bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining and improving the role of emergency medical services in Cape Town, South Africa
Authors: Anest Trisha , Stewart de Ramirez Sarah , Balhara Kamna S , Hodkinson Peter , Wallis Lee , Hansoti Bhakti
Published: February 2016

Introduction

Low and middle income countries bear a disproportionate burden of paediatric morbidity and mortality. South Africa, a middle income country, has unacceptably high mortality in children less than 5 years of age. Many factors that contribute to the child mortality rate are time sensitive and require efficient access to emergency care. Delays and barriers within the emergency medical services (EMS) system increase paediatric morbidity and mortality from time sensitive illnesses.

Methods

This study is a qualitative evaluation of the prehospital care system for paediatric patients in Cape Town, South Africa. A purposive sample of healthcare personnel within and interacting with the EMS system were interviewed. A structured interview form was used to gather data. All interviews were audio recorded and transcribed; two independent reviewers performed blinded content analysis of the transcribed script.

Results

33 structured interviews were conducted over a 4 week period. Eight broad themes were identified during coding, including: access, communication, community education, equipment, infrastructure, staffing, training and triage. Subcategories were used to identify areas for targeted intervention. Overall agreement between the two independent coders was 93.36%, with a κ coefficient of 0.69.

Conclusions

The prehospital system is central to delivering time sensitive care for paediatric patients. In a single centre middle income setting, communication barriers between dispatch personnel and medical facilities/EMS personnel were deemed to be a high priority intervention in order to improve care delivery. Other areas for targeted interventions should include broadening the advanced life support provider base and introducing basic medical language in dispatch staff training.
Cerebral vasospasm and delayed cerebral infarctions in 225 patients with non-aneurysmal subarachnoid hemorrhage: the underestimated risk of Fisher 3 blood distribution
Authors: Konczalla Juergen , Kashefiolasl Sepide , Brawanski Nina , Lescher Stephanie , Senft Christian , Platz Johannes , Seifert Volker
Published: February 2016

Objective

Recent data have shown increasing numbers of non-aneurysmal subarachnoid hemorrhage (NASAH). However, data are limited and often only small series have been published. Our objective was to analyze the rate of cerebral vasospasm (CVS), delayed cerebral infarction (DCI), and their influence on the clinical outcome, especially in patients with diffuse Fisher 3 bleeding pattern NASAH (Fi3).

Methods

Between 1999 and 2014, 225 patients had NASAH. CVS, DCI, and outcome (according to the modified Rankin Scale at 6 months) were analyzed retrospectively. Patients were stratified according to the bleeding type. After univariate analysis a multivariate analysis was performed and NASAH Fi3 was also compared with aneurysmal SAH Fi3.

Results

Patient characteristics and the outcome of perimesencephalic (PM) and non-PM (NPM) SAH were similar. Excluding Fi3, PM and NPM without Fi3 had similar patient characteristics, clinical course, and outcome. In particular, the Fi3 subgroup had a significantly increased risk of CVS, DCI, unfavorable outcome, hydrocephalus, and death. Early hydrocephalus was associated with Fi3 and intraventricular hemorrhage. The multivariate regression model showed the variables elderly patients, Fi3, and early hydrocephalus as independent and significant predictors for an unfavorable outcome. A further comparison of NASAH Fi3 with aneurysmal SAH Fi3 showed similar characteristics, CVS rate, and mortality.

Conclusions

Patients with NASAH without a Fi3 bleeding pattern had a similar excellent outcome to patients with PM-SAH. Patients with Fi3 had a high risk for early hydrocephalus, CVS, DCI, and an unfavorable outcome, similar to patients with aneurysmal SAH. After multivariate analysis, early hydrocephalus, elderly patients, and Fi3 were identified as negative prognostic factors. Therefore, patients with Fi3 are at risk and need careful clinical observation.
Survey of ankle–brachial pressure index use and its perceived barriers by general practitioners in the UK
Authors: Yap Kannan R , Dattani N , Sayers R D , Bown M J
Published: February 2016

Background

Peripheral arterial disease (PAD) is often undetected until complications arise, despite it being a major healthcare burden and an independent risk factor for cardiovascular death and systemic atherosclerosis. Appropriate diagnostic tools are as important as clinical knowledge and skill to investigate patients for PAD. Currently, the ankle–brachial pressure index (ABPI) is the recommended diagnostic tool for PAD.

Purpose

We explore current opinions on ABPI by general practitioners (GPs) and the limitations to its implementation in primary care practice.

Methods

GPs attending a regional 1-day study event, were surveyed in October 2014. Survey questionnaires were placed at the top of each conference pack for each attendee. The survey questionnaire was modelled from the ankle–brachial index (ABI) usage survey questionnaire used in the PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) preceptorship study.

Results

All respondents were GPs, with a survey response rate of 77.1%. All respondents regarded ABPI as an important test, that is primarily performed by nursing staff (79.5%) in their respective GP surgeries. 70% and 97% of GPs found ABPI useful for the diagnosis of asymptomatic and symptomatic PAD, respectively. 69% of GPs regarded ABPI as a feasible test in primary care practice. Time constraints (84%), staff availability (89%) and staff training (72%) were cited as the main limitations to its use.

