bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe hyponatraemia and autonomic dysreflexia in a quadriplegic person
Authors: Patel Roshan , Malliwal Rohit
Published: June 2019

Spinal cord injury (SCI) is associated with a range of secondary health issues. Altered neurological function can complicate diagnosis, which may have serious consequences. Here we present the case of a tetraplegic person presenting with confusion and bradycardia. Initial testing revealed severe hyponatraemia (sodium 96 mmol/L) and ST elevation associated with labile blood pressure. Delayed further investigation identified sigmoid volvulus—endoscopic decompression led to resolution of haemodynamic lability and a diagnosis of autonomic dysreflexia. Low mood and poor documentation in the community were found to contribute to poor compliance with an established bowel management plan. Inpatient care involved electrolyte correction and establishment of regular bowel motions. The patient was discharged at baseline neurology with psychological support. This case highlights poor awareness of the secondary health issues affecting those with SCI and the complex relationship between mental and physical health.
Atrial fibrillation ablation with a spring sensor-irrigated contact force-sensing catheter compared with other ablation catheters: systematic literature review and meta-analysis
Authors: Macle Laurent , Frame Diana , Gache Larry M , Monir George , Pollak Scott J , Boo Lee Ming
Published: June 2019

Objectives

The objective of our review was to systematically assess available evidence on the effectiveness, safety and efficiency of a spring sensor-irrigated contact force (CF) catheter (THERMOCOOL SMARTTOUCH Catheter (ST)) for percutaneous ablation of paroxysmal or persistent atrial fibrillation (AF), compared with other ablation catheters, or with the ST with the operator blinded to CF data.

Design

Systematic literature review and meta-analysis.

Background

Emerging evidence suggests improved clinical outcomes of AF ablation using CF-sensing catheters; however, reviews to date have included data from multiple, distinct CF technologies.

Methods

We conducted a systematic review and meta-analysis of published studies comparing the use of ST versus other ablation catheters for the treatment of AF. A comprehensive search of electronic and manual sources was conducted. The primary endpoint was freedom from recurrent atrial tachyarrhythmia (AT) at 12 months. Procedural and safety data were also analysed.

Results

Thirty-four studies enrolling 5004 patients were eligible. The use of ST was associated with increased odds of freedom from AT at 12 months (71.0%vs60.8%; OR 1.454, 95% CI 1.12 to 1.88, p=0.004) over the comparator group, and the effect size was most evident in paroxysmal AF patients (75.6%vs64.7%; OR 1.560, 95% CI 1.09 to 2.24, p=0.015). Procedure and fluoroscopy times were shorter with ST (p=0.05 and p<0.01, respectively, vs comparator groups). The reduction in procedure time is estimated at 15.5 min (9.0%), and fluoroscopy time 4.8 min (18.7%). Complication rates, including cardiac tamponade, did not differ between groups.

Conclusions

Compared with the use of other catheters, AF ablation using the CF-sensing ST catheter for AF is associated with improved success rates, shorter procedure and fluoroscopy times and similar safety profile.
Effect of real-time visual feedback device ‘Quality Cardiopulmonary Resuscitation (QCPR) Classroom’ with a metronome sound on layperson CPR training in Japan: a cluster randomized control trial
Authors: Tanaka Shota , Tsukigase Kyoko , Hara Takahiro , Sagisaka Ryo , Myklebust Helge , Birkenes Tonje Soraas , Takahashi Hiroyuki , Iwata Ayana , Kidokoro Yutaro , Yamada Momoyo , Ueta Hiroki , Takyu Hiroshi , Tanaka Hideharu
Published: June 2019

Objectives

‘Quality Cardiopulmonary Resuscitation (QCPR) Classroom’ was recently introduced to provide higher-quality Cardiopulmonary Resuscitation (CPR) training. This study aimed to examine whether novel QCPR Classroom training can lead to higher chest-compression quality than standard CPR training.

Design

A cluster randomised controlled trial was conducted to compare standard CPR training (control) and QCPR Classroom (intervention).

Setting

Layperson CPR training in Japan.

Participants

Six hundred forty-two people aged over 15 years were recruited from among CPR trainees.

Interventions

CPR performance data were registered without feedback on instrumented Little Anne prototypes for 1 min pretraining and post-training. A large classroom was used in which QCPR Classroom participants could see their CPR performance on a big screen at the front; the control group only received instructor’s subjective feedback.

Primary and secondary outcome measures

The primary outcomes were compression depth (mm), rate (compressions per minute (cpm)), percentage of adequate depth (%) and recoil (%). Survey scores were a secondary outcome. The survey included participants’ confidence regarding CPR parameters and ease of understanding instructor feedback.

Results

In total, 259 and 238 people in the control and QCPR Classroom groups, respectively, were eligible for analysis. After training, the mean compression depth and rate were 56.1±9.8 mm and 119.2±7.3 cpm in the control group and 59.5±7.9 mm and 116.8±5.5 cpm in the QCPR Classroom group. The QCPR Classroom group showed significantly more adequate depth than the control group (p=0.001). There were 39.0% (95% CI 33.8 to 44.2; p<0.0001) and 20.0% improvements (95% CI 15.4 to 24.7; P<0.0001) in the QCPR Classroom and control groups, respectively. The difference in adequate recoil between pretraining and post-training was 2.7% (95% CI −1.7 to 7.1; pre 64.2±36.5% vs post 66.9%±34.6%; p=0.23) and 22.6% in the control and QCPR Classroom groups (95% CI 17.8 to 27.3; pre 64.8±37.5% vs post 87.4%±22.9%; p<0.0001), respectively.

