bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral and quantum chemical analysis of ethyl 4-[3-(adamantan-1-yl)-4-phenyl-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazole-1-yl]methylpiperazine-1-carboxylate
Authors: Al-Ghulikah Hanan A. , Meniailava Darya , Vysotskaya Ulada , Matsukovich Anna , El-Emam Ali A. , Shundalau Maksim
Published: October 2019

The Fourier transform infrared and Raman spectra of the adamantane-based compound ethyl 4-[3-(adamantan-1-yl)-4-phenyl-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-1-yl]methylpiperazine-1-carboxylate were recorded in the ranges of 3200–650[Formula: see text]cm[Formula: see text] and 3200–150[Formula: see text]cm[Formula: see text], respectively. The UV/Vis spectrum of solution of the title compound in ethanol was measured in the range of 450–200[Formula: see text]nm. The DFT calculations at the B3LYP/cc-pVDZ and B3LYP/cc-pVTZ levels of the theory were performed to obtain the equilibrium geometric structure and to predict vibrational IR and Raman spectra of the title molecule. The TDDFT calculations at the CAM-B3LYP/cc-pVTZ level of the theory, as well as MRPT calculations at the CASSCF(4,5)/XMCQDPT2 level of the theory were carried out to reproduce the electronic absorption spectrum. The experimental IR, Raman and UV/Vis spectra were interpreted on the basis of results of quantum chemical modeling. Based on Mulliken and Löwdin atomic population analysis, it was established that the compound under study exhibits features of an intramolecular charge transfer.
Benchmark study of the linear and nonlinear optical polarizabilities in proto-type NLO molecule of para-nitroaniline
Authors: Muhammad Shabbir , Shehzad Rao Aqil , Iqbal Javed , Al-Sehemi Abdullah G. , Saravanabhavan M. , Khalid Muhammad
Published: October 2019

In the present investigation, for the first time, we have performed a thorough study about different functionals and basis sets for linear and nonlinear optical (NLO) properties of para-nitroaniline ([Formula: see text]-NA), which is considered as proto-type NLO molecule, among organic NLO materials. There is a dire need of such data base for [Formula: see text]-NA because many investigators are using such values of [Formula: see text]-NA for comparative analysis. A range of different functionals including HF, BLYP, PW91, PBE, B3LYP, M06, M06-2X, PBE0, BHandHLYP, CAM-B3LYP, LC-BLYP, and B3LYP-D3 are applied in conjugation with several commonly basis sets such as 6-31G*, 6-311G*, 6-311G**, 6-311+G**, cc-pVDZ, and cc-pVTZ. A variety of functional and basis sets combinations are calculated and graphically compared with each other. The calculated total dipole moment for the [Formula: see text]-NA is found to be 6.79[Formula: see text]D which is quite closer to experