bluuebunny/crossref_metadata_2025 huggingface dataset:
An Experimental Study on the Hydromechanical Behaviours of the Evolution of Postearthquake Landslide Deposits
Authors: Cai Huan , Yang Zong-Ji , Wang Li-Yong , Lei Xiao-Qin , Fu Xiao-Long , Liu Shi-Hao , Qiao Jian-Ping
Published: July 2019

In this study, a series of experiments of the full-scale physical model was employed to investigate the hydromechanical behaviours of the postearthquake landslide evolution, in forms of rill erosion and shallow headward failure on the rill bank slopes under unsaturated conditions. Soil-water characteristic curves (SWCC) were established using the Brooks-Corey (BC) and van Genuchten (VG) models. The stability of the shallow failure was then analyzed via a one-dimensional and unsaturated stability analysis model of the infinite slope. This measurement revealed that the preferential flow and the matrix flow coexisted when infiltration occurred and the VG model performs better in fitting the SWCC than the BC model. Consistent feedback between stability calculations and experimental observations enables the analysis of mechanisms of rill erosion and slope failure of postseismic landslide under the impact of preferential flow. Furthermore, the seepage-induced internal erosion phenomenon was observed in the experiment. This work thus provides a new perspective on the triggering mechanisms of debris flow during the postseismic period.
Correlations between Traditional and Nontraditional Indicators of Adiposity, Inflammation, and Monocyte Subtypes in Patients with Stable Coronary Artery Disease
Authors: Garofallo Silvia Bueno , Portal Vera Lucia , Markoski Melissa Medeiros , Dias Lucinara Dadda , Quadrosa Alexandre Schaan de , Marcadenti Aline
Published: July 2019

Background. Recruitment of monocytes and low-grade inflammation process are both involved in obesity and in atherosclerosis. Thus, the aim of this study was to evaluate the correlation among indicators of adiposity, monocyte subtypes, and inflammatory markers in patients with stable coronary artery disease (CAD).Methods. This was a cross-sectional study including 97 patients with stable CAD aged >40 years. Traditional anthropometric indicators of adiposity (body mass index (BMI); waist, hip, and neck circumferences; and waist-hip ratio) and nontraditional anthropometric indicators of adiposity (lipid accumulation product index (LAP), visceral adiposity index (VAI), and deep-abdominal-adipose-tissue index (DAAT)) were determined. Immunoprecipitation, turbidimetry, coagulometric method, and CBA were used for the evaluation of inflammatory markers (hs-CRP, IL-2, IL-4, IL-6, IL-10, and INF-γ). Monocyte subtypes were identified by flow cytometry and defined as CD14++ CD16− (Mon1), CD14++ CD16+ (Mon2), and CD14+ CD16++ (Mon3). Pearson’s correlation coefficient and adjusted partial correlation were calculated.Results. Monocyte subtypes were correlated with inflammation regardless of nutritional status according to BMI. In overweight individuals, LAP was correlated with IL-4 and fibrinogen (P<0.01andP<0.05, respectively) and VAI with IL-4 (P<0.05). In obese patients, the BMI, waist, neck, and hip circumferences, and DAAT were correlated with IL-6 (P<0.05), regardless of age and sex. The hip circumference was correlated positively with Mon1 (r = 0.40,P=0.007) and negatively with Mon3 (r = −0.35,P=0.02) in obese subjects.Conclusion. Monocyte subtypes are correlated with inflammation in patients with stable CAD independently of BMI, whereas traditional and nontraditional indicators of adiposity are correlated differently with inflammatory markers and monocytes, according to the nutritional status.
Permeability Characteristic and Failure Behavior of Filled Cracked Rock in the Triaxial Seepage Experiment
Authors: Liu Xinyu , Zhu Zhende , Liu Aihua
Published: July 2019

Filling is commonly found in natural cracked rock mass. As the weakest part of the rock, the filling properties directly affect the rock deformation and strength, permeability, and so on and affect the safety and stability of the rock mass engineering. In this study, a single slit has been preset in sandstones and filled with different physical properties materials. Based on the laboratory triaxial seepage test, the permeability and strength characteristics of filled cracked sandstones are analyzed, and the failure modes are obtained. The main findings of this study are as follows: (1) The permeability coefficient peak value of the filled cracked rock appears before the stress peak. (2) At the same confining pressure growth rate, the peak stress growth rate of the filled cracked rock is generally higher than that of the intact rock and the strength growth rate of the cracked rock increases with the length of the fracture. The strength characteristics of the filling in the uniaxial compression tests and triaxial seepage tests are significantly affected by the hydraulic properties. (3) The strength and permeability coefficients of cracked rock filled with cement mortar are more sensitive to the change of confining pressure, while under the same condition, the ones of cracked rock filled with gypsum mortar are stable. (4) According to the failure mechanism, under the seepage stress, the secondary cracks can be divided into 3 types and the failure modes can be divided into 2 types.
A Dual-Broadband Printed Dipole Antenna for 2G/3G/4G Base Station Applications
Authors: Zhu XiongZhi , Zhang JinLing , Cui Tong , Zheng ZhanQi
Published: July 2019