Conclusions

QCPR Classroom helped students achieve high-quality CPR training, especially for proper compression depth and full recoil. For good educational achievement, a novel QCPR Classroom with a metronome sound is recommended.
Structural and numerical analysis of an implicit logarithmic scheme for diffusion equations with nonlinear reaction
Authors: Macías-Díaz Jorge E. , İnan Bilge
Published: June 2019

In this work, we investigate a numerical diffusion equation with nonlinear reaction, defined spatially over a closed and bounded interval of the real line. The partial differential equation is expressed in an equivalent logarithmic form, and initial and Dirichlet boundary data are imposed upon the problem. An implicit finite-difference discretization of this logarithmic model is proposed then. We show that the numerical scheme is capable of preserving the constant solutions of the continuous model. Moreover, we establish the existence of positive and bounded numerical solutions using analytical arguments. Finally, an extensive set of numerical simulations is provided in order to illustrate the performance of the scheme. The results verify that the logarithmic scheme converges to the exact solution of the continuous problem, with first order of convergence in time and second order in space. Moreover, we provide some comparisons on the efficiency of the implicit method against an explicit logarithmic scheme of the literature. The results show that the present discretization is a more efficient technique.
Noncommutative DKP field and pair creation in curved space–time
Authors: Achour Mohamed , Khodja Lamine , Zaim Slimane
Published: June 2019

This study is about the application of the noncommutativity on the DKP equation up to first-order in [Formula: see text] for the process of pair creation of spin-1 particles from vacuum in [Formula: see text] curved space–time. The density of particles created in the vacuum can be calculated with the help of the Bogoliubov transformations. The noncommutative density of created particles is found to decrease as [Formula: see text], so that the rate of particle creation increases whenever a noncommutativity parameter is small and this corresponds to the spirit of quantum mechanics.
Hawking’s radiation of sine–Gordon black holes in two dimensions
Authors: Nach M.
Published: June 2019

In the framework of the integrable model of the sine–Gordon equation, we describe a recent method to recover the Hawking temperature from the sine–Gordon black hole (sGBH). We present the SGBH metric, its event horizon and give the Hawking temperature of sine–Gordon black hole. We use the complex path analysis method to examine the Hawking radiation and give the possibility of estimating the evaporation time of the SGBH.
Ado theorem for nilpotent Hom–Lie algebras
Authors: Makhlouf Abdenacer , Zusmanovich Pasha
Published: June 2019

We prove an analog of the Ado theorem — the existence of a finite-dimensional faithful representation — for a certain kind of finite-dimensional nilpotent Hom–Lie algebras.
DOES HARMFUL CLIMATE INCREASE OR DECREASE MIGRATION? EVIDENCE FROM RURAL HOUSEHOLDS IN NIGERIA
Authors: CATTANEO CRISTINA , MASSETTI EMANUELE
Published: June 2019

This paper analyzes whether migration is an adaptation strategy that households employ to cope with climate in Nigeria. We estimate our model using the cross-sectional variation in climate and long-term migration decisions because we are interested in the average response to long-term climatic conditions. For households that operate farms, we find that the relationship between climate and migration is nonlinear. In particular, climates closer to ideal farming conditions are associated with a higher propensity to migrate, whereas in the least favorable climatic conditions, the propensity to migrate declines. The marginal effect of rainfall and temperature changes on migration varies by season. We estimate the impact of climate change on the number of migrant households in 2031–2060 and 2071–2100, ceteris paribus. With current population levels, climate change generates between 3.6 and 6.3 million additional migrants, most of them being internal. However, these estimates are not statistically significant.
Loss of cells expressing fibroblast activation protein has variable effects in models of TGF-β and chronic bleomycin-induced fibrosis
Authors: Kimura Toru , Monslow James , Klampatsa Astero , Leibowitz Michael , Sun Jing , Liousia Maria , Woodruff Patrick , Moon Edmund , Todd Leslie , Puré Ellen , Albelda Steven M.
Published: June 2019

Fibroblast activation protein (FAP), a cell surface serine protease, is upregulated on a subset of activated fibroblasts (often distinct from α-smooth muscle actin-expressing myofibroblasts) associated with matrix remodeling, including fibroblasts in idiopathic pulmonary fibrosis (Acharya PS, Zukas A, Chandan V, Katzenstein AL, Puré E. Hum Pathol 37: 352–360, 2006.). As FAP+fibroblasts could be pivotal in either breakdown and/or production of collagen and other matrix components, the goal of this study was to define the role of FAP+cells in pulmonary fibrosis in two established, but different, mouse models of chronic lung fibrosis: repetitive doses of intratracheal bleomycin and a single dose of an adenoviral vector encoding constitutively active TGF-β1 (Ad-TGFβ). To determine their role in fibrotic remodeling, FAP-expressing cells were depleted by injection of T cells expressing a chimeric antigen receptor specific for murine FAP in mice with established fibrosis. The contribution of FAP to the function of FAP-expressing cells was assessed in FAP knockout mice. Using histological analyses, quantification of soluble collagen content, and flow cytometry, we found that loss of FAP+cells exacerbated fibrosis in the bleomycin model, a phenotype largely recapitulated by the genetic deletion of FAP, indicating that FAP plays a role in this model. In contrast, depletion of FAP+cells or genetic deletion of FAP had little effect in the Ad-TGFβ model highlighting the potential for distinct mechanisms driving fibrosis depending on the initiating insult. The role of FAP in human lung fibrosis will need to be well understood to guide the use of FAP-targeted therapeutics that are being developed.
Expression of Toll-Like Receptors (TLR2 and TLR4) in the Eyes of Mice with Disseminated Acanthamoebiasis
Authors: Kot Karolina , Kosik-Bogacka Danuta , Łanocha-Arendarczyk Natalia , Wojtkowiak-Giera Agnieszka , Kolasa-Wołosiuk Agnieszka
Published: June 2019