Conclusions

Targeted training of nursing staff may improve ABPI usage, although a less time-consuming test for PAD may be another option.
Seed-borne viral dsRNA elements in three cultivatedRaphanusandBrassicaplants suggest three cryptoviruses
Authors: Li Liqiang , Liu Jianning , Zhang Qiong , Fu Runying , Zhu Xiwu , Li Chao , Chen Jishuang
Published: February 2016

Since the 1970s, several dsRNA viruses, including Radish yellow edge virus, Raphanus sativus virus 1, Raphanus sativus virus 2, and Raphanus sativus virus 3, have been identified and reported as infecting radish. In the present study, in conjunction with a survey of seed-borne viruses in cultivated Brassica and Raphanus using the dsRNA diagnostic method, we discovered 3 novel cryptoviruses that infect Brassica and Raphanus: Raphanus sativus partitivirus 1, which infects radish (Raphanus sativus); Sinapis alba cryptic virus 1, which infects Sinapis alba; and Brassica rapa cryptic virus 1 (BrCV1), which infects Brassica rapa. The genomic organization of these cryptoviruses was analyzed and characterized. BrCV1 might represent the first plant partitivirus found in Gammapartitivirus. Additionally, the evolutionary relationships among all of the partitiviruses reported in Raphanus and Brassica were analyzed.
Optimal Setting of Multiple FACTS Devices to Improve Voltage Stability: A Novel GSA
Authors: Ram Inkollu Sai , Kota Venkata Reddy
Published: February 2016

In this paper, a novel GSA technique is used for improving the voltage stability of the system with multiple FACTS devices. The proposed novel algorithm is used to optimize the location, size and number of FACTS devices. The GSA is enhanced with the use of boundary for optimizing the parameters of the system. Therefore, the voltage stability is improved while satisfying a given set of operating and physical constraints. Here, multiple FACTS devices are used to evaluate the performance of proposed algorithm and these devices are connected in single line and double line of the bus system. The optimal locations and power ratings of the FACTS devices are determined, based on the voltage collapse rating and power loss of the system. The proposed technique is implemented in MATLAB platform and tested with IEEE 30 bus system. The performance of the proposed method is evaluated by locating multiple FACTS devices and compared with the PSO-adaptive GSA and GA-GSA technique.
Steady State Analysis Operation of Self-Excited Wound Rotor Induction Generator Under Constant Frequency and Tolerated Output Voltage
Authors: Mourad Selmi , Habib Rehaoulia
Published: February 2016

Self-excited induction generators (SEIG) are found to be most suitable candidate for wind energy conversion application required at remote windy locations. The major drawbacks of these generators are the poor voltage and frequency control under load and prime mover speed perturbations. In this paper, an attempt has been made to optimize the control strategy under various load and prime mover conditions, of the self-excited wound rotor induction generator (SEWRIG). By tolerating a slight deviation of the output voltage and ensuring a constant frequency with an adequate external rotor resistance, only four values of excitation capacitor are required for the whole range of operation. The effectiveness of the adopted strategy has been confirmed by comparing on a 0.8-[Formula: see text]kW wound rotor induction generator the simulated results to the corresponding obtained with an experimental test. A close agreement between the computed and experimental results confirms the efficiency of the adopted method.
SHRINKAGE ESTIMATION OF MEAN-VARIANCE PORTFOLIO
Authors: LIU YAN , CHAN NGAI HANG , NG CHI TIM , WONG SAMUEL PO SHING
Published: February 2016

This paper studies the optimal expected gain/loss of a portfolio at a given risk level when the initial investment is zero and the number of stocks [Formula: see text] grows with the sample size [Formula: see text]. A new estimator of the optimal expected gain/loss of such a portfolio is proposed after examining the behavior of the sample mean vector and the sample covariance matrix based on conditional expectations. It is found that the effect of the sample mean vector is additive and the effect of the sample covariance matrix is multiplicative, both of which over-predict the optimal expected gain/loss. By virtue of a shrinkage method, a new estimate is proposed when the sample covariance matrix is not invertible. The superiority of the proposed estimator is demonstrated by matrix inequalities and simulation studies.
The Anomalous Distributions and Soret Coefficient in a Nonequilibrium Colloidal System
Authors: Zhou Yanjun , Du Jiulin
Published: February 2016

We study the density distribution and Soret coefficient in a nonequilibrium colloidal system by using the overdamped Langevin equation for Brownian motion in an inhomogeneous strong friction medium. Based on the relation between the temperature gradient, the interaction potential and the [Formula: see text]-parameter in nonextensive statistics, we show that the colloidal particle density can be a function of the temperature and anomalously follows the noted [Formula: see text]-distribution, or equivalently it can also be a function of the potential energy following Tsallis distribution. With the [Formula: see text]-parameter we can establish a new formula of Soret coefficient and thus, bridge the gap between the ideally theoretical Soret coefficient and available experiments.
SURGICAL DECISION OF CORONARY ARTERY BYPASS GRAFTING FOR NORMAL LEFT ANTERIOR DESCENDING ARTERY (LAD) AND LAD WITH STENOSIS: SEQUENTIAL GRAFT OR NOT
Authors: ZHAO XI , LIU YOUJUN , XIE JINSHENG , ZHAO ZHOU , QIAO AIKE
Published: February 2016