A new dual-broadband printed dipole antenna for base station applications is proposed in this communication. This antenna has three different dipoles with the same feed point and an extra parasitic strip. The two arms of the three dipoles are printed on opposite sides of the substrate and symmetrical on the centerline, but the parasitic strip at the end of the dipole is just put on one side. Besides, a U-shaped reflector is designed at the bottom of the antenna to realize good radiation characteristics in the working frequency. The simulated and measured results show good agreement. The two studied bands are both broadened which, respectively, achieve 36.7% (690–1000MHz) and 47.3% (1710–2770MHz) for the lower and higher bands so as to satisfy the 2G/3G/4G wireless communication, and the corresponding gains of 4-5dBi and 5-6dBi are also obtained.
KIF5A Promotes Bladder Cancer Proliferation In Vitro and In Vivo
Authors: Tian Da-Wei , Wu Zhou-Liang , Jiang Li-Ming , Gao Jie , Wu Chang-Li , Hu Hai-Long
Published: July 2019

Background. Bladder cancer is a common malignancy with uncontrolled and rapid growth. Although lots of the important regulatory networks in bladder cancer have been found, the cancer-relevant genes remain to be further identified. Methods. We examined the KIF5A expression levels in bladder cancer and normal bladder tissue samples via immunohistochemistry and observed the effect of KIF5A on bladder tumor cell proliferation in vitro and in vivo. Additionally, a coexpression between KIF5A and KIF20B in tumor tissues was explored. Results. KIF5A expression level was higher in the bladder cancer tissues than in the adjacent nontumor tissues. Patients with higher KIF5A expression displayed advanced clinical features and shorter survival time than those with lower KIF5A expression. Moreover, KIF5A knockdown inhibited bladder cancer cell proliferation, migration, and invasion demonstrated in vivo and in vitro. In addition, coexpression was found between KIF5A and KIF20B in tumor tissues. Conclusion. The results demonstrated that KIF5A is a critical regulator in bladder cancer development and progression, as well as a potential target in the treatment of bladder cancer.
Comparison of Chronic Hemodialysis Patients under Strict Volume Control with respect to Cardiovascular Disease
Authors: Ersoy Dursun Fadime , Gunal Ali Ihsan , Kirciman Ercan , Karaca Ilgin , Dagli Mustafa Necati
Published: July 2019

Background. The objective of this study was to determine the effects of strict volume control and nondipper situation on cardiovascular disease in chronic hemodialysis patients.Methods. This study is an observational and cross-sectional study including 62 patients with normotensive chronic hemodialysis using no antihypertensive drugs. A series of measurements including ambulatory blood pressure monitoring, left ventricular mass index by echocardiography, common carotid artery intima-media thickness by ultrasound, and body fluids by bioimpedance analysis were conducted for all subjects.Results. The patients were divided into two groups as dippers and nondippers according to their ambulatory blood pressure monitoring results. Average 48 h systolic, diastolic, and mean arterial blood pressure and nocturnal systolic, diastolic, and mean arterial blood pressure were significantly different between the dipper and nondipper groups (p<0.05). Before and after dialysis, extracellular fluid/intracellular fluid and extracellular fluid/dry body weight ratios were significantly higher in the nondipper group. Left ventricle mass index and interventricular septum thickness were significantly higher in the nondipper group (p<0.05). Left ventricle ejection fraction was significantly lower and common carotid artery intima-media thickness was higher in the nondipper group with a statistical significance (p<0.05). A two-predictor logistic model was fitted to the data to predict the comparability of dippers and nondippers.Conclusion. According to logistic regression analysis, the odds ratio for daytime diastolic blood pressure indicates that nondippers are 0.45 times more likely to have high blood pressure than dippers in daytime. But in night time, nondippers are about 2.55 times more likely to have high blood pressure comparing to dippers. An important finding of this study is that nondipping pattern is associated with cardiac hypertrophy and lower left ventricle ejection fraction in dialysis of patients with no hypertension. The results also suggest that applying strict volume control to achieve a normal blood pressure alone is not sufficient to reduce the risk of cardiovascular morbidity and mortality if the patients do not have a dipper status of nocturnal blood pressure.
Effect of Rock Particle Content on the Mechanical Behavior of a Soil‐Rock Mixture (SRM) via Large‐Scale Direct Shear Test
Authors: Liu Longqi , Mao Xuesong , Xiao Yajun , Wu Qian , Tang Ke , Liu Feifei
Published: July 2019