Toll-like receptors (TLRs) play a key role in the innate immune response to numerous pathogens, includingAcanthamoebaspp. The aim of this study was to determine the expression of TLR2 and TLR4 in the eyes of mice following intranasal infection withAcanthamoebaspp. in relation to the host’s immunological status. Amoebae used in this study were isolated from the bronchial aspirate of a patient with acute myeloid leukemia (AML) and atypical symptoms of pneumonia. We found statistically significant differences in the expression of TLR2 and TLR4 in the eye of immunocompetent mice at 8, 16, and 24 days afterAcanthamoebaspp. infection (dpi) compared to control group. Immunosuppressed mice showed significant differences in the expression of TLR2 at 16 and 24 dpi compared to uninfected animals. Our results indicate that TLR2 and TLR4 are upregulated in the eyes of mice in response toAcanthamoebaspp. We suggest that it is possible for trophozoites to migrate through the optic nerve from the brain to the eyes. The course of disseminated acanthamoebiasis may be influenced by the host’s immunological status, and the observed changes in expression of TLR2 and TLR4 in the host’s organs may indicate the role of these receptors in the pathomechanism of acanthamoebiasis.
Security Cryptanalysis of NUX for the Internet of Things
Authors: Liu Yu , Liu Xiaolei , Zhao Yanmin
Published: June 2019

In order to adopt the restricted environment, such as radio frequency identification technology or sensor networking, which are the important components of the Internet of Things, lightweight block ciphers are designed. NUX is a 31-round iterative ultralightweight cipher proposed by Bansod et al. In this paper, we examine the resistance of NUX to differential and linear analysis and search for 1~31-round differential characteristics and linear approximations. In design specification, authors claimed that 25-round NUX is resistant to differential and linear attack. However, we can successfully perform 29-round differential attack on NUX with the 22-round differential characteristic found in this paper, which is 4 rounds more than the limitation given by authors. Furthermore, we present the key recovery attack on 22-round NUX using a 19-round linear approximation determined in this paper. Besides, distinguishing attack, whose distinguisher is built utilizing the property of differential propagation through NUX, is implemented on full NUX with data complexity 8.
Smith Predictor‐Taylor Series‐Based LQG Control for Time Delay Compensation of Vehicle Semiactive Suspension
Authors: Tao Laihua , Chen Shian , Fang Guisheng , Zu Guanghao
Published: June 2019

A Smith predictor‐Taylor series‐based LQG (STLQG) control to compensate time delay of a semiactive suspension system is newly presented. This control consists of a Taylor series‐based LQG (TLQG) control and a Smith predictor based on the TLQG. The TLQG control compensates one half of time delay to decrease magnification from whole time delay compensation. The Smith predictor based on the TLQG compensates the other half to decrease horizontal shift from whole time delay compensation using the Smith predictor‐based LQG. Finally, a practical case illustrates advantages of the STLQG control.
The Role of Herbal Bioactive Components in Mitochondria Function and Cancer Therapy
Authors: Tao Fangfang , Zhang Yanrong , Zhang Zhiqian
Published: June 2019

Mitochondria are highly dynamic double-membrane organelles which play a well-recognized role in ATP production, calcium homeostasis, oxidation-reduction (redox) status, apoptotic cell death, and inflammation. Dysfunction of mitochondria has long been observed in a number of human diseases, including cancer. Targeting mitochondria metabolism in tumors as a cancer therapeutic strategy has attracted much attention for researchers in recent years due to the essential role of mitochondria in cancer cell growth, apoptosis, and progression. On the other hand, a series of studies have indicated that traditional medicinal herbs, including traditional Chinese medicines (TCM), exert their potential anticancer effects as an effective adjunct treatment for alleviating the systemic side effects of conventional cancer therapies, for reducing the risk of recurrence and cancer mortality and for improving the quality of patients’ life. An amazing feature of these structurally diverse bioactive components is that majority of them target mitochondria to provoke cancer cell-specific death program. The aim of this review is to summarize the in vitro and in vivo studies about the role of these herbs, especially their bioactive compounds in the modulation of the disturbed mitochondrial function for cancer therapy.
Numerical Modeling of 3D Flow Field among a Compound Stilling Basin
Authors: Zhou Zhao , Wang Junxing
Published: June 2019

Due to great velocity gradients among the outgoing flow, it is much common to form large‐scale reverse flow with oblique movements outside the conventional separated stilling basin. Aimed at above problems, this paper proposes to remove the longitudinal splitter wall and then physically and numerically investigate the corresponding influence upon the compound stilling basin. The standard k‐ε, renormalization group k‐ε, realizable k‐ε, and large eddy simulation turbulence models are all employed to reveal downstream three‐dimensional flow field. Experimental validation of numerical results shows that the renormalization group k‐ε turbulence model is the most successful in predicting the flow field among the four models. Both methods prove that the removed splitter wall exerts great impact upon downstream stilling basin. In view of the removed splitter wall, discharging inflow would greatly diffuse to form a typical three‐dimensional (3D) hydraulic jump with large‐scale reverse flow. High energy dissipation region and high turbulent kinetic energy region are both moved upstream. Thus, the velocity decay among the discharging flow in the compound stilling basin is significantly enhanced. Compared to the separated stilling basin, the maximum velocity and average velocity of the outgoing flow, respectively, decrease more than 30%, and 20% in the compound stilling basin. Additionally, the velocity gradients between the left and the right outgoing flow reduce by over 65% with turbulent kinetic energy gradients almost down to zero. The outgoing flow from the compound stilling basin becomes much uniform with the phenomenon of obliquely moving flow totally eliminated.
Effect of Improvement and Application of Composite Prefabricated Vertical Drain Method in Marine Soft Ground: A Case Study
Authors: Jiang Jianqing , Liu Reqiang
Published: June 2019