Sequential graft was used frequently in clinical studies. In this study, the hemodynamic effect of one kind of sequential graft in two different conditions of the lesion was discussed and some recommendations on the surgical procedures were made. A patient-specific three-dimensional (3D) model of left anterior descending artery (LAD) was reconstructed. A moderate stenosis exist in the trunk of LAD between the first and the second diagonal branch (D1 and D2). Another 3D model without stenosis was also reconstructed based on the patient-specific model. Sequential graft and single graft were applied on these two 3D model. Thus four 3D models were built so that the hemodynamic effect of sequential graft can be discussed. The zero-dimensional (0D)/3D coupling method was used to perform the numerical simulation by coupling the 3D artery model with a 0D lumped parameter model of the cardiovascular system. The flow rates in the branches of LAD and the graft flow were calculated and illustrated in this paper. The wall shear stress (WSS) and oscillatory shear index (OSI) were also calculated and depicted. If the native LAD is stenosis, sequential graft should be applied for the short-term outcomes. Moreover, the long-term patency of the sequential graft applied on the stenosis LAD is good. The long-term patency of the single graft was bad. But the short-term outcomes are almost the same when LAD is not stenosis. If no stenosis exist in the native LAD, a graft with smaller diameter should be applied to improve the long-term patency.
A Robust Computational Method for System of Singularly Perturbed Differential Difference Equations with Discontinuous Convection Coefficients
Authors: Subburayan V.
Published: February 2016

In this paper, a standard numerical method with piecewise linear interpolation on Shishkin mesh is suggested to solve a weakly coupled system of singularly perturbed boundary value problem for second-order ordinary differential difference equations with discontinuous convection coefficients and source terms. An error estimate is derived by using the supremum norm and it is of almost first-order convergence. Numerical results are provided to illustrate the theoretical results.
A Smoothed Particle Galerkin Formulation for Extreme Material Flow Analysis in Bulk Forming Applications
Authors: Wu C. T. , Hu W. , Koishi M.
Published: February 2016

This paper presents a new particle formulation for extreme material flow analyses in the bulk forming applications. The new formulation is first established by an introduction of a smoothed displacement field to the standard Galerkin formulation to eliminate zero-energy modes in conventional particle methods. The discretized system of linear equations is consistently derived and integrated using a direct nodal integration scheme. The linear formulation is next extended to the large deformation quasi-static analysis of inelastic materials. As quasi-static Lagrangian simulation proceeds in the severe deformation range, the analysis method is switched to explicit dynamics formulation and an adaptive Lagrangian kernel approach is preformed to reset the reference configuration and maintain the injective deformation mapping at the particles. Both nonconvex and convex meshfree approximations are investigated in this study. Several numerical benchmarks are provided to demonstrate the effectiveness and accuracy of the proposed method.
Ultrasound promoted preparation of Mn(III)-porphyrin nanoparticles: An efficient heterogeneous catalyst for oxidation of alkenes, alkanes and sulfides
Authors: Rayati Saeed , Nejabat Fatemeh , Naghashian Nasireh
Published: February 2016

In the present research meso-tetrakis(4-carboxyphenyl)porphyrinatomanganese(III) acetate (Mn(TCPP)OAc) nanoparticles have been prepared for the first time without any stabilizing agent or supporting matrix under ultrasonic irradiation. Scanning electron microscopy (SEM) was used to characterize and investigate the nanocatalyst. Rapid, efficient, facile and highly selective oxidation of a wide range of olefins by tetra-[Formula: see text]-butylammonium hydrogen monopersulfate over the prepared manganese nanocatalyst was investigated. Also oxidation of sulfides and alkanes in the presence of the (Mn(TCPP)OAc) nanoparticles were studied. The catalyst is recovered by filtration and reused at least five times.
Highly selective and efficient oxidation of sulfide to sulfoxide catalyzed by platinum porphyrins
Authors: Alemohammad Tahereh , Rayati Saeed , Safari Nasser
Published: February 2016

Two platinum porphyrins, meso-tetramesitylporphyrinatoplatinum and meso-tetrakis(pentaflourophenyl) porphyrinatoplatinum, are explored for catalytic application in the selective oxidation of sulfide to sulfoxide by iodosylbenzene. The obtained overall turnover number of 90,000 in the oxidation of thioanisole in the presence of meso-tetrakis(pentaflourophenyl) porphyrinatoplatinum indicates the pronounced catalytic activity of the platinum porphyrins. Perfect selectivity toward sulfoxide or sulfone also was achieved via stoichiometric control of reactants.
Priority Research Questions on the Environmental Impacts of Pharmaceutical and Personal Care Products in China: Insights from Chinese Scientists
Authors: WANG Xiaowen , BA BOXALL Alistair , HOWLEY Peter , A RUDD Murray
Published: February 2016

