent (RE) and afferent (RA) arteriolar resistances, glomerular hydrostatic pressure (PGLO) from inulin (GFR) and paraaminohippurate [effective renal plasma flow (ERPF)] clearances, plasma protein and estimated ultrafiltration coefficients (KFG). Female patients with T1D with hyperfiltration (T1D-H) had higher RE(1,985 ± 487 vs. 1,381 ± 296 dyne·sec−1·cm−5, P < 0.001) and filtration fraction (FF, 0.20 ± 0.047 vs. 0.16 ± 0.03 P < 0.05) and lower ERPF (876 ± 245 vs. 1,111 ± 298 134 ml·min−1·1.73 m2P < 0.05) compared with male T1D-H patients. Overall, T1D-H patients had higher PGLOand lower RAvs. HC subjects, although there were no sex-based differences. In conclusion, female T1D-H patients had higher REand FF and lower ERPF than their male counterparts with no associated sex differences in RA. Prospective intervention studies should consider sex as a modifier of renal hemodynamic responses to renal protective therapies.
Whole body acid-base modeling revisited
Authors: Ring Troels , Nielsen Søren
Published: December 2016

The textbook account of whole body acid-base balance in terms of endogenous acid production, renal net acid excretion, and gastrointestinal alkali absorption, which is the only comprehensive model around, has never been applied in clinical practice or been formally validated. To improve understanding of acid-base modeling, we managed to write up this conventional model as an expression solely on urine chemistry. Renal net acid excretion and endogenous acid production were already formulated in terms of urine chemistry, and we could from the literature also see gastrointestinal alkali absorption in terms of urine excretions. With a few assumptions it was possible to see that this expression of net acid balance was arithmetically identical to minus urine charge, whereby under the development of acidosis, urine was predicted to acquire a net negative charge. The literature already mentions unexplained negative urine charges so we scrutinized a series of seminal papers and confirmed empirically the theoretical prediction that observed urine charge did acquire negative charge as acidosis developed. Hence, we can conclude that the conventional model is problematic since it predicts what is physiologically impossible. Therefore, we need a new model for whole body acid-base balance, which does not have impossible implications. Furthermore, new experimental studies are needed to account for charge imbalance in urine under development of acidosis.
Search for Excited Spin-3/2 Neutrinos at LHeC
Authors: Ozansoy A. , Arı V. , Çetinkaya V.
Published: December 2016

We study the potential of the nextepcollider, namely, LHeC, with two optionss=1.3 TeV ands=1.98 TeV, to search for excited spin-1/2 and spin-3/2 neutrinos. We calculate the single production cross-section of excited spin-1/2 and spin-3/2 neutrinos according to their effective currents describing their interactions between gauge bosons and SM leptons. We choose theν⋆→eWdecay mode of excited neutrinos andW→jjdecay mode ofW-boson for the analysis. We put some kinematical cuts for the final state detectable particles and plot the invariant mass distributions for signal and the corresponding backgrounds. In order to obtain accessible limits for excited neutrino couplings, we show thef-f′andciV-ciAcontour plots for excited spin-1/2 and excited spin-3/2 neutrinos, respectively.
Emerging Perils of Extended Spectrumβ-Lactamase Producing Enterobacteriaceae Clinical Isolates in a Teaching Hospital of Nepal
Authors: Parajuli Narayan Prasad , Maharjan Pooja , Joshi Govardhan , Khanal Puspa Raj
Published: December 2016