One of the commonly used techniques to improve marine soft ground is the drainage consolidation method by plastic board drains (PBDs). But some complex marine soft ground will cause construction inconvenience of PBDs in certain areas of these sites, thus affecting the improvement effect. An alternative possible approach to overcoming these deficiencies may be the combination of PBDs and sand wick drains (SWDs) (i.e., composite prefabricated vertical drains (CPVDs)) as vertical drainage channels in the same site. In order to verify the suitability and performance of this method in marine soft ground improvement, a case study was performed based on the field monitoring and construction of the marine soft ground of an intercity express railway project in China. The construction procedure using the CPVD system, the field monitoring instrumentation scheme, and the design of fill surcharge level were described, and the field monitoring data were presented. The settlement characteristics, dissipation features of pore water pressure, and the horizontal movement pattern were assessed. In addition, predictions of ultimate settlement, postconstruction settlement, and consolidation degree were discussed by applying a modified hyperbolic model. The results show that the marine ground improved by the CPVD system is suitable for the construction of intercity express railway and high‐speed railway. The improvement construction period of complex marine soft ground will be greatly shortened by the proposed parallel construction programme. This work will provide technical supports and application reference for the improvement of the similar marine soft ground.
Early Electrophysiological Disintegration of Hippocampal Neural Networks in a Novel Locus Coeruleus Tau-Seeding Mouse Model of Alzheimer’s Disease
Authors: Ahnaou A. , Walsh C. , Manyakov N. V. , Youssef S. A. , Drinkenburg W. H.
Published: June 2019

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by loss of synapses and disrupted functional connectivity (FC) across different brain regions. Early in AD progression, tau pathology is found in the locus coeruleus (LC) prior to amyloid-induced exacerbation of clinical symptoms. Here, a tau-seeding model in which preformed synthetic tau fibrils (K18) were unilaterally injected into the LC of P301L mice, equipped with multichannel electrodes for recording EEG in frontal cortical and CA1-CA3 hippocampal areas, was used to longitudinally quantify over 20 weeks of functional network dynamics in (1) power spectra; (2) FC using intra- and intersite phase-amplitude theta-gamma coupling (PAC); (3) coherence, partial coherence, and global coherent network efficiency (Eglob) estimates; and (4) the directionality of functional connectivity using extended partial direct coherence (PDC). A sustained leftward shift in the theta peak frequency was found early in the power spectra of hippocampal CA1 networks ipsilateral to the injection site. Strikingly, hippocampal CA1 coherence and Eglob measures were impaired in K18-treated animals. Estimation of instantaneous EEG amplitudes revealed deficiency in the propagation directionality of gamma oscillations in the CA1 circuit. Impaired PAC strength evidenced by decreased modulation of the theta frequency phase on gamma frequency amplitude further confirms impairments of the neural CA1 network. The present results demonstrate early dysfunctional hippocampal networks, despite no spreading tau pathology to the hippocampus and frontal cortex. The ability of the K18 seed in the brainstem LC to elicit such robust functional alterations in distant hippocampal structures in the absence of pathology challenges the classic view that tau pathology spread to an area is necessary to elicit functional impairments in that area.
Laboratory Investigation into Early‐Age Strength Improvement of Cold Recycled Asphalt Mixture Containing Asphalt Emulsion and Cement
Authors: Du Yinfei , Kong Lingxiang , Wei Tangzhong
Published: June 2019

Cold recycled asphalt mixture (CRAM) has been reported to be able to provide a cleaner method to rehabilitate damaged asphalt pavement. This work used the CRAM containing emulsified asphalt (AE) and cement to investigate the methods of improving its early‐age strength by considering mixture composition, including the types of AE and cement and the contents of AE, cement, and moisture. The curing conditions, such as temperature and humidity, were also involved. The results show that the mixture should be carefully designed to determine optimum AE and moisture content. Also, high cement content was helpful to increase the early‐age strength. By changing the curing environment, it was found that raising curing temperature and applying a relatively low humidity contributed to the early‐age strength improvement. The interaction of cement hydration and AE demulsification was investigated using microimage and laboratory experiments. The results show that AE particles were easy to cluster because of the negative ions released by cement hydration. AE delayed the early cement hydration but improved the later intensity of cement hydration. The coupling effect of AE and cement resulted in higher early‐age strength than those of the mixtures only with cement or only with AE. The results presented in this work are expected to give guidance for preparing a CRAM with high early‐age strength.
Effects of Nonthermal Plasma on Wheat Grains and Products
Authors: Scholtz V. , Šerá B. , Khun J. , Šerý M. , Julák J.
Published: June 2019

This paper presents the review of effects of nonthermal plasma (NTP) treatment on both the wheat grains and flour with potential to be applied in practice. The NTP can be used in wheat grain surface disinfection, grain germination and vitality improving, and wheat flour modification and disinfection. NTP causes effective decontamination from bacteria and fungi together with insect pests and causes minimal damage to wheat grains; it inactivates enzymes and enhances the grain shelf life; it enhances the germination and initial state of growth resulting in the increase of final yield. Moreover, the production of qualitatively better dough is also mentioned.
Seismic Behavior of Shear Connectors of Steel Vierendeel Sandwich Plate
Authors: Jiang Lan , Ma Kejian , Zhang Huagang , Wu Qin , Lu Hongna , Yang Qizhu
Published: June 2019