Pharmaceuticals and personal care products (PPCPs) can enter the environment through various routes. Given the emerging importance of PPCP contaminants in China, we used semi-structured interviews to probe Chinese scientists’ perspectives, opinions, and attitudes on current and future PPCP research needs. We interviewed 14 respondents, nearly all of whom recognized the potential for adverse effects on human and ecosystem health even though current scientific evidence supporting harmful outcomes was viewed as tentative. Respondents identified poor disposal practices at hospitals and PPCP factories as important targets for focused control measures that could have high impact. Some thought public media could be used to build awareness of PPCPs among citizens; others thought that accurate information needed to be provided directly to policymakers and regulators. To make appropriate and cost-effective decisions regarding PPCP discharge to the environment, cross-disciplinary cooperation will be needed between Chinese environmental scientists, medical scientists, engineers, and economists.
Research on the Influential Factors of Rural Human Resources Development of Tianjin in the Context of New-Type Urbanization
Authors: WU Baohua
Published: February 2016

This thesis expounds the current situation of rural human resources of Tianjin with the method of qualitative and quantitative analysis and the macroscopic and microscopic data under the research background of new-type urbanization. Then the paper summarizes the factors influencing rural human resources development by factor analysis method. Based on the study mentioned above, it puts forward the countermeasures and suggestions on rural human resources development.
A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes
Authors: Simpson A. J. , Bood J. R. , Anderson S. D. , Romer L. M. , Dahlén B. , Dahlén S.-E. , Kippelen P.
Published: February 2016

Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11β-prostaglandin F2α(11β-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12–20)% (median and interquartile range) following placebo was attenuated to 7 (5–9)% with the administration of terbutaline ( P < 0.001). EVH caused a significant increase in 11β-PGF2αfrom 41 (27–57) ng/mmol creatinine at baseline to 58 (43–72) ng/mmol creatinine at its peak post-EVH following placebo ( P = 0.002). The rise in 11β-PGF2αwas inhibited with administration of terbutaline: 39 (28–44) ng/mmol creatinine at baseline vs. 40 (33–58) ng/mmol creatinine at its peak post-EVH ( P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.
Motor control of landing from a countermovement jump in simulated microgravity
Authors: Gambelli C. N. , Theisen D. , Willems P. A. , Schepens B.
Published: February 2016

Landing from a jump implies proper positioning of the lower limb segments and the generation of an adequate muscular force to cope with the imminent collision with the ground. This study assesses how a hypogravitational environment affects the control of landing after a countermovement jump (CMJ). Eight participants performed submaximal CMJs on Earth (1- g condition) and in a weightlessness environment with simulated gravity conditions generated by a pull-down force (1-, 0.6-, 0.4-, and 0.2- g0 conditions). External forces applied to the body, movements of the lower limb segments, and muscular activity of six lower limb muscles were recorded. 1) All subjects were able to jump and stabilize their landing in all experimental conditions, except one subject in 0.2- g0 condition. 2) The mechanical behavior of lower limb muscles switches during landing from a stiff spring to a compliant spring associated with a damper. This is true whatever the environment, on Earth as well as in environments where sensory inputs are altered. 3) The motor control of landing in simulated 1 g0 reveals an increased “safety margin” strategy, illustrated by increased stiffness and damping coefficient compared with landing on Earth. 4) The motor command is adjusted to the task constraints: muscular activity of lower limb extensors and flexors, stiffness and damping coefficient decrease according to the decreased gravity level. Our results show that even if in daily living gravity can be perceived as a constant factor, subjects can cope with altered sensory signals, taking advantage of the remaining information (visual and/or decreased proprioceptive inputs).
Barometric calibration of a luminescent oxygen probe
Authors: Golub Aleksander S. , Pittman Roland N.
Published: February 2016

The invention of the phosphorescence quenching method for the measurement of oxygen concentration in blood and tissue revolutionized physiological studies of oxygen transport in living organisms. Since the pioneering publication by Vanderkooi and Wilson in 1987, many researchers have contributed to the measurement of oxygen in the microcirculation, to oxygen imaging in tissues and microvessels, and to the development of new extracellular and intracellular phosphorescent probes. However, there is a problem of congruency in data from different laboratories, because of interlaboratory variability of the calibration coefficients in the Stern-Volmer equation. Published calibrations for a common oxygen probe, Pd-porphyrin + bovine serum albumin (BSA), vary because of differences in the techniques used. These methods are used for the formation of oxygen standards: chemical titration, calibrated gas mixtures, and an oxygen electrode. Each method in turn also needs calibration. We have designed a barometric method for the calibration of oxygen probes by using a regulated vacuum to set multiple Po2standards. The method is fast and accurate and can be applied to biological fluids obtained during or after an experiment. Calibration over the full physiological Po2range (1–120 mmHg) takes ∼15 min and requires 1–2 mg of probe.
Frequency-selective transmission of graded signals in large monopolar neurons of blowflyCalliphora vicinacompound eye
Authors: Rusanen Juha , Weckström Matti
Published: February 2016