The mechanical strength of the landslide deposits directly affects the safety and operation of the roads in the western mountainous area of China. Therefore, the research is aimed at studying the mechanisms of a landslide deposit sample with different rock particle contents by analyzing its characteristics of the stress‐strain behavior, the “jumping” phenomenon, the volumetric strain, and the shear strength parameters via a large‐scale direct shear test. Stress‐strain results show that stress‐strain curves can be divided into 3 different stages: liner elastic stage, yielding stage, and strain‐hardening stage. The shear strength of SRM behaves more like “soil” at a lower rock particle content and behaves more like “rock joints” at a higher rock particle content. Characteristics of the “jumping” phenomenon results show that the “intense jumping” stage becomes obvious with the increasing rock particle content and the normal stress. However, the lower the rock particle content is, the more obvious the “jumping” phenomenon under the same normal stress is. Volumetric strain results show that the sample with a lower rock particle content showed a dilatancy behavior under the low normal stress and shrinkage behavior under the high normal stress. The dilatancy value becomes smaller with the increasing normal stress. The maximum shear stress value of the rock particle content corresponds to the maximum value of dilatancy or shrinkage. We also conclude that the intercept of the Mohr failure envelope of the soil‐rock mixture should be called the “equivalent cohesion,” not simply called the “cohesion.” The higher the normal stress and rock particle content are, the bigger the equivalent cohesion and the internal friction angle is.
Network Pharmacology-Based Prediction and Verification of the Targets and Mechanism for Panax Notoginseng Saponins against Coronary Heart Disease
Authors: Dong Yan , Duan Lian , Chen Heng-wen , Liu Yong-mei , Zhang Yun , Wang Jie
Published: July 2019

Coronary heart disease (CHD) is the worldwide leading cause for cardiovascular death. Panax notoginseng saponin (PNS), which is the main bioactive compound of panax notoginseng, has been generally accepted to exert a remarkable effect on CHD for a long time. However, to reveal the underlying treatment target and corresponding mechanism of PNS against CHD is still a substantial challenge. In this work, the targets and mechanism of PNS against CHD were successfully achieved by pharmacology-based prediction and experimental verification. 36 common targets were screened out through integrating the gene expression profile of CHD and the chemical-protein data of PNS. Then, two key nodes were further selected for verification by experiment after analyzing GO function, KEGG pathway, coexpression, and topology analysis. Results showed that PNS has protected the human umbilical vein endothelial cells from H2O2-induced oxidative stress by inhibiting early cell apoptosis via upregulating VEGFA mRNA expression. Therefore, our research has successfully pointed out one treatment target and apoptotic inhibition caused by PNS with method of integrating bioinformatics prediction and experimental verification, which has partially explained the pharmacological mechanism of PNS against CHD.
A 2D Nested Array Based DOA Estimator for Incoherently Distributed Sources via Sparse Representation Utilizing L1-Norm
Authors: Wu Tao , Li Yiwen , Li Zhengxin , Huang Yijie , Xu Jiwei
Published: July 2019

Nested arrays are sparse arrays composed of subarrays with nonuniform sensor spacing. Compared with traditional uniform arrays, nested arrays have more degree of freedoms (DOFs) and larger apertures. In this paper, a nested array has been proposed as well as a direction-of-arrival (DOA) estimation method for two-dimensional (2D) incoherently distributed (ID) sources. A virtual array is firstly obtained through vectorization of the cross-correlation matrix of subarrays. Sensor positions of the virtual array and the optimal configuration of the nested array are derived next. Then rotational invariance relationship for generalized steering matrix of the virtual array with respect to nominal azimuth is deduced. According to the rotational invariance relationship, sparse representation model under l1-norm constraint is established, which is resolved by transferring the objective function to second-order cone constraints and combining a estimation residual error constraint for receive vector of the virtual array. Simulations are conducted to investigate the effectiveness of the proposed method in underdetermined situation and examine different experiment factors including SNR, snapshots, and angular spreads as well as sensor number of subarrays. Results show that the proposed method has better performance than uniform parallel arrays with the same number of sensors.
Evaluation of Chondroprotective Activity of Channa striatus in Rabbit Osteoarthritis Model
Authors: Abdul Kadir Azidah , Abdul Kadir Arifah , Abd Hamid Roslida , Mat Jais Abdul Manan , Omar Julia , Sadagatullah Abdul Nawfar , Badrin Salziyan , Win Thin Thin , Sirajudeen K. N. S. , Salleh Annas
Published: July 2019

Objectives. The objective of the study is to evaluate the chondroprotective activity of Channa striatus (Channa) and glucosamine sulphate (glucosamine) on histomorphometric examinations, serum biomarker, and inflammatory mediators in experimental osteoarthritis (OA) rabbit model. Design. Anterior cruciate ligament transection (ACLT) was performed to induce OA in thirty-three male New Zealand white rabbits and were randomly divided into three groups: Channa, glucosamine, and control group. The control group received drinking water and the Channa and glucosamine groups were orally administered with 51.4 mg/kg of Channa extract and 77.5 mg/kg of glucosamine sulphate in drinking water, respectively, for eight weeks and then sacrificed. The articular cartilage was evaluated macroscopically and histologically using semiquantitative and quantitative methods. Serum cartilage oligomeric matric protein (COMP), cyclooxygenase 2 (COX-2) enzyme, and prostaglandin E2 (PGE2) were also determined. Results. Macroscopic analysis revealed that Channa group have a significantly lower severity grade of total macroscopic score compared to the control (p < 0.001) and glucosamine (p < 0.05) groups. Semiquantitative histology scoring showed that both Channa and glucosamine groups had lower severity grading of total histology score compared to the control group (p < 0.001). In comparison with the control, Channa group had lower histopathological changes in three compartments of the joint compared to glucosamine group which had lower histological scoring in two compartments only. The cartilage thickness, area, and roughness of both Channa (p < 0.05) and glucosamine (p < 0.05) groups were superior compared to the control group. However, the Channa group demonstrated significantly less cartilage roughness compared to the glucosamine group (p < 0.05). Serum COMP levels were lower in both Channa (p < 0.05) and glucosamine (p < 0.05) groups compared to the control group. Conclusion. Both oral administration of Channa extract and glucosamine exhibited chondroprotective action on an ACLT OA-induced rabbit model. However, Channa was superior to glucosamine in maintaining the structure of the cartilage.
Physical and Numerical Modelling of Post-Pumping Seawater Intrusion
Authors: Stoeckl Leonard , Walther Marc , Morgan Leanne K.
Published: July 2019