As a new type of floor structure, steel vierendeel sandwich plates are widely applied in large‐span buildings with multiple storeys. Shear connectors are important stressed members of such plates. To evaluate the seismic performance of the shear connectors, a full‐scale test piece in two different connection forms, namely, A and B, is designed and tested under alternating load. Test analysis of the two connection specimens covers the failure modes, hysteresis curves, and main parameters (e.g., bearing capacity, ductility, stiffness degradation, and energy dissipation coefficient). The following results concerning type A connection are obtained: First, it exhibits good ductility and long yielding platform; second, elastoplasticity of steel is fully exerted with it; third, it absorbs and dissipates energy well with strong energy consumption; and fourth, when failure occurs, cracks usually happen in the heat‐affected zone of the weld in the core zone. The following conclusions about type B are drawn: first, it has large bearing capacity with high stiffness; also, when failure occurs, the ribbed stiffeners crack and flexion deformity happen.
Biomechanical Analysis of a Growing Rod with Sliding Pedicle Screw System for Early-Onset Scoliosis
Authors: Ouyang Zhihua , Wang Wenjun , Vaudreuil Nicholas , Tisherman Robert , Yan Yiguo , Bosch Patrick , Kang James , Bell Kevin
Published: June 2019

Early-onset scoliosis (EOS) remains a challenging condition for which current nonfusion surgeries require iterative lengthening surgeries. A growing rod with sliding pedicle screw system (GRSPSS) was developed to treat spinal deformities without repeated operative lengthening. This study was performed to evaluate whether GRSPSS had similar stability as a conventional pedicle screw system to maintain deformity correction. A serial-linkage robotic manipulator with a six-axis load cell positioned on the end-effector was utilized to evaluate the mechanical stability of the GRSPSS versus conventional fixed scoliosis instrumentation. Ten skeletally mature thoracic female Katahdin sheep spines (T4-L1) were subjected to 2.5 Nm of flexion-extension (FE), lateral bending (LB), and axial rotation (AR) in 2° increments for each state. The overall range of motion (ROM), apical segment ROM, and stiffness were calculated and reported. A two-tailed paired t-test was used to detect significant differences (p<0.05) between the fixed group and GRSPSS fixation. There were no significant differences in overall range of motion (ROM), apical segment ROM, or stiffness for FE or LB between the GRSPSS group and fixed group. In AR, the GRSPSS group showed increased ROM compared to the fixed group for the overall spine (36.0° versus 19.2°, p<0.01) and for the instrumented T8-T10 segments (7.0° versus 2.9°, p=0.02). Similarly, the fixed rod elastic zone (EZ) stiffness was significantly greater than the GRSPSS EZ stiffness (0.29 N/m versus 0.17 N/m, p<0.001). The space around the rod allows for the increased AR observed with the GRSPSS fusion technique and is necessary for axial growth. The GRSPSS fusion model shows equivalent flexion and LB stability to current fusion models and represents a stable fusion technique and may allow for longitudinal growth during childhood.
Deletion of Calcineurin Promotes a Protumorigenic Fibroblast Phenotype
Authors: Lieberman Allyson , Barrett Richard , Kim Jaewon , Zhang Kathy L. , Avery Diana , Monslow James , Kim Hyunsoo , Kim Bang-Jin , Puré Ellen , Ryeom Sandra
Published: June 2019

Fibroblast activation is a crucial step in tumor growth and metastatic progression. Activated fibroblasts remodel the extracellular matrix (ECM) in primary tumor and metastatic microenvironments, exerting both pro- and antitumorigenic effects. However, the intrinsic mechanisms that regulate the activation of fibroblasts are not well-defined. The signaling axis comprising the calcium-activated Ser/Thr phosphatase calcineurin (CN), and its downstream target nuclear factor of activated T cells, has been implicated in endothelial (EC) and immune cell activation, but its role in fibroblasts is not known. Here, we demonstrate that deletion of CN in fibroblasts in vitro altered fibroblast morphology and function consistent with an activated phenotype relative to wild-type fibroblasts. CN-null fibroblasts had a greater migratory capacity, increased collagen secretion and remodeling, and promoted more robust EC activation in vitro. ECM generated by CN-null fibroblasts contained more collagen with greater alignment of fibrillar collagen compared with wild-type fibroblast-derived matrix. These differences in matrix composition and organization imposed distinct changes in morphology and cytoskeletal architecture of both fibroblasts and tumor cells. Consistent with this in vitro phenotype, mice with stromal CN deletion had a greater incidence and larger lung metastases. Our data suggest that CN signaling contributes to the maintenance of fibroblast homeostasis and that loss of CN is sufficient to promote fibroblast activation.

Significance:

Calcineurin signaling is a key pathway underlying fibroblast homeostasis that could be targeted to potentially prevent fibroblast activation in distant metastatic sites.
High-Plex Predictive Marker Discovery for Melanoma Immunotherapy–Treated Patients Using Digital Spatial Profiling
Authors: Toki Maria I. , Merritt Christopher R. , Wong Pok Fai , Smithy James W. , Kluger Harriet M. , Syrigos Konstantinos N. , Ong Giang T. , Warren Sarah E. , Beechem Joseph M. , Rimm David L.
Published: June 2019

Purpose:

Protein expression in formalin-fixed, paraffin-embedded tissue is routinely measured by IHC or quantitative fluorescence (QIF) on a handful of markers on a single section. Digital spatial profiling (DSP) allows spatially informed simultaneous assessment of multiple biomarkers. Here we demonstrate the DSP technology using a 44-plex antibody cocktail to find protein expression that could potentially be used to predict response to immune therapy in melanoma.