Introduction. Infections due to extended spectrumβ-lactamase producing Enterobacteriaceae are on the rise. They pose serious public health problems due to their resistance to large number of antibiotics. However, little is known about the genotypes of ESBL from Nepal. Therefore, the study presents results of phenotypic and molecular characterization of ESBL producingEscherichia coliandKlebsiellaspp. isolated from various clinical specimens in a tertiary care teaching hospital of Nepal.Methods. A total of 172 Enterobacteriaceae clinical isolates recovered from various clinical specimens were analyzed for their antibiotic susceptibility test. Detection of ESBLs was carried out using combination disk test and multiplex PCR for their genotypes (CTX-M, SHV, and TEM).Results. Out of 172 clinical isolates, 70 (40.6%) of them were found ESBL producers. The major source of ESBL producers was urinary tract samples and the highest ESBL production was observed inEscherichia coli(46.5%). Among ESBL genotypes, CTX-M (91.4%) was most predominant, followed by TEM (65.7%) and SHV (11.4%) in both of the isolates.Conclusions. High level of drug resistance and ESBL production was observed among the clinical isolates. There is a need for longitudinal and nationwide surveillance for drug resistance in clinical isolates and antimicrobial stewardship is necessary to guide the appropriate and judicious antibiotic use.
Proteome Changes of Human Bone Marrow Mesenchymal Stem Cells Induced by 1,4-Benzoquinone
Authors: Wu Wei , Zhang Ling , Zhang Min , Zhu Li-Jin , Xia Hai-Ling , Lou Jian-Lin , Liu Jia-Ren , Xiao Yun
Published: December 2016

Benzene is metabolized to hydroquinone in liver and subsequently transported to bone marrow for further oxidization to 1,4-benzoquinone (1,4-BQ), which may be related to the leukemia and other blood disorders. In the present study, we investigated the proteome profiles of human primary bone marrow mesenchymal stem cells (hBM-MSCs) treated by 1,4-BQ. We identified 32 proteins that were differentially expressed. Two of them, HSP27 and Vimentin, were verified at both mRNA and protein levels and their cellular localization was examined by immunofluorescence. We also found increased mRNA level of RAP1GDS1, a critical factor of metabolism that has been identified as a fusion partner in various hematopoietic malignancies. Therefore, these differentially expressed proteins can play important roles in benzene-mediated hematoxicity.
Daphnetin Protects against Cerebral Ischemia/Reperfusion Injury in Mice via Inhibition of TLR4/NF-κB Signaling Pathway
Authors: Liu Jia , Chen Qianxue , Jian Zhihong , Xiong Xiaoxing , Shao Lingmin , Jin Tong , Zhu Xiqun , Wang Lei
Published: December 2016

Growing evidences indicate that immune-mediated mechanisms contribute to the development of cerebral ischemia/reperfusion (I/R) injury. Daphnetin (DAP) is a coumarin derivative extracted from Daphne odora var., which displays anti-inflammatory properties. However, the effect of DAP on cerebral I/R injury is not yet clear. Recent studies have demonstrated that TLR4/NF-κB signaling pathway takes part in the damaging inflammatory process of cerebral I/R injury. The present study aimed to investigate the effect of DAP on cerebral I/R injury in vivo and its possible mechanisms. DAP was administered before middle cerebral artery occlusion and reperfusion in mice. The neurological scores, cerebral infarct sizes, the levels of inflammatory cytokines, apoptotic neural cells, and the levels of TLR4, NF-κB p65, and IκBα were estimated. The results showed that an obvious improvement of neurological scores and infarct sizes was observed in DAP-treated mice after MCAO/R. DAP treatment decreased the overexpression of TNF-α, IL-1β, and IL-6 and attenuated neural cells apoptosis. Moreover, DAP treatment decreased the TLR4 expression, IκB-α degradation, and nuclear translocation of NF-κB. Taken together, our results suggested that DAP exerted neuroprotective and anti-inflammatory effects on cerebral I/R injury. The potential mechanism was involved in the inhibition of TLR4/NF-κB mediated inflammatory signaling pathway.
A New Adaptive Control for Five-Phase Fault-Tolerant Flux-Switching Permanent Magnet Motor
Authors: Tang Hongyu , Zhao Wenxiang , Gu Chenyu
Published: December 2016

The five-phase fault-tolerant flux-switching permanent magnet (FT-FSPM) motor can offer high efficiency and high fault-tolerant capability. In this paper, its operation principle is presented briefly and its mathematical model is derived. Further, a new adaptive control for an FT-FSPM motor, based on the backstepping method and the sliding mode control strategy, is proposed. According to the backstepping method, the current controllers and voltage control laws are designed to track the speed and minimize the current static error, which enhance the dynamic response and the ability to suppress external disturbances. In order to overcome the influence of parameter variations, according to sliding mode control theory, the virtual control variables and the adaptive algorithm are utilized to approach uncertainty terms. Three Lyapunov functions are designed, and the stability of the closed-loop system is analyzed in detail. Finally, both simulation and experimental results are presented to verify the proposed control method.
Acupuncture for Functional Dyspepsia: What Strength Does It Have? A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Pang Bo , Jiang Tao , Du Yuan-Hao , Li Jing , Li Bo , Hu Ya-Cai , Cai Qiu-Han
Published: December 2016