This paper explores post-pumping seawater intrusion (PP-SWI), which is the phenomenon of seawater intruding further inland than the location of a well, after pumping has ceased. Despite numerous papers on the topic of seawater intrusion and pumping, this is the first time that PP-SWI has been described in the literature, to our knowledge. This paper describes a laboratory-scale investigation of the phenomenon and we demonstrate that PP-SWI can be reproduced within physical experiments. We also show, using numerical modelling, that PP-SWI is caused by disequilibrium in the flow field following the cessation of pumping. Specifically, in our simulations, the cone of depression persisted after the cessation of pumping (first moving inland and then retreating toward the coastal boundary) which caused a lag in the reestablishment of fresh water flow toward the coast, after pumping had stopped. It was during this period of flow-field disequilibrium that PP-SWI occurred. We expect systems with larger postextraction disequilibrium to be most susceptible to PP-SWI and recommend future research to improve understanding of the relationship between hydrogeological parameters, extraction rates, well location, and incidence of PP-SWI. In those systems where PP-SWI is most likely, quantitative analysis of groundwater extraction and SWI will need to employ transient approaches to ensure that SWI is not underestimated.
The Physicochemical Properties of Graphene Nanocomposites Influence the Anticancer Effect
Authors: Yang Wenbo , Deng Xiangyu , Huang Wei , Qing Xiangcheng , Shao Zengwu
Published: July 2019

Graphene nanocomposite is an inorganic nanocomposite material, which has been widely used in the treatment of tumor at present due to its ability of drug loading, modifiability, photothermal effect, and photodynamic effect. However, the application of graphene nanocomposite is now limited due to the fact that the functions mentioned above are not well realized. This is mainly because people do not have a systematic understanding of the physical and chemical properties of GO nanomolecules, so that we cannot make full use of GO nanomolecules to make the most suitable materials for the use of medicine. Here, we are the first to discuss the influence of the physicochemical properties of graphene nanocomposite on the various functions related to their antitumor effects. The relationship between some important physicochemical properties of graphene nanocomposite such as diameter, shape, and surface chemistry and their functions related to antitumor effects was obtained through analysis, which provides evidence for the application of related materials in the future.
Efficient Cancelable Iris Template Generation for Wearable Sensors
Authors: Jeong Jae Yeol , Jeong Ik Rae
Published: July 2019

When biometric authentication is performed on On-Body Wearable Wireless Networks, a cancelable template is useful to protect biometric information. A cancelable template generation method converts the original biometric information into irreversibly transformed information to protect the original biometric information. If a cancelable template is damaged or leaked, it can be replaced with another cancelable template. In 2017, Dwivedi et al. proposed a novel cancelable iris template generation scheme based on the randomized look-up table mapping. So far their scheme is the most accurate scheme with respect to EER compared to the previous cancelable iris template generation schemes. However, their scheme is not alignment-free and so is not efficient enough for wearable sensors. In the paper, we first suggest how to improve the accuracy of the Dwivedi et al.’s scheme using the partial sort technique. Our experiment result shows that our suggested scheme is more accurate than the Dwivedi et al.’s scheme under almost all parameter settings. More concretely, our scheme achieves EER 0.09%, whereas the Dwivedi et al.’s scheme achieves EER 0.43% in the best parameter settings for the CASIA-V3-Interval iris database. We also suggest how to improve the efficiency of the Dwivedi et al.’s scheme. Our second scheme is alignment-free by processing IrisCode column-wise, whereas the Dwivedi et al.’s scheme handles IrisCode row-wise. Our experiment shows that our second scheme is 15 times faster than the Dwivedi et al.’s scheme, so our scheme is efficient enough for wearable sensors. Though our second scheme has very high EER under some parameter settings, our second scheme achieves EER 0.53% in the best parameter settings for the CASIA-V3-Interval iris database.
Activation and Expression of Peroxisome Proliferator-Activated Receptor Alpha Are Associated with Tumorigenesis in Colorectal Carcinoma
Authors: Morinishi Tatsuya , Tokuhara Yasunori , Ohsaki Hiroyuki , Ibuki Emi , Kadota Kyuichi , Hirakawa Eiichiro
Published: July 2019