Experimental Design: The NanoString GeoMx DSP technology is compared with automated QIF (AQUA) for immune marker compartment-specific measurement and prognostic value in non–small cell lung cancer (NSCLC). Then we use this tool to search for novel predictive markers in a cohort of 60 patients with immunotherapy-treated melanoma on a tissue microarray using a 44-plex immune marker panel measured in three compartments (macrophage, leukocyte, and melanocyte) generating 132 quantitative variables.

Results:

The spatially informed variable assessment by DSP validates by both regression and variable prognostication compared with QIF for stromal CD3, CD4, CD8, CD20, and PD-L1 in NSCLC. From the 132 variables, 11 and 15 immune markers were associated with prolonged progression-free survival (PFS) and overall survival (OS). Notably, we find PD-L1 expression in CD68-positive cells (macrophages) and not in tumor cells was a predictive marker for PFS, OS, and response.

Conclusions:

DSP technology shows high concordance with QIF and validates based on both regression and outcome assessment. Using the high-plex capacity, we found a series of expression patterns associated with outcome, including that the expression of PD-L1 in macrophages is associated with response.
Aggressive Progression in Glioblastoma Cells through Potentiated Activation of Integrin α5β1 by the Tenascin-C–Derived Peptide TNIIIA2
Authors: Fujita Motomichi , Yamamoto Tetsuya , Iyoda Takuya , Fujisawa Tatsuya , Sasada Manabu , Nagai Reo , Kudo Chikako , Otsuka Kazuki , Kamiya Sadahiro , Kodama Hiroaki , Fukai Fumio
Published: June 2019

Tenascin-C is a member of the matricellular protein family, and its expression level is correlated to poor prognosis in cancer, including glioblastoma, whereas its substantial role in tumor formation and malignant progression remains controversial. We reported previously that peptide TNIIIA2 derived from the cancer-associated alternative splicing domain of tenascin-C molecule has an ability to activate β1-integrin strongly and to maintain it for a long time. Here, we demonstrate that β1-integrin activation by TNIIIA2 causes acquisition of aggressive behavior, dysregulated proliferation, and migration, characteristic of glioblastoma cells. TNIIIA2 hyperstimulated the platelet-derived growth factor–dependent cell survival and proliferation in an anchorage-independent as well as -dependent manner in glioblastoma cells. TNIIIA2 also strongly promoted glioblastoma multiforme cell migration, which was accompanied by an epithelial–mesenchymal transition–like morphologic change on the fibronectin substrate. Notably, acquisition of these aggressive properties by TNIIIA2 in glioblastoma cells was abrogated by peptide FNIII14 that is capable of inducing inactivation in β1-integrin activation. Moreover, FNIII14 significantly inhibited tumor growth in a mouse xenograft glioblastoma model. More importantly, FNIII14 sensitized glioblastoma cells to temozolomide via downregulation of O6-methylguanine-DNA methyltransferase expression. Consequently, FNIII14 augmented the antitumor activity of temozolomide in a mouse xenograft glioblastoma model. Taken altogether, the present study provides not only an interpretation for the critical role of tenascin-C/TNIIIA2 in aggressive behavior of glioblastoma cells, but also an important strategy for glioblastoma chemotherapy. Inhibition of the tenascin-C/β1-integrin axis may be a therapeutic target for glioblastoma, and peptide FNIII14 may represent a new approach for glioblastoma chemotherapy.

Significance:

These findings provide a proposal of new strategy for glioblastoma chemotherapy based on integrin inactivation.
Therapeutic Effect of Y-27632 on Tumorigenesis and Cisplatin-Induced Peripheral Sensory Loss through RhoA–NF-κB
Authors: Zhu Yi , Howard George A. , Pittman Keith , Boykin Christi , Herring Laura E. , Wilkerson Emily M. , Verbanac Kathryn , Lu Qun
Published: June 2019

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer therapy that frequently requires a reduction or cessation of treatments and negatively impacts the patient's quality of life. There is currently no effective means to prevent or treat CIPN. In this study, we developed and applied CIPN in an immunocompetent, syngeneic murine Lewis Lung Carcinoma (LLCab) model that enabled the elucidation of both tumor and host responses to cisplatin and treatments of Y-27632, a selective inhibitor of Rho kinase/p160ROCK. Y-27632 not only preserved cisplatin's efficacy toward tumor suppression but also the combination treatment inhibited tumor cell proliferation and increased cellular apoptosis. By alleviating the cisplatin-induced loss of epidermal nerve fibers (ENFs), Y-27632 protected tumor-bearing mice from cisplatin-induced reduction of touch sensation. Furthermore, quantitative proteomic analysis revealed the striking cisplatin-induced dysregulation in cellular stress (inflammation, mitochondrial deficiency, DNA repair, etc.)–associated proteins. Y-27632 was able to reverse the changes of these proteins that are associated with Rho GTPase and NF-κB signaling network, and also decreased cisplatin-induced NF-κB hyperactivation in both footpad tissues and tumor. Therefore, Y-27632 is an effective adjuvant in tumor suppression and peripheral neuroprotection. These studies highlight the potential of targeting the RhoA–NF-κB axis as a combination therapy to treat CIPN.