The functional roles of voltage-gated K+(Kv) channels in visual system interneurons remain poorly studied. We have addressed this problem in the large monopolar cells (LMCs) of the blowfly Calliphora vicina, using intracellular recordings and mathematical modeling methods. Intracellular recordings were performed in two cellular compartments: the synaptic zone, which receives input from photoreceptors, and the axon, which provides graded potential output to the third-order visual neurons. Biophysical properties of Kvconductances in the physiological voltage range were examined in the dark with injections of current in the discontinuous current-clamp mode. Putative LMC types 1/2 and 3 (L1/2 and L3, respectively) had dissimilar Kvchannelomes: L1/2 displayed a prominent inactivating Kvconductance in the axon, while L3 cells were characterized by a sustained delayed-rectifier Kvconductance. To study the propagation of voltage signals, the data were incorporated into the previously developed mathematical model. We demonstrate that the complex interaction between the passive membrane properties, Kvconductances, and the neuronal geometry leads to a resonance-like filtering of signals with peak frequencies of transmission near 15 and 40 Hz for L3 and L1/2, respectively. These results point to distinct physiological roles of different types of LMCs.
Corrosion Behavior of Carbon Steels in CCTS Environment
Authors: Cabrini M. , Lorenzi S. , Pastore T.
Published: February 2016

The paper reports the results of an experimental work on the effect of steel microstructures on morphology and protectiveness of the corrosion scale formed in water saturated by supercritical CO2. Two HSLA steels were tested. The microstructures were modified by means of different heat treatments. Weight loss was measured after exposure at CO2partial pressure of 80 bar and 60°C temperature. The morphology of the scale was analyzed by means of scanning electron microscope (SEM) energy-dispersive X-ray spectroscopy (EDX). Cathodic potentiodynamic tests were carried out on precorroded specimens for evaluating the effect of preformed scales on cathodic polarization curves in CO2saturated sulphuric acid solution at pH 3, which is the value estimated for water saturated by supercritical CO2. The results are discussed in order to evaluate the effect of iron carbide network on scale growth and corrosion rate. Weight loss tests evidenced average corrosion rate values in the range 1–2.5 mm/y after 150-hour exposure. The presence of thick siderite scale significantly reduces the corrosion rate of carbon steel. A slight decrease of the corrosion rate was observed as the scale thickness increases and moving from martensite to microstructures containing carbides.
Scrotal Abscess Precipitating Late Infection of a Malleable Penile Prosthesis: The Risk Never Evanesces
Authors: Mustafa Osama , Althakafi Sultan , Kattan Said , Kattan Mohamed , AlHathal Naif
Published: February 2016

Although infrequent, infections represent the dreadful complication of penile prosthesis implantation. The incidence substantially decreases after a few infection-free postoperative months. We report herein a case of a very late penile prosthesis infection from a fistualizing scrotal abscess in a 67-year-old man. The patient presented with a one-month history of persistent penile-base discharge from a right hemiscrotal swelling. On examination, mild penile tenderness and a discharging penoscrotal-junction sinus were noted. Microbiological wound culture was positive forStaphylococcus epidermidis. Magnetic resonance imaging revealed this multiloculated fluid collection’s communication with the right corporal body. Removal of the prosthesis was performed. Pathological evaluation of the dissected fistula was suggestive of acute on top of chronic inflammatory reactions. To our knowledge, this is the first report of a scrotal abscess leading to penile prosthesis infection 15 years after an uneventful implantation.
Effective Concentration of a Multikinase Inhibitor within Bone Marrow Correlates with In Vitro Cell Killing in Therapy-Resistant Chronic Myeloid Leukemia
Authors: Mu Chaofeng , Wu Xiaoyan , Ma Helen , Tao Wenjing , Zhang Guodong , Xia Xiaojun , Shen Jianliang , Mai Junhua , Sun Tong , Sun Xiaoping , Arlinghaus Ralph B. , Shen Haifa
Published: February 2016

Leukemia cells escape BCR-ABL–targeted therapy by developing mutations, such as T315I, in the p210BCR-ABL fusion protein in Philadelphia chromosome–positive chronic myeloid leukemia (CML). Although most effort has been focused on development of new tyrosine kinase inhibitors, enrichment of these small-molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I-mutant CML cells to 10 μmol/L of the multikinase inhibitor TG101209 suppressed BCR-ABL–independent signaling and caused cell-cycle arrest at G2–M. Further increase in drug concentration to 17.5 μmol/L blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 μmol/L for effective killing of CML cells in vivo. Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapy-resistant CML. Mol Cancer Ther; 15(5); 899–910. ©2016 AACR.
Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo
Authors: Winship Amy L. , Van Sinderen Michelle , Donoghue Jacqueline , Rainczuk Kate , Dimitriadis Evdokia
Published: February 2016

Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. IL11 is a cytokine that regulates cell cycle, invasion, and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumors and uterine lavage fluid in women with endometrial cancer, and alters endometrial epithelial cancer cell adhesion and migration in vitro, but its role in endometrial tumorigenesis in vivo is unknown. We injected mice subcutaneously with human-derived Ishikawa or HEC1A endometrial epithelial cancer cells (ectopic), or HEC1A cells into the uterus (orthotopic) to develop endometrial cancer mouse models. Administration of anti-human IL11 receptor (R) α blocking antibody dramatically reduced HEC1A-derived tumor growth in both models and reduced peritoneal metastatic lesion spread in the orthotopic model, compared with IgG. Anti-human IL11Rα retained a well-differentiated, endometrial epithelial phenotype in the HEC1A ectopic mice, suggesting it prevented epithelial-to-mesenchymal transition. Blockade of mouse IL11Rα with anti-mouse IL11Rα antibody did not alter tumor growth, suggesting that cancer epithelial cell IL11 signaling is required for tumor progression. In vitro, anti-human IL11Rα antibody significantly reduced Ishikawa and HEC1A cell proliferation and invasion and promoted apoptosis. Anti-human, but not anti-mouse, IL11Rα antibody reduced STAT3, but not ERK, activation in HEC1A cells in vitro and in endometrial tumors in xenograft mice. We demonstrated that targeted blockade of endometrial cancer epithelial cell IL11 signaling reduced primary tumor growth and impaired metastasis in ectopic and orthotopic endometrial cancer models in vivo. Our data suggest that therapeutically targeting IL11Rα could inhibit endometrial cancer growth and dissemination. Mol Cancer Ther; 15(4); 720–30. ©2016 AACR.
DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?
Authors: Voest Emile E. , Bernards Rene
Published: February 2016