Peroxisome proliferator-activated receptor alpha (PPAR-α) belongs to the PPAR family and plays a critical role in inhibiting cell proliferation and tumorigenesis in various tumors. However, the role of PPAR-αin colorectal tumorigenesis is unclear. In the present study, we found that fenofibrate, a PPAR-αagonist, significantly inhibited cell proliferation and induced apoptosis in colorectal carcinoma cells. In addition, PPAR-αwas expressed in the nucleus of colorectal carcinoma cells, and the expression of nuclear PPAR-αincreased in colorectal carcinoma tissue compared with that of normal epithelium tissue (P<0.01). The correlation between the expression of nuclear PPAR-αand clinicopathological factors was evaluated in human colorectal carcinoma tissues, and the nuclear expression of PPAR-αwas significantly higher in well-to-moderately differentiated adenocarcinoma than in mucinous adenocarcinoma (P<0.05). These findings indicate that activation of PPAR-αmay be involved in anticancer effects in colorectal carcinomas, and nuclear expression of PPAR-αmay be a therapeutic target for colorectal adenocarcinoma treatment.
A New Method to Estimate the Joint Roughness Coefficient by Back Calculation of Shear Strength
Authors: Huan Jiu-yang , He Ming-ming , Zhang Zhi-qiang , Li Ning
Published: July 2019

The joint roughness coefficient (JRC) is an important factor affecting the shear properties of rock joints, and its accurate estimation is a challenging task in rock engineering. Existing JRC evaluation approaches such as the empirical comparison method and the statistical parameter method have some unresolved defects. In this study, a new method is proposed for JRC estimation to overcome the deficiencies of existing approaches based on back calculation of shear strength. First, the 10 standard roughness joints are established in numerical rock samples generated by the bonded particle method (BPM). Secondly, the microscopic parameters of the intact rock and joints are calibrated, and a series of direct shear tests of joint samples are carried out under different normal stresses. Finally, the empirical relationships between shear strength and JRC are proposed under high correlation conditions. The results show that the modified smooth joint model (MSJM) is proved to better simulate the mechanical properties of rough joints than the smooth joint model (SJM). When the shear strength of target joint is substituted in the corresponding relationship, the JRC of joint along the shear direction can be conveniently obtained. In addition, the JRC values of 10 standard roughness joint profiles under shear direction of from right to left (FRTL) are obtained. By estimating the JRC of 9 target joints in the literature, it can be seen that the new method proposed in this paper can well reflect the directionality of roughness and it is convenient to apply.
Clinical Characteristics in Patients with Rheumatoid Arthritis: Differences between Genders
Authors: Intriago M. , Maldonado G. , Cárdenas J. , Ríos C.
Published: July 2019

Objective. To compare the clinical characteristics of a group of men and women with rheumatoid arthritis (RA) and determine the differences between genders. Materials and Methods. A descriptive and comparative cross-sectional study was developed with a group of 50 men and a control group of 50 women with RA, from a rheumatology center in the city of Guayaquil, Ecuador. Data collected included clinical manifestations, comorbidities, treatment, and disease activity. Clinical and activity differences between sexes were analyzed. Results. Women were more devoted to housework (66%), while men consumed more tobacco (34%) and alcohol (38%). Fatigue (60%), loss of appetite (54%), and weight loss (44%) were more common in women. No differences were found in comorbidities or treatment. Women had higher values of DAS-28 (3.4 vs 2.5), HAQ-DI (1.1 vs 0.4), ESR (33.0 vs 23.2), painful joints (8 vs 3), swollen joints (6 vs 2), and overall physician assessment (3 vs 2). Conclusion. The results are similar to other publications that establish that women have a more aggressive disease with greater activity of the disease and disability.
Bifurcation Analysis of an SIR Model with Logistic Growth, Nonlinear Incidence, and Saturated Treatment
Authors: Pérez Ángel G. C. , Avila-Vales Eric , García-Almeida Gerardo Emilio
Published: July 2019

There is a wide range of works that have proposed mathematical models to describe the spread of infectious diseases within human populations. Based on such models, researchers can evaluate the effect of applying different strategies for the treatment of diseases. In this article, we generalize previous models by studying an SIR epidemic model with a nonlinear incidence rate, saturated Holling type II treatment rate, and logistic growth. We compute the basic reproduction number and determine conditions for the local stability of equilibria and the existence of backward bifurcation and Hopf bifurcation. We also show that, when the disease transmission rate and treatment parameter are varied, our model undergoes a Bogdanov‐Takens bifurcation of codimension 2 or 3. Simulations of the solutions and numerical continuation of equilibria are carried out to generate 2D and 3D bifurcation diagrams, as well as several related phase portraits that illustrate our results. Our work shows that incorporating these factors into epidemic models can lead to very complex dynamics.
ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17–Mutant KIT
Authors: Apsel Winger Beth , Cortopassi Wilian A. , Garrido Ruiz Diego , Ding Lucky , Jang Kibeom , Leyte-Vidal Ariel , Zhang Na , Esteve-Puig Rosaura , Jacobson Matthew P. , Shah Neil P.
Published: July 2019

KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17–mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations.