Background. Although the effectiveness of acupuncture therapy on functional dyspepsia (FD) has been systematically reviewed, the available reports are still contradictive and no robust evidence has been provided to date. Objective. To assess the current evidence of high quality on the effects of acupuncture for patients with FD. Methods. A comprehensive literature database search was conducted to identify randomized controlled trials (RCTs) comparing acupuncture therapies (including manual acupuncture and electroacupuncture) to sham acupuncture and medication use. A meta‐analysis was performed following a strict methodology. Results. 16 RCTs involving 1436 participants were included. The majority of the trials were determined to be of low quality. Positive results were found for acupuncture in improving the Nepean Dyspepsia Index (NDI) and scores of the MOS 36‐Item Short‐Form Health Survey (SF‐36), as well as in alleviating relevant symptoms (especially postprandial fullness and early satiation) of FD patients. Conclusion. Based on current available evidence, acupuncture therapy achieves statistically significant effect for FD in comparison with sham acupuncture and is superior to medication (prokinetic agents) in improving the symptoms and quality of life of FD patients. Nonetheless, despite stringent methodological analyses, the conclusion of our review still needs to be strengthened by additional RCTs of higher quality.
Model and Simulation of Network Crisis Information Diffusion under Uncertain Environment
Authors: Deng Yi-Rui , Zhang Rui-Hong
Published: December 2016

Network crisis information diffusion will have a certain impact on the public’s psychology and behavior and will cause harm to the normal operation social of the public system and the effective allocation of the public resources. So we should timely control the key factors which affect the diffusion process to reduce the damage. Using cellular automata theory, the paper views the public as a series of cellular automata and sets up some cellular state evolution rules. With the help of MATLAB simulated evolution, this paper explores the diffusion rule of crisis information diffusion process and finds out the key factors of crisis information diffusion process and its influence on the diffusion scale and effect, so as to put forward coping strategies. It is hoped that this paper provides reference for the theoretical study of the crisis information diffusion and provides suggestion for the real world to control the crisis information diffusion.
Shaping Single Offset Reflector Antennas Using Local Axis-Displaced Confocal Quadrics
Authors: Penchel Rafael A. , Bergmann José R. , Moreira Fernando J. S.
Published: December 2016

This work investigates a novel numerical procedure for the solution of an exact formulation for the Geometrical Optics synthesis of a single reflector antenna by simultaneously imposing Snell’s Law and Conservation of Energy in a tube of rays, yielding a second-order nonlinear partial differential equation of Monge-Ampère type, which can be solved as a boundary value problem. The investigation explores the interpolating properties of confocal quadrics to locally represent the shaped reflector surface. It allows the partial derivatives involved in the formulation to be analytically expressed. To illustrate the method, two examples of offset single reflectors shaped to radiate a Gaussian power density within a superelliptical contoured beam are presented. The results are validated by Physical Optics analysis with equivalent edge currents.
Mucosal Vaccine Development Based on Liposome Technology
Authors: Bernasconi Valentina , Norling Karin , Bally Marta , Höök Fredrik , Lycke Nils Y.
Published: December 2016

Immune protection against infectious diseases is most effective if located at the portal of entry of the pathogen. Hence, there is an increasing demand for vaccine formulations that can induce strong protective immunity following oral, respiratory, or genital tract administration. At present, only few mucosal vaccines are found on the market, but recent technological advancements and a better understanding of the principles that govern priming of mucosal immune responses have contributed to a more optimistic view on the future of mucosal vaccines. Compared to live attenuated vaccines, subcomponent vaccines, most often protein-based, are considered safer, more stable, and less complicated to manufacture, but they require the addition of nontoxic and clinically safe adjuvants to be effective. In addition, another limiting factor is the large antigen dose that usually is required for mucosal vaccines. Therefore, the combination of mucosal adjuvants with the recent progress in nanoparticle technology provides an attractive solution to these problems. In particular, the liposome technology is ideal for combining protein antigen and adjuvant into an effective mucosal vaccine. Here, we describe and discuss recent progress in nanoparticle formulations using various types of liposomes that convey strong promise for the successful development of the next generation of mucosal vaccines.
The Cognitive Functions in Adults with Chronic Pain: A Comparative Study
Authors: Nadar Mohammed Shaban , Jasem Zainab , Manee Fahad S.
Published: December 2016