Summary: Precision treatment with targeted cancer drugs requires the selection of patients who are most likely to benefit from a given therapy. We argue here that the use of a combination of both DNA and transcriptome analyses will significantly improve drug response prediction. Cancer Discov; 6(2); 130–2. ©2016 AACR.
Pruning Cancer's Evolutionary Tree with Lesion-Directed Therapy
Authors: Hiley Crispin T. , Swanton Charles
Published: February 2016

Summary: Next-generation sequencing of spatially and temporally separated biopsies and circulating tumor DNA directs therapy in response to tumor evolution and acquired resistance in colorectal cancer. Cancer Discov; 6(2); 122–4. ©2016 AACR.

See related article by Russo et al., p. 147.
The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy
Authors: Yu Ruichao , Bo Hong , Villani Vincenzo , Spencer Philip J. , Fu Ping
Published: February 2016

Background/Aims: There is increasing evidence showing that innate immune responses and inflammatory processes play an important role in the development and progression of diabetic nephropathy (DN). The potential effect of innate immunity in the early stage of DN is still unclear. Toll-Like-Receptor 4 (TLR4) is vigorously involved in the progress of kidney diseases in a sterile environment. The activation of the interleukin 17 (IL-17) pathway produces inflammatory cytokines, appearing in various kidney diseases. Unfortunately the relationship between TLR4 and IL-17 has not been investigated in diabetic nephropathy to date. The aim of this study is to investigate whether mammalian target of rapamycin (mTOR) inhibition may be dependent on TLR4 signaling and the pro-inflammatory factor IL-17 to delay the progression of DN. Methods: Streptozotocin (STZ)-induced diabetic rats were randomly assigned to 3 experimental groups: a diabetic nephropathy group (DN, n = 6); and a diabetic nephropathy treated with rapamycin group (Rapa, n = 6) and a control group (Control, n =6). Body weight, fasting blood sugar, and 24h urine albumin were assessed at week 2, week 4 and week 8. Renal tissues were harvested for H&E, PAS staining, as well as an immunohistochemistry assay for TLR4 and IL-17. TLR4 quantitative expression was measured by Western-Blot analysis and RT-PCR. Results: Our results demonstrated that the expression of both TLR4 and IL-17 were upregulated in early stage DN and reduced by rapamycin. TLR4 and IL-17 both increased and positively related to 24h urinary albumin and kidney/weight ratio. However, neither TLR4 nor IL-17 made a significant difference on fasting blood sugar. Conclusions: Taken together, our results confirm and extend previous studies identifying the significance of the TLR4 and Th17 pathways in development of early stage DN. Furthermore, we suggest this overexpression of TLR4 might be involved in the immunopathogenesis of DN through activation of Th17 cells. Rapamycin may attenuate DN via reduction of the TLR4 signaling pathway and Th17 cells signaling. Although the underlying mechanisms need to be explored, the observed increase of TLR4 and IL-17 during the early stages of DN and their suppression with rapamycin treatment suggest the importance of TLR4 and IL-17 in DN pathophysiology.
Protective Effects of Myrtol Standardized Against Radiation-Induced Lung Injury
Authors: Zhao De-yun , Qu Hong-jin , Guo Jia-ming , Zhao Hai-nan , Yang Yan-yong , Zhang Pei , Cao Kun , Lei Xiao , Cui Jian-guo , Liu Cong , Cai Jian-ming , Gao Fu , Li Bai-long
Published: February 2016

Background/Aims: As a major complication after thoracic radiotherapy, radiation-induced lung injury (RILI) has great impact on long term quality of life and could result in fatal respiratory insufficiency The present study was aimed to evaluate the effects of Myrtol standardized on RILI, and to investigate the underlying mechanism. Methods: A mouse model of radiation-induced lung injury was generated by using thoracic irradiation with a single dose of 16Gy. Mice were orally administrated with Myrtol (25 mg/kg/day) for 4 weeks after irradiation, while prednisone (5 mg/kg/day) was used as a positive control. After then, the body weight and lung coefficient were calculated. The severity of fibrosis was evaluated by observing pulmonary sections after radiation and collagen content in lung tissues was calculated following the hydroxyproline (HYP) assay. Pathological changes were observed in all the groups by using HE staining and Masson staining. The serum levels of TGF-β1, TNF-α, IL-1β, IL-6, and PGE2 were also measured with an ELISA assay. Western blot assay was used to measure the impact of Myrtol on AKT and its downstream signaling pathway, including MMP-2 and MMP-9. The levels of Vimentin and α-SMA were evaluated with an immunofluorescence assay. Results: Treatment with Myrtol standardized, but not prednisone, reduced lung coefficient and collagen deposition in lung tissues, while attenuated histological damages induced by irradiation. Myrtol standardized also reduced the production of MDA, while increased the level of SOD. It was also observed that Myrtol standardized inhibited TGF-β1 and a series of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, PGE2. While in prednisone group, even though the early pneumonitis was ameliorated, the collagen disposition remained unchanged in latter times. Immunofluorescence analysis also revealed elevation of vimentin and α-SMA in the alveoli after a single dose of 16Gy. Conclusion: The present results suggest Myrtol standardized as an effective agent for attenuating the lung injury induced by irradiation.
Beat Rate Variability in Murine Embryonic Stem Cell-Derived Cardiomyocytes: Effect of Antiarrhythmic Drugs
Authors: Niehoff Julius , Matzkies Matthias , Nguemo Filomain , Hescheler Jürgen , Reppel Michael
Published: February 2016