Significance:

This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.
Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death
Authors: Tesfay Lia , Paul Bibbin T. , Konstorum Anna , Deng Zhiyong , Cox Anderson O. , Lee Jingyun , Furdui Cristina M. , Hegde Poornima , Torti Frank M. , Torti Suzy V.
Published: July 2019

Activation of ferroptosis, a recently described mechanism of regulated cell death, dramatically inhibits growth of ovarian cancer cells. Given the importance of lipid metabolism in ferroptosis and the key role of lipids in ovarian cancer, we examined the contribution to ferroptosis of stearoyl-CoA desaturase (SCD1, SCD), an enzyme that catalyzes the rate-limiting step in monounsaturated fatty acid synthesis in ovarian cancer cells. SCD1 was highly expressed in ovarian cancer tissue, cell lines, and a genetic model of ovarian cancer stem cells. Inhibition of SCD1 induced lipid oxidation and cell death. Conversely, overexpression of SCD or exogenous administration of its C16:1 and C18:1 products, palmitoleic acid or oleate, protected cells from death. Inhibition of SCD1 induced both ferroptosis and apoptosis. Inhibition of SCD1 decreased CoQ10, an endogenous membrane antioxidant whose depletion has been linked to ferroptosis, while concomitantly decreasing unsaturated fatty acyl chains in membrane phospholipids and increasing long-chain saturated ceramides, changes previously linked to apoptosis. Simultaneous triggering of two death pathways suggests SCD1 inhibition may be an effective component of antitumor therapy, because overcoming this dual mechanism of cell death may present a significant barrier to the emergence of drug resistance. Supporting this concept, we observed that inhibition of SCD1 significantly potentiated the antitumor effect of ferroptosis inducers in both ovarian cancer cell lines and a mouse orthotopic xenograft model. Our results suggest that the use of combined treatment with SCD1 inhibitors and ferroptosis inducers may provide a new therapeutic strategy for patients with ovarian cancer.

Significance:

The combination of SCD1 inhibitors and ferroptosis inducers may provide a new therapeutic strategy for the treatment of ovarian cancer patients.

See related commentary by Carbone and Melino, p. 5149
Effects of Switching to a Heat-Not-Burn Tobacco Product on Biologically Relevant Biomarkers to Assess a Candidate Modified Risk Tobacco Product: A Randomized Trial
Authors: Lüdicke Frank , Ansari S. Michael , Lama Nicola , Blanc Nicolas , Bosilkovska Marija , Donelli Andrea , Picavet Patrick , Baker Gizelle , Haziza Christelle , Peitsch Manuel , Weitkunat Rolf
Published: July 2019

Background:

Cigarette smoking increases the risk of chronic diseases; heating instead of burning tobacco can lower these risks, contributing to tobacco harm reduction. This study (with 984 adult American smokers) examined whether favorable changes occur in 8 co-primary endpoints (HDL-C, WBC, FEV1%pred, COHb, Total NNAL, sICAM-1, 11-DTX-B2, 8-epi-PGF2α) indicative of biological and functional effects when cigarette smokers switch to the heat-not-burn Tobacco Heating System 2.2 (THS). Additionally, these biomarkers of exposure (BoExp) were quantified: MHBMA, 3-HPMA, Total NNN, CEMA, 3-OH-B[a]P, HMPMA, Total 1-OHP, NEQ, and CO exhaled.

Methods:

Participants were randomized to continued smoking of their preferred cigarette brand (n = 496) or to using THS (IQOS brand; n = 488) for 6 months. THS has a maximum heating temperature of 350°C, delivering 1.21 mg nicotine/stick and 3.94 mg glycerin/stick under the Health Canada Intense smoking regimen.

Results:

The main outcome was a favorable change 6 months after baseline, with statistically significant improvements in 5 of 8 biomarkers of effect (HDL-C, WBC, FEV1%pred, COHb, Total NNAL) when smokers switched to THS compared with those who continued to smoke cigarettes. Likewise, BoExp were markedly reduced.

Conclusions:

All endpoints showed favorable changes in the same direction as with smoking cessation and improved biological effects were observed in smokers who predominantly used THS compared with continued cigarette smoking, with similar nicotine levels in both groups.

Impact:

Improvements in 5 of 8 biomarkers of effect are supportive of the research hypothesis, suggestive of disease risk reduction potential for smokers switching to THS instead of continuing to smoke cigarettes.
Evaluation of Rare and Common Variants from Suspected Familial or Sporadic Nasopharyngeal Carcinoma (NPC) Susceptibility Genes in Sporadic NPC
Authors: Liu Zhiwei , Goldstein Alisa M. , Hsu Wan-Lun , Yu Kelly J. , Chien Yin-Chu , Ko Jenq-Yuh , Jian James Jer-Min , Tsou Yung-An , Leu Yi-Shing , Liao Li-Jen , Chang Yen-Liang , Wang Cheng-Ping , Wu Jia-Shing , Hua Chun-Hung , Lee Jehn-Chuan , Yang Tsung-Lin , Hsiao Chuhsing Kate , Wu Ming-Shiang , Tsai Ming-Hsui , Huang Kuei-Kang , Yu Kai , Jones Kristie , Zhu Bin , Yeager Meredith , Yu Guoqin , Lou Pei-Jen , Chen Chien-Jen , Hildesheim Allan
Published: July 2019

Background:

Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC.

Methods:

We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case–control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted.