Background. Several studies have reported an association between chronic pain and reduction of cognitive abilities of adults living in Western cultures. No literature could be found on the relationship between chronic pain and cognition among Middle Eastern adults. Objective. To compare four of the most commonly reported cognitive domains [memory, attention, processing speed, and executive functioning] among Middle Eastern adults with and without chronic pain. Methods. This matched group comparative study included 69 community residing and functionally independent Middle Eastern adults. Forty participants had chronic pain and 29 were pain-free. We administered five standardized cognitive assessments that are independent of culture and language to measure variable tasks of memory, attention, processing speed, and executive functioning. The study was conducted in a rehabilitation research setting with a controlled environment. Results. Evidence of decreased cognitive processing was found in patients with chronic pain. The chronic pain participants performed significantly worse than the pain-free participants on the cognitive measures of long-term memory, selective attention, processing speed, and executive functioning. Conclusion. The effect of Middle Eastern culture on the cognitive abilities of patients with chronic pain was negligible. Despite the wide variations between Eastern and Western cultures, the performance of our Middle Eastern participants in this study was consistent with performance of Western adults reported in previous studies.
Aspirin Protects against Acinar Cells Necrosis in Severe Acute Pancreatitis in Mice
Authors: Lu Guotao , Tong Zhihui , Ding Yanbing , Liu Jinjiao , Pan Yiyuan , Gao Lin , Tu Jianfeng , Wang Yuhui , Liu George , Li Weiqin
Published: December 2016

Aspirin has a clear anti-inflammatory effect and is used as an anti-inflammatory agent for both acute and long-term inflammation. Previous study has indicated that aspirin alleviated acute pancreatitis induced by caerulein in rat. However, the role of aspirin on severe acute pancreatitis (SAP) and the necrosis of pancreatic acinar cell are not yet clear. The aim of this study was to determine the effects of aspirin treatment on a SAP model induced by caerulein combined with Lipopolysaccharide. We found that aspirin reduced serum amylase and lipase levels, decreased the MPO activity, and alleviated the histopathological manifestations of pancreas and pancreatitis-associated lung injury. Proinflammatory cytokines were decreased and the expression of NF-κB p65 in acinar cell nuclei was suppressed after aspirin treatment. Furthermore, aspirin induced the apoptosis of acinar cells by TUNEL assay, and the expression of Bax and caspase 3 was increased and the expression of Bcl-2 was decreased. Intriguingly, the downregulation of critical necrosis associated proteins RIP1, RIP3, and p-MLKL was observed; what is more, we additionally found that aspirin reduced the COX level of pancreatic tissue. In conclusion, our data showed that aspirin could protect pancreatic acinar cell against necrosis and reduce the severity of SAP. Clinically, aspirin may potentially be a therapeutic intervention for SAP.
Validation of Administrative Osteoarthritis Diagnosis Using a Clinical and Radiological Population-Based Cohort
Authors: Rahman M. Mushfiqur , Kopec Jacek A. , Goldsmith Charlie H. , Anis Aslam H. , Cibere Jolanda
Published: December 2016