Background/Aims: Heart rate variability (HRV) refers to the fluctuation of the time interval between consecutive heartbeats in humans. It has recently been discovered that cardiomyocytes derived from human embryonic and induced pluripotent stem cells show beat rate variability (BRV) that is similar to the HRV in humans. In the present study, clinical aspects of HRV were transferred to an in vitro model. The aims of the study were to explore the BRV in murine embryonic stem cell (mESC)-derived cardiomyocytes and to demonstrate the influence of antiarrhythmic drugs on BRV as has been shown in clinical trials previously. Methods: The Microelectrode Array (MEA) technique was used to perform short-term recordings of extracellular field potentials (FPs) of spontaneously beating cardiomyocytes derived from mESCs (D3 cell line, αPig-44). Offline analysis was focused on time domain and nonlinear methods. Results: The Poincaré-Plot analysis of measurements without pharmacological intervention revealed that three different shapes of scatter plots occurred most frequently. Comparable shapes have been described in clinical studies before. The antiarrhythmic drugs Ivabradine, Verapamil and Sotalol augmented BRV, whereas Flecainide decreased BRV parameters at low concentrations (SDSD 79.0 ± 8.7% of control at 10-9 M, p < 0.05) and increased variability measures at higher concentrations (SDNN 258.8 ± 42.7% of control at 10-5 M, p < 0.05). Amiodarone and Metoprolol did not alter BRV significantly. Conclusions: Spontaneously beating cardiomyocytes derived from mESCs showed BRV that appears to be similar to the HRV known from humans. Antiarrhythmic drugs affected BRV parameters similar to clinical observations. Therefore, our study demonstrates that this in vitro model can contribute to a better understanding of electrophysiological properties of mESC-derived cardiomyocytes and might serve as a valuable tool for drug safety screening.
The Tyrosine Kinase Pyk2 Contributes to Complement-Mediated Phagocytosis in Murine Macrophages
Authors: Paone Christoph , Rodrigues Natalie , Ittner Ella , Santos Carina , Buntru Alexander , Hauck Christof R.
Published: February 2016

Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase (FAK) family and is mainly expressed in neuronal and hematopoietic cells. As FAK family members are involved in signaling connections downstream of integrins, we studied the role of Pyk2 in complement-receptor 3 (CR3, also known as Mac-1, integrin αMβ2, CD11b/CD18)-mediated phagocytosis, a key process in innate immunity. Using 3 independent approaches, we observed that Pyk2 contributes to CR3-dependent phagocytosis by RAW 264.7 macrophages, but is dispensable for Fcγ receptor (FcγR)-mediated uptake. Reduction of Pyk2 expression levels via siRNA, the pharmacological inhibition of Pyk2 kinase activity as well as macrophage treatment with a cell permeable TAT fusion protein containing the C-terminus of Pyk2 (TAT-PRNK) significantly impaired CR3-mediated phagocytosis without affecting FcγR-mediated uptake. In addition, Pyk2 was strongly recruited to complement opsonized Escherichia coli and the pharmacological inhibition of Pyk2 significantly decreased uptake of the bacteria. Finally, CRISPR/Cas-mediated disruption of the pyk2 gene in RAW 264.7 macrophages confirmed the role of this protein tyrosine kinase in CR3-mediated phagocytosis. Together, our data demonstrate that Pyk2 selectively contributes to the coordination of phagocytosis-promoting signals downstream of CR3, but is dispensable for FcγR-mediated phagocytosis.
β-Catenin Expression in Oropharyngeal Squamous Cell Carcinomas: Comparison and Correlation with p16 and Human Papillomavirus in situ Hybridization
Authors: Nwanze Julum , Cohen Cynthia , Schmitt Alessandra C. , Siddiqui Momin T.
Published: February 2016