Results:

We found that NPC was associated with combined common and rare variants in CDKN2A/2B (P = 1.3 × 10−4), BRD2 (P = 1.6 × 10−3), TNFRSF19 (P = 4.0 × 10−3), and CLPTM1L/TERT (P = 5.4 × 10−3). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of CDKN2A/2B, P = 4.6 × 10−4; for rare variants, P = 0.04). We also observed a suggestive association with rare variants in HNRNPU (P = 3.8 × 10−3) for NPC risk. In addition, we validated four previously reported NPC risk–associated SNPs.

Conclusions:

Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC.

Impact:

NPC-associated genes, including CLPTM1L/TERT, BRD2, and HNRNPU, suggest a role for telomere length maintenance in NPC etiology.
Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling
Authors: Gupta Nehal , Srivastava Sanjay K.
Published: July 2019

Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug, atovaquone, against several breast cancer cell lines. Our results showed that atovaquone treatment induced apoptosis and inhibited the growth of all the breast cancer cell lines tested, including several patient-derived cells. In addition, atovaquone treatment significantly reduced the expression of HER2, β-catenin, and its downstream molecules such as pGSK-3β, TCF-4, cyclin D1, and c-Myc in vitro. Efficacy of atovaquone was further evaluated in an in vivo tumor model by orthotropic implantation of two highly aggressive 4T1 and CI66 breast cancer cells in the mammary fat pad of female mice. Our results demonstrated that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60%, respectively. Paclitaxel is the first-line chemotherapeutic agent for metastatic breast cancer. We demonstrate that atovaquone administration suppressed the growth of 4T1 paclitaxel-resistant tumors by 40%. Tumors from atovaquone-treated mice exhibited reduced HER2, β-catenin, and c-Myc levels alongside an increase in apoptosis in all the three tumor models when analyzed by Western blotting, IHC, and TUNEL assay. Taken together, our results indicate that atovaquone effectively reduces the growth of primary and paclitaxel-resistant breast tumors. Atovaquone is already in the clinics with high safety and tolerability profile. Therefore, the findings from our studies will potentially prompt further clinical investigation into repurposing atovaquone for the treatment of patients with advanced breast cancer.
Mechanisms of Resistance to EGFR Inhibition Reveal Metabolic Vulnerabilities in Human GBM
Authors: McKinney Andrew , Lindberg Olle R. , Engler Jane R. , Chen Katharine Y. , Kumar Anupam , Gong Henry , Lu Kan V. , Simonds Erin F. , Cloughesy Timothy F. , Liau Linda M. , Prados Michael , Bollen Andrew W. , Berger Mitchel S. , Shieh Joseph T.C. , James C. David , Nicolaides Theodore P. , Yong William H. , Lai Albert , Hegi Monika E. , Weiss William A. , Phillips Joanna J.
Published: July 2019

Amplification of the epidermal growth factor receptor gene (EGFR) represents one of the most commonly observed genetic lesions in glioblastoma (GBM); however, therapies targeting this signaling pathway have failed clinically. Here, using human tumors, primary patient-derived xenografts (PDX), and a murine model for GBM, we demonstrate that EGFR inhibition leads to increased invasion of tumor cells. Further, EGFR inhibitor–treated GBM demonstrates altered oxidative stress, with increased lipid peroxidation, and generation of toxic lipid peroxidation products. A tumor cell subpopulation with elevated aldehyde dehydrogenase (ALDH) levels was determined to comprise a significant proportion of the invasive cells observed in EGFR inhibitor–treated GBM. Our analysis of the ALDH1A1 protein in newly diagnosed GBM revealed detectable ALDH1A1 expression in 69% (35/51) of the cases, but in relatively low percentages of tumor cells. Analysis of paired human GBM before and after EGFR inhibitor therapy showed an increase in ALDH1A1 expression in EGFR-amplified tumors (P < 0.05, n = 13 tumor pairs), and in murine GBM ALDH1A1-high clones were more resistant to EGFR inhibition than ALDH1A1-low clones. Our data identify ALDH levels as a biomarker of GBM cells with high invasive potential, altered oxidative stress, and resistance to EGFR inhibition, and reveal a therapeutic target whose inhibition should limit GBM invasion.
Diagnostic Failure of Cognitive Impairment in Nursing Home Residents May Lead to Impaired Medical Care
Authors: Westerlind Björn , Östgren Carl Johan , Midlöv Patrik , Marcusson Jan
Published: July 2019

Background/Objectives: Dementia and cognitive impairment are common in nursing homes. Few studies have studied the impact of unnoted cognitive impairment on medical care. This study aimed to estimate the prevalence of diagnostic failure of cognitive impairment in a sample of Swedish nursing home residents and to analyze whether diagnostic failure was associated with impaired medical care. Method: A total of 428 nursing home residents were investigated during 2008–2011. Subjects without dementia diagnosis were grouped by result of the Mini Mental State Examination (MMSE), where subjects with <24 points formed a possible dementia group and the remaining subjects a control group. A third group consisted of subjects with diagnosed dementia. These three groups were compared according to baseline data, laboratory findings, drug use, and mortality. Results: Dementia was previously diagnosed in 181 subjects (42%). Among subjects without a dementia diagnosis, 72% were cognitively impaired with possible dementia (MMSE <24). These subjects were significantly older, did not get anti-dementia treatment, and had higher levels of brain natriuretic peptide compared to the diagnosed dementia group, but the risks of malnutrition and pressure ulcers were similar to the dementia group. Conclusions: Unnoted cognitive impairment is common in nursing home residents and may conceal other potentially treatable conditions such as heart failure. The results highlight a need to pay increased attention to cognitive impairment among nursing home residents.
Patent Ductus Arteriosus and the Effects of Its Late Closure in Preterm Infants with Severe Bronchopulmonary Dysplasia
Authors: Ansems Sophia M. , Kirpalani Haresh , Mercer-Rosa Laura , Wang Yan , Hopper Rachel K. , Fraga María V. , Jensen Erik A.
Published: July 2019