Implications:

This study, for the first time, demonstrated the dual antineoplastic and neuroprotective effects of Rho kinase/p160ROCK inhibition in a syngeneic immunocompetent tumor-bearing mouse model, opening the door for further clinical adjuvant development of RhoA–NF-κB axis to improve chemotherapeutic outcomes.
Identification of De Novo Enhancers Activated by TGFβ to Drive Expression of CDKN2A and B in HeLa Cells
Authors: Liu Yen-Ting , Xu Lin , Bennett Lynda , Hooks Jared C. , Liu Jing , Zhou Qinbo , Liem Priscilla , Zheng Yanbin , Skapek Stephen X.
Published: June 2019

Disruption of the CDKN2A (INK4A/ARF) and B (INK4B) genes, which encode three function-independent tumor suppressors, is one of the most common events in human cancer. Because their relative importance in tumor prevention appears to be species- and context-specific, studying their regulation can shed light on mechanisms by which they are bypassed in malignant transformation. We previously unveiled a new pathway in which TGFβ selectively induces Arf at mouse Cdkn2a in eye development and cultured fibroblasts. As TGFβ signaling is often derailed in cancer development or progression, we investigated its control of CDKN2A/B in human cancer. Computational analyses of sequencing and array data from nearly 11,000 patients with cancer in TCGA showed discordant expression of ARF and INK4A in most cancer subtypes, with gene copy-number loss and promoter methylation involved in only a subset. Using HeLa cells as a model, we found that exogenous TGFβ induced ARF mRNA and protein, and ARF knockdown limited TGFβ-mediated growth suppression. TGFβ-mediated ARF mRNA induction required SMAD2/3, p38MAPK, and SP1, and ARF mRNA was induced without added RNAPII recruitment. Chromatin immunoprecipitation unveiled a remote enhancer element engaged by TGFβ by a mechanism that partially depended on p38MAPK. CRISPR-based editing of this enhancer limited induction of ARF and INK4B by TGFβ, but not by oncogenic RAS.

Implications:

Our findings reveal new molecular mechanisms by which CDKN2A/B regulation is coupled to external cues, and those findings represent entry points to further explore pharmacologic strategies to restore their expression in cancer.
Long-Term Effect of Different Optimizing Methods for Cardiac Resynchronization Therapy in Patients with Heart Failure: A Randomized and Controlled Pilot Study
Authors: Zhang Yu  , Xing Qiang  , Zhang Jiang-Hua , Jiang Wei-Feng  , Qin Mu  , Liu Xu 
Published: June 2019

Aim: During cardiac resynchronization therapy (CRT), optimized programming of the atrioventricular (AV) delay and ventricular-to-ventricular (VV) interval can lead to improved hemodynamics, symptomatic response, and left ventricular systolic function. Currently, however, there is no recommendation for the best optimization method. This study aimed to compare the long-term clinical outcomes of 4 different CRT optimization methods. Methods: One hundred and twenty-four consecutive CRT patients with severe heart failure and left bundle-branch block configuration were randomly assigned into four groups to undergo AV/VV delay optimization through echocardiogram (ECHO; n = 30), electrocardiogram (ECG; n = 32), QuickOpt algorithm (n = 28), and nominal AV/VV (n = 36) groups. Patients were followed up and underwent examinations, including New York Heart Association (NYHA) cardiac functional classification, 6-min walking distance (6MWD), and echocardiography, at 6, 12, 24, 36, and 48 months, respectively. The patients’ survival and clinical outcomes were compared among the four groups. Results: Kaplan-Meier survival analyses showed that the median survival was the same in the 4 groups: ECHO, 43 months; ECG, 44 months; QuickOpt, 44 months, and nominal, 41 months. At the 6-month follow-up, the reduction in left ventricular end diastolic diameter (LVEDD) was significantly less in the nominal group (–1.91 ± 2.58 mm) than that in the other three groups (ECHO: –3.70 ± 2.78 mm, p = 0.012; ECG: –3.53 ± 3.14 mm, p = 0.020; QuickOpt: –3.46 ± 2.65 mm, p = 0.032); 6MWD was significantly shorter in the nominal group (87.88 ± 34.76 m) than that in the other three groups (ECHO: 120.63 ± 56.93 m, p = 0.006; ECG: 114.97 ± 54.95 m, p = 0.020; QuickOpt: 114.57 ± 35.41 m, p = 0.027). Left ventricular ejection fraction (LVEF) significantly increased in ECHO (7.23 ± 2.76%, p = 0.010), ECG (8.50 ± 3.17%, p < 0.001), and QuickOpt (8.39 ± 2.90%, p < 0.001) compared with the nominal group (5.35 ± 2.59%). There were no significant differences among the groups in the aforementioned parameters at 24, 36, and 48 months, respectively. Conclusion: While LVEDD, LVEF, 6MWD, and NYHA were significantly improved in ECHO, ECG, and QuickOpt at 6 months, there were no significant improvements in any of the groups at 12, 24, and 48 months. These findings suggested that the long-term effect of the four CRT methods for heart failure was not significantly different.
Diagnostic Value of Different Noninvasive Criteria of Latent Myocarditis in Comparison with Myocardial Biopsy
Authors: Blagova Olga , Osipova Yuliya , Nedostup Alexander , Kogan Evgeniya , Zaitsev Alexander , Fomin Victor
Published: June 2019