Objectives.The validity of administrative osteoarthritis (OA) diagnosis in British Columbia, Canada, was examined against X-rays, magnetic resonance imaging (MRI), self-report, and the American College of Rheumatology criteria.Methods.During 2002–2005, 171 randomly selected subjects with knee pain aged 40–79 years underwent clinical assessment for OA in the knee, hip, and hands. Their administrative health records were linked during 1991–2004, in which OA was defined in two ways: (AOA1) at least one physician’s diagnosis or hospital admission and (AOA2) at least two physician’s diagnoses in two years or one hospital admission. Sensitivity, specificity, and predictive values were compared using four reference standards.Results.The mean age was 59 years and 51% were men. The proportion of OA varied from 56.3 to 89.7% among men and 77.4 to 96.4% among women according to reference standards. Sensitivity and specificity varied from 21 to 57% and 75 to 100%, respectively, and PPVs varied from 82 to 100%. For MRI assessment, the PPV of AOA2 was 100%. Higher sensitivity was observed in AOA1 than AOA2 and the reverse was true for specificity and PPV.Conclusions.The validity of administrative OA in British Columbia varied due to case definitions and reference standards. AOA2 is more suitable for identifying OA cases for research using this Canadian database.
Formulation of Bilayer Benzydamine HCl Patch Targeted For Gingivitis
Authors: Sanghai Piyush , Nandgude Tanaji , Poddar Sushilkumar
Published: December 2016

In the present study bilayer patch of benzydamine HCl was developed using solvent casting method. Different substrates were attempted like Petri dish, glass-and-ring, and teflon-and-ring for selection of the proper option to formulate patch that should give easily peelable film with adequate mechanical properties. HPMC E15 LV was used in different concentrations for obtaining proper viscosity of solution for pouring on to surface and ring, that it should not leak from ring. The second layer was optimized by using different polymer like eudragit RSPO, eudragit RSPO + EC, and eudragit NE30 D for efficient layer bonding. The minimum release from backing membrane was established by diffusion study as compared to from drug loaded layer. The optimized batches were evaluated for folding endurance, weight variation, thickness, drug content, drug release, tensile strength, layer separation, mucoadhesion, moisture uptake, and layer bonding. The novel gingival patch of benzydamine HCl developed would be beneficial in optimizing the therapy.
Cardinal Basis Piecewise Hermite Interpolation on Fuzzy Data
Authors: Vosoughi H. , Abbasbandy S.
Published: December 2016

A numerical method along with explicit construction to interpolation of fuzzy data through the extension principle results by widely used fuzzy-valued piecewise Hermite polynomial in general case based on the cardinal basis functions, which satisfy a vanishing property on the successive intervals, has been introduced here. We have provided a numerical method in full detail using the linear space notions for calculating the presented method. In order to illustrate the method in computational examples, we take recourse to three prime cases: linear, cubic, and quintic.
Is Universal Screening Necessary? Incidence of Tuberculosis among Tibetan Refugees Arriving in Calgary, Alberta
Authors: Lim Rachel , Jarand Julie , Field Stephen K. , Fisher Dina
Published: December 2016

Background. Canadian policy requires refugees with a history of tuberculosis (TB) or abnormal chest radiograph to be screened after arrival for TB. However, Tibetan refugees are indiscriminately screened, regardless of preimmigration assessment. We sought to determine the incidence of latent (LTBI) and active TB, as well as treatment-related outcomes and associations between preimmigration factors and TB infection among Tibetan refugees arriving in Calgary, Alberta. Design. Retrospective cohort study including Tibetan refugees arriving between 2014 and 2016. Associations between preimmigration factors and incidence of latent and active TB were determined using Chi-square tests. Results. Out of 180 subjects, 49 percent had LTBI. LTBI was more common in migrants 30 years of age or older (P=0.009). Treatment initiation and completion rates were high at 90 percent and 76 percent, respectively. No associations between preimmigration factors and treatment completion were found. A case of active TB was detected and treated. Conclusion. Within this cohort, the case of active TB would have been detected through the usual postsurveillance process due to a history of TB and abnormal chest radiograph. Forty-nine percent had LTBI, compared to previously quoted rates of 97 percent. Tibetan refugees should be screened for TB in a similar manner to other refugees resettling in Canada.
A Pilot Study to Assess the Feasibility of the Spanish Diabetes Self-Management Program in the Basque Country
Authors: Gamboa Moreno Estibaliz , Ochoa de Retana Garcia Lourdes , del Campo Pena Maria Emma , Sánchez Perez Álvaro , Martinez Carazo Catalina , Arbonies Ortiz Juan Carlos , Rua Portu Maria Angeles , Piñera Elorriaga Koldo , Zenarutzabeitia Pikatza Amaya , Urquiza Bengoa Miren Nekane , Méndez Sanpedro Tomás , Oses Portu Ana , Gorostidi Fano Lourdes , Aguirre Sorondo Miren Bakarne , Vrotsou Kalliopi , Rotaeche Del Campo Rafael
Published: December 2016