Background: The natural history and optimal management of a patent ductus arteriosus (PDA) among infants with established severe bronchopulmonary dysplasia (sBPD) remains uncertain. Objectives: To describe the characteristics of PDA present at ≥36 weeks’ postmenstrual age (PMA) and the effects of late surgical PDA closure in a referral cohort of very preterm infants with sBPD. Study Design: This retrospective cohort study was performed in a tertiary neonatal intensive care unit. Study infants were born at <32 weeks’ gestation between 2010 and 2016, diagnosed with sBPD, and had an echocardiographic PDA at ≥36 weeks’ PMA. We reviewed echocardiograms performed closest to 3 time points (≥36 weeks’ PMA, hospital discharge, and 1 year of age) and assessed clinical outcomes among infants with versus without late PDA treatment. Results: Among 329 infants with sBPD, 59 had a PDA at ≥36 weeks’ PMA. Most PDAs were small (n = 33) and shunted left to right (n = 53). The PDA closed spontaneously prior to discharge in 5 of 21 infants who did not undergo surgical closure and decreased in size in 3. The PDA spontaneously closed by 1 year of age in 6 out of 12 infants with an open duct at discharge. PDA surgery (n = 23) at ≥36 weeks’ PMA was not associated with increased risk for the composite outcome of tracheostomy, systemic vasodilator at discharge, or death after adjusting for potential confounders (OR 3.2, 95% CI 0.81–13.0). Conclusions: The majority of conservatively treated late PDAs closed spontaneously or decreased in size.PDA surgery was not associated with severe adverse clinical outcomes.
Trends in Melanoma Mortality in the Population Groups of South Africa
Authors: Wright Caradee Yael , Kapwata Thandi , Singh Elvira , Green Adele C. , Baade Peter , Kellett Patricia , Norval Mary
Published: July 2019

The incidence of cutaneous melanoma (CM) is increasing in countries around the world. However, little is known about melanoma trends in African countries by population group. We studied CM mortality in South Africa from 1997 to 2014 to partly address this knowledge gap. Unit record mortality data for all South Africans who died from CM (n = 8,537) were obtained from Statistics South Africa. Join-point regression models were used to assess whether there was a statistically significant change in the direction and/or magnitude of the annual trends in CM mortality. A significant increasing trend of 11% per year was observed in age-adjusted mortality rates in men between 2000 and 2005 (p < 0.01), rising from 2 to 3 per 100,000. There was also a statistically significant increase of 180% per year among White South Africans from 1997 to 1999 (p < 0.05) and of 3% from 1999 to 2014 (p < 0.01). These results may be used to inform CM awareness campaigns and will motivate efforts to improve the collection and analysis of relevant statistics regarding the present burden of CM in South Africa.
Pathological Effects of Cortisol on Intervertebral Disc Cells and Mesenchymal Stem Cells from Lower Back Pain Patients
Authors: Hingert Daphne , Nilsson Johanna , Barreto Henriksson Helena , Baranto Adad , Brisby Helena
Published: July 2019

In western countries, lower back pain (LBP) is one of the most common disorders, experienced by more than 80% of the population. Chronic LBP due to disc degeneration has been linked to ongoing inflammatory processes in the disc and endplates. Pain effects the body in different ways, inducing a general stress response in which the body responds by releasing the stress hormone cortisol. Little is known about the impact of pain-induced stress on the progression of disc degeneration. Thus, the effects of cortisol on disc cells (DCs) and human mesenchymal stem cells (hMSCs) were explored in vitro with the objective of investigating the repercussions of cortisol on these cell types involved in de- and regenerative mechanisms of the disc. DC and hMSC pellet cultures were exposed to cortisol at two concentrations (150 and 300 ng/mL) for 28 days to simulate pain-induced stress. Cell viability, histological staining, and GAG DNA, along with apo­ptotic assays were conducted. Detection of OCT4, SOX9, IL-1R, and CXCR2 expressions was performed by immunohistochemistry. With cortisol treatment, restricted cell proliferation and less GAG production in both DCs and hMSCs were observed. Suppression of the differentiation and immunomodulatory efficacy of hMSCs was also detected. Moreover, elevated expressions of IL-1R and CXCR2 were detected in both cell types. To conclude, constant exposure to cortisol even at a physiological level enhanced pathological cellular processes in both DCs and hMSCs, which further jeopardized chondrogenesis. This suggests that cortisol resulting from pain-induced stress is a contributing component of intervertebral disc degeneration and may negatively affect regenerative attempts of the disc.