Purpose: The aim of this study was to quantify the value of various clinical, laboratory, and instrumental signs in the diagnosis of myocarditis in comparison with morphological studies of the myocardium. Methods: In 100 patients (65 men, 44.7 ± 12.5 years old) with “idiopathic” arrhythmias (n = 20) and dilated cardiomyopathy (DCM; n = 80), we performed the following: 71 endomyocardial biopsies (EMB), 13 intraoperative biopsies, 5 studies of explanted hearts, and 11 autopsies with virus investigation (real-time PCR) of the blood and myocardium. Antiheart antibodies (AHA) were also measured as well as cardiac CT (n = 45), MRI (n = 25), and coronary angiography (n = 47). The comparison group included 50 patients (25 men, 53.7 ± 11.7 years old) with noninflammatory heart diseases who underwent open heart surgery. Results: Active/borderline myocarditis was diagnosed in 76.0% of the study group and in 21.6% of patients in the comparison group (p < 0.001). The myocardial viral genome was observed more frequently in patients in the comparison group than in the study group (65.0 and 40.2%; p < 0.01). We evaluated the diagnostic value of noninvasive markers of myocarditis. The panel of AHA had the greatest importance in the identification of myocarditis: sensitivity was 81.5%, and the positive and negative predictive values were 75.0 and 60.5%. This defined the diagnostic value of noninvasive markers of myocarditis and established a diagnostic algorithm providing an individual assessment of the likelihood of myocarditis development. Conclusion: AHA have the greatest significance in the diagnosis of latent myocarditis in patients with “idiopathic” arrhythmias and DCM. The use of a complex of noninvasive criteria allows the probability of myocarditis to be estimated and the indications for EMB to be determined.
The Hinrichsen Embryology Collection: Digitization of Historical Histological Human Embryonic Slides and MRI of Whole Fetuses
Authors: Maricic Nenad , Khaveh Nadia , Marheinecke Corinna , Wald Jan , Helluy Xavier , Liermann Dieter , Zaehres Holm , Brand-Saberi Beate
Published: June 2019

The number of human embryology collections is very limited worldwide. Some of these comprise the Carnegie Collection, Kyoto Collection, and the Blechschmidt Collection. One further embryonic collection is the Hinrichsen Collection of the Ruhr University Bochum, Germany, which also contains very well-preserved embryos/fetuses, along with approximately 16,000 histological sections. The digitization of this collection is indispensable to enable conservation of the collection for the future and to provide a large group of embryologists, researchers, and physicians access to these histological slides. A small selection of these scans is available at the website of the Digital Embryology Consortium [https://­human-embryology.org/wiki/Main_Page].
Laparoscopy in Acute Care Surgery: Repair of Perforated Duodenal Ulcer
Authors: Jamal Mohammad H. , Karam Abdulazeez , Alsharqawi Nourah , Buhamra Abdulla , AlBader Ibtesam , Al-Abbad Jasem , Dashti Mohammad , Abulhasan Yaser B. , Almahmeed Husain , AlSabah Salman
Published: June 2019

Introduction: The use of laparoscopic management as a first choice for the treatment of duodenal perforation is gaining ground but is not routine in many centers. In this report, we aim to report our experience with laparoscopy as the first approach for the repair of duodenal perforation. Materials and Methods: This is a retrospective review of patients during our initial experience with the use of laparoscopy for the treatment of duodenal perforation between 2009 and 2013. Results: A total of 100 patients underwent management of duodenal perforation. Laparoscopy was attempted initially in 76 patients (76%) and completed in 64 patients (64%). The length of hospital stay was shorter in the laparoscopic group (mean 2.6) than in the open group (mean 3.1) (p = 0.008). Complications developed in 14 patients (20%). There was a tendency towards fewer admissions to intensive care, less acute kidney injuries, and less acute respiratory distress syndrome in the laparoscopic group. In patients who underwent laparoscopic surgery, the chances of uneventful recovery were 4.3 times higher than in those patients who underwent open surgery (95% CI 1.3–13.5, p = 0.014). Conclusions: Laparoscopy in the treatment of perforated duodenal ulcer is safe and can be utilized as a routine approach for the treatment of this pathology.
Multiple Assays to Determine Methylguanine-Methyltransferase Status in Lung Carcinoids and Correlation with Clinical and Pathological Features
Authors: Vatrano Simona , Giorcelli Jessica , Votta Arianna , Capone Guendalina , Izzo Stefania , Gatti Gaia , Righi Luisella , Napoli Francesca , Scagliotti Giorgio , Papotti Mauro , Volante Marco , Rapa Ida
Published: June 2019

Background: O6-methylguanine-methyltransferase (MGMT) is a key enzyme for the DNA repair machinery strongly associated with response to alkylating agents in different tumors. Data on its expression and related clinical impact in neuroendocrine tumors are limited to the gastro-entero-pancreatic system, with controversial results in terms of prognostic or predictive value. In lung carcinoids, although clinical efficacy of alkylating agents has been shown in small studies, very few data to date are available on MGMT status. Objective: To assess MGMT status in lung carcinoids using multiple assays and to compare data with major clinical and pathological features. Methods: A retrospective series of 95 lung carcinoids and 51 control cases of high-grade neuroendocrine lung carcinomas was analyzed for MGMT promoter methylation, MGMT gene expression, and MGMT protein expression using pyrosequencing, quantitative real-time PCR, and immunohistochemistry, respectively. Results: MGMT protein expression was inversely correlated with MGMT promoter methylation and positively with MGMT gene expression. MGMT promoter methylation progressively increased from carcinoids to high-grade carcinomas. In the carcinoid group, decreased MGMT gene expression was significantly associated with aggressive features (atypical histotype, grade G2, larger tumor size, higher T stage, and positive nodal status) but not with survival. MGMT promoter methylation was associated with lower stage and negative nodal status. Conclusions: Our study investigated MGMT status in a large series of lung carcinoids in the attempt to move forward a rational use of alkylating agents in these tumors. Interestingly, low MGMT gene expression defines a subgroup of lung carcinoids with aggressive features.