Purpose. The purpose of this study was to assess the feasibility of the Spanish Diabetes Self-Management Program (SDSMP) in the primary care setting of the Basque Health Service and offer initial estimations of the randomized controlled trial (RCT) effects. Methods. Ten health centers (HCs) participated in a single-arm pilot study with a 6-month follow-up period between February 2011 and June 2012. Recruitment was performed via invitation letters, health professionals, and the local media. Each intervention group consisted of 8–15 people. The ability of each HC in forming up to 2 groups, participants’ compliance with the course, and coordination and data collection issues were evaluated. Glycated haemoglobin (HbA1c) was the main outcome variable. Secondary outcomes were cardiovascular risk factors, drugs consumption, medical visits, quality of life, self-efficacy, physical exercise, and diet. Results. Two HCs did not organize a course. A total of 173 patients initiated the program, 2 dropped out without baseline data, and 90% completed it. No pre-post HbA1c differences existed. Certain improvements were observed in blood pressure control, self-efficacy, physical activity, and some dietary habits. Conclusion. The SDSMP is feasible in our setting. Our experience can be of interest when planning and conducting this program in similar health settings. The trial is registered with ClinicalTrials.gov identifier NCT01642394.
Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors
Authors: Abramson Vandana G. , Supko Jeffrey G. , Ballinger Tarah , Cleary James M. , Hilton John F. , Tolaney Sara M. , Chau Nicole G. , Cho Daniel C. , Pearlberg Joseph , Lager Joanne , Shapiro Geoffrey I. , Arteaga Carlos L.
Published: December 2016

Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors.

Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated.

Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA-mutant versus PIK3CA wild-type tumors (P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug.

Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status. Clin Cancer Res; 23(14); 3520–8. ©2016 AACR.
Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors
Authors: Wielgos Monica E. , Rajbhandari Rajani , Cooper Tiffiny S. , Wei Shi , Nozell Susan , Yang Eddy S.
Published: December 2016

HER2+ breast tumors have been shown to express elevated levels of PARP1 protein. Yet, the mechanism by which PARP1 is upregulated in HER2+ breast cancer is unknown. Here, knockdown of HER2 (ERBB2) in HER2+ breast cancer cells resulted in a reduction in PARP1 protein. Conversely, ectopic overexpression of HER2 in a non-HER2–overexpressing cell line resulted in increased PARP1 protein levels. Alterations in HER2 expression had no significant effect on PARP1 transcript levels. Instead, HER2 mRNA status was inversely correlated with let-7a miRNA levels in breast cancer cells. Ectopic expression of let-7a miRNA resulted in downregulation of PARP1 protein, whereas expression of the let-7a anti-miRNA increased PARP1 protein. Furthermore, luciferase assays demonstrate that let-7a regulates PARP1 via its 3′UTR. Importantly, let-7a was significantly lower in human HER2+ breast tumors compared with HER2− breast tumors and inversely correlated with PARP1 protein levels. Finally, HER2+ breast cancer cells exhibited similar cytotoxicity to ectopic let-7a expression as the PARP inhibitor veliparib (ABT-888). Collectively, these results reveal that increased PARP1 expression in HER2+ breast cancers is regulated by the let-7a miRNA, and that let-7a is a potential strategy to suppress PARP1 activity.

Implications: This study reports the novel findings that HER2 increases PARP1 protein via suppression of the let-7a miRNA, which regulates the PARP1 3′-UTR. Moreover, HER2 status correlates with high PARP1 and low let-7a in breast cancer clinical specimens. Mol Cancer Res; 15(3); 340–7. ©2016 AACR.
Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma
Authors: Zhu Fen , Hwang Byounghoon , Miyamoto Shigeki , Rui Lixin
Published: December 2016