Background: The Wnt/β-catenin signaling pathway has been noted to be upregulated in head and neck cancers, including oropharyngeal squamous cell carcinoma (OSCC). This study compared the efficacy of β-catenin immunohistochemistry (IHC), p16 IHC and automated human papillomavirus (HPV) in situ hybridization (ISH) in OSCC. Methods: Sixty-eight OSCCs (48 surgical specimens and 20 fine-needle aspirations) were evaluated. Nuclear staining only of β-catenin was assessed as 0-3+ intensity (relative to controls of benign squamous mucosa). p16 was interpreted as positive if 70% of tumor cells showed brown nuclear and cytoplasmic staining. HPV ISH was interpreted as positive if a minimum of one tumor cell showed brown punctate dot-like nuclear positivity. p16 IHC and HPV ISH were then correlated with β-catenin staining. HPV ISH was used as the gold standard. Results: Twenty-five of 48 surgical specimens (52.1%) and 11 of 20 cell blocks (55%) stained positively for β-catenin, making a total of 36 of 68 (52.9%) staining positively for β-catenin, as compared to 61.7% positive for p16 IHC and 70.6% positive by automated HPV ISH, the gold standard method for OSCC diagnosis. χ2 analysis revealed no significant correlation between β-catenin and HPV ISH (p > 0.05) and demonstrated a strong correlation between p16 and HPV ISH (p < 0.05). Conclusion: β-Catenin IHC is not a sensitive or specific marker of HPV and is unlikely to be a useful adjunct to p16 IHC or HPV ISH in the setting of advanced OSCC. However, as this study focused on samples of advanced OSCC, β-catenin IHC may still find some use in the diagnosis of early-stage OSCC.
Sleep Disturbances at 3 Months after Cerebral Infarction
Authors: Suh Minhee , Choi-Kwon Smi , Kim Jong S.
Published: February 2016

Background: Post-stroke sleep disturbances (PSSD) are common and associated with various adverse outcomes. However, PSSD in the sub-acute stages of stroke have been scarcely studied. We aimed to evaluate the characteristics of and the factors related to PSSD in stroke patients 3 months post stroke. Methods: A total of 199 patients were evaluated for PSSD at 3 months after stroke. The qualities of nighttime sleep and excessive daytime sleepiness (EDS) were assessed using the Verran Snyder-Halpern sleep scale and Epworth Sleepiness Scale, respectively. Presence of motor dysfunction and post-stroke pain, post-stroke depression, fatigue and social support were evaluated. Results: Eighty-eight patients (44.2%) had poor quality of nighttime sleep. Twenty-eight patients (14.4%) reported EDS. Poor quality of nighttime sleep was independently associated with depression (p = 0.044) and EDS (p = 0.041) whereas fatigue (p < 0.001) and poor nighttime sleep (p = 0.045) were independently associated with EDS. Post-stroke pain and social support showed no association with PSSD. Conclusions: We found that the occurrence of PSSD 3 months after stroke is common. Although causality remained to be determined, depression and nighttime sleep disturbances were related, whereas fatigue and nighttime sleep disturbances were related to EDS.
Probucol-Oxidized Products, Spiroquinone and Diphenoquinone, Promote Reverse Cholesterol Transport in Mice
Authors: Yakushiji Emi , Ayaori Makoto , Nishida Takafumi , Shiotani Kazusa , Takiguchi Shunichi , Nakaya Kazuhiro , Uto-Kondo Harumi , Ogura Masatsune , Sasaki Makoto , Yogo Makiko , Komatsu Tomohiro , Lu Rui , Yokoyama Shinji , Ikewaki Katsunori
Published: February 2016

Objective—

Oxidized products of probucol, spiroquinone and diphenoquinone, were shown to increase cell cholesterol release and plasma high-density lipoprotein (HDL) by inhibiting degradation of ATP-binding cassette transporter A1. We investigated whether these compounds enhance reverse cholesterol transport in mice.

Approach and Results—

Spiroquinone and diphenoquinone increased ATP-binding cassette transporter A1 protein (2.8- and 2.6-fold, respectively,
P
<0.01) and apolipoprotein A-I–mediated cholesterol release (1.4- and 1.4-fold,
P
<0.01 and
P
<0.05, respectively) in RAW264.7 cells. However, diphenoquinone, but not spiroquinone, enhanced cholesterol efflux to HDL (+12%,
P
<0.05), whereas both increased ATP-binding cassette transporter G1 protein, by 1.8- and 1.6-fold, respectively. When given orally to mice, both compounds significantly increased plasma HDL-cholesterol, by 19% and 20%, respectively (
P
<0.05), accompanied by an increase in hepatic and macrophage ATP-binding cassette transporter A1 but not ATP-binding cassette transporter G1. We next evaluated in vivo reverse cholesterol transport by injecting RAW264.7 cells labeled with
3
H-cholesterol intraperitoneally into mice. Both spiroquinone and diphenoquinone increased fecal excretion of the macrophage-derived
3
H-tracer, by 25% and 28% (
P
<0.01 and
P
<0.05), respectively. spiroquinone/diphenoquinone did not affect fecal excretion of HDL-derived
3
H-cholesterol, implying that macrophage-to-plasma was the most important step in spiroquinone/diphenoquinone-mediated promotion of in vivo reverse cholesterol transport. Finally, spiroquinone significantly reduced aortic atherosclerosis in apolipoprotein E null mice when compared with the vehicle.

Conclusions—

Spiroquinone and diphenoquinone increase functional ATP-binding cassette transporter A1 in both the macrophages and the liver, elevate plasma HDL-cholesterol, and promote overall reverse cholesterol transport in vivo. These compounds are promising as therapeutic reagents against atherosclerosis.