JAKs are non-receptor tyrosine kinases that are generally found in association with cytokine receptors. In the canonical pathway, roles of JAKs have well been established in activating STATs in response to cytokine stimulation to modulate gene transcription. In contrast, a noncanonical role of JAK2 has recently been discovered, in which JAK2 in the nucleus imparts the epigenetic regulation of gene transcription through phosphorylation of tyrosine 41 on the histone protein H3. Recent work further demonstrated that this noncanonical mechanism is conserved with JAK1, which is activated by the autocrine cytokines IL6 and IL10 in activated B-cell–like diffuse large B-cell lymphoma (ABC DLBCL), a cancer type that is particularly difficult to treat and has poor prognosis. However, how JAK1 gains access to the nucleus to enable epigenetic regulation remains undefined. Here, we investigated this question and revealed that JAK1 has a classical nuclear localization signal toward the N-terminal region, which can be recognized by multiple importin α isoforms. Moreover, the nuclear import of JAK1 is independent of its kinase activity but is required for the optimal expansion of ABC DLBCL cells in vitro.

Implications: This study demonstrates that the nuclear import of JAK1 is essential for the optimal fitness of ABC DLBCL cells, and targeting JAK1 nuclear localization is a potential therapeutic strategy for ABC DLBCL. Mol Cancer Res; 15(3); 348–57. ©2016 AACR.
Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
Authors: Anagnostou Valsamo , Smith Kellie N. , Forde Patrick M. , Niknafs Noushin , Bhattacharya Rohit , White James , Zhang Theresa , Adleff Vilmos , Phallen Jillian , Wali Neha , Hruban Carolyn , Guthrie Violeta B. , Rodgers Kristen , Naidoo Jarushka , Kang Hyunseok , Sharfman William , Georgiades Christos , Verde Franco , Illei Peter , Li Qing Kay , Gabrielson Edward , Brock Malcolm V. , Zahnow Cynthia A. , Baylin Stephen B. , Scharpf Robert B. , Brahmer Julie R. , Karchin Rachel , Pardoll Drew M. , Velculescu Victor E.
Published: December 2016

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non–small cell lung cancer after initial response to immune checkpoint blockade with anti–PD-1 or anti–PD-1/anti–CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.

Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264–76. ©2017 AACR.

See related commentary by Yang, p. 250.

This article is highlighted in the In This Issue feature, p. 235
Relationship Between Distance and Change in Surface ECG Morphology During Pacemapping as a Guide to Ablation of Ventricular Arrhythmias
Authors: Li Anthony , Davis Joseph Samuel , Wierwille Jeremiah , Herold Keith , Morgan Dennis , Behr Elijah , Shorofsky Stephen , Saba Magdi
Published: December 2016

Background—

Pacemapping is used to localize the exit site of ventricular arrhythmia. Although the relationship between distance and change in QRS morphology is its basis, this relationship has not been systematically quantified.

Methods and Results—

Patients (n=68) undergoing ventricular arrhythmia ablation between March 2012 and July 2013 were recruited. Pacemapping was targeted to areas of voltage >0.5 mV. Linear mixed-effects models were constructed of distance against morphology difference measured by the root mean square error sum across all 12 ECG leads (E12). Forty of 68 (58%) patients had structural heart disease, and 21/40 (53%) patients were ischemic. Nine hundred thirty-five pacing points were collected, generating 6219 pacing site pair combinations (3087 [50%] ventricular bodies, 756 [12%] outflow tract, and 162 [3%] epicardial). In multivariable analysis, increase in E12 was predicted by increasing distance (0.07 per mm; 95% confidence interval 0.07–0.08;
P
<0.001). Compared with the left ventricle, E12 values were lower in the right ventricle (
P
=0.037) and left ventricular outflow tract (
P
<0.001) and higher in left ventricle–right ventricle pairs (
P
=0.021) and left ventricular epicardium (
P
=0.08). There was no difference in E12 in the right ventricular outflow tract compared with the right–left ventricular outflow tract (
P
=0.75) pairs. Structural heart disease or inadvertent pacing in scar was not associated with changes in E12; however, the presence of latency and split potentials were associated with higher and lower E12 values, respectively (
P
<0.001).

Conclusions—

A robust positive relationship exists between distance and QRS morphological change when restricting pacing points to areas of voltage >0.5 mV. Significant differences in the spatial resolution of pacemapping exist within the heart.
Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction
Authors: Kanelidis Anthony J. , Premer Courtney , Lopez Juan , Balkan Wayne , Hare Joshua M.
Published: December 2016

Rationale:

Accumulating data support a therapeutic role for mesenchymal stem cell (MSC) therapy; however, there is no consensus on the optimal route of delivery.

Objective:

We tested the hypothesis that the route of MSC delivery influences the reduction in infarct size and improvement in left ventricular ejection fraction (LVEF).

Methods and Results:

We performed a meta-analysis investigating the effect of MSC therapy in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy preclinical studies (58 studies; n=1165 mouse, rat, swine) which revealed a reduction in infarct size and improvement of LVEF in all animal models. Route of delivery was analyzed in AMI swine studies and clinical trials (6 clinical trials; n=334 patients). In AMI swine studies, transendocardial stem cell injection reduced infarct size (n=49, 9.4% reduction; 95% confidence interval, −15.9 to −3.0), whereas direct intramyocardial injection, intravenous infusion, and intracoronary infusion indicated no improvement. Similarly, transendocardial stem cell injection improved LVEF (n=65, 9.1% increase; 95% confidence interval, 3.7 to 14.5), as did direct intramyocardial injection and intravenous infusion, whereas intracoronary infusion demonstrated no improvement. In humans, changes of LVEF paralleled these results, with transendocardial stem cell injection improving LVEF (n=46, 7.0% increase; 95% confidence interval, 2.7 to 11.3), as did intravenous infusion, but again intracoronary infusion demonstrating no improvement.

Conclusions:

MSC therapy improves cardiac function in animal models of both AMI and chronic ischemic cardiomyopathy. The route of delivery seems to play a role in modulating the efficacy of MSC therapy in AMI swine studies and clinical trials, suggesting the superiority of transendocardial stem cell injection because of its reduction in infarct size and improvement of LVEF, which has important implications for the design of future studies.
Neurological Injury and Cerebral Blood Flow in Single Ventricles Throughout Staged Surgical Reconstruction
Authors: Fogel Mark A. , Li Christine , Elci Okan U. , Pawlowski Tom , Schwab Peter J. , Wilson Felice , Nicolson Susan C. , Montenegro Lisa M. , Diaz Laura , Spray Thomas L. , Gaynor J. William , Fuller Stephanie , Mascio Christopher , Keller Marc S. , Harris Matthew A. , Whitehead Kevin K. , Bethel Jim , Vossough Arastoo , Licht Daniel J.
Published: December 2016

Background:

Patients with a single ventricle experience a high rate of brain injury and adverse neurodevelopmental outcome; however, the incidence of brain abnormalities throughout surgical reconstruction and their relationship with cerebral blood flow, oxygen delivery, and carbon dioxide reactivity remain unknown.

Methods:

Patients with a single ventricle were studied with magnetic resonance imaging scans immediately prior to bidirectional Glenn (pre-BDG), before Fontan (BDG), and then 3 to 9 months after Fontan reconstruction.

Results:

One hundred sixty-eight consecutive subjects recruited into the project underwent 235 scans: 63 pre-BDG (mean age, 4.8±1.7 months), 118 BDG (2.9±1.4 years), and 54 after Fontan (2.4±1.0 years). Nonacute ischemic white matter changes on T2-weighted imaging, focal tissue loss, and ventriculomegaly were all more commonly detected in BDG and Fontan compared with pre-BDG patients (
P
<0.05). BDG patients had significantly higher cerebral blood flow than did Fontan patients. The odds of discovering brain injury with adjustment for surgical stage as well as ≥2 coexisting lesions within a patient decreased (63%–75% and 44%, respectively) with increasing amount of cerebral blood flow (
P
<0.05). In general, there was no association of oxygen delivery (except for ventriculomegaly in the BDG group) or carbon dioxide reactivity with neurological injury.

Conclusions:

Significant brain abnormalities are commonly present in patients with a single ventricle, and detection of these lesions increases as children progress through staged surgical reconstruction, with multiple coexisting lesions more common earlier than later. In addition, this study demonstrated that BDG patients had greater cerebral blood flow than did Fontan patients and that an inverse association exists of various indexes of cerebral blood flow with these brain lesions. However, CO
2
reactivity and oxygen delivery (with 1 exception) were not associated with brain lesion development.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02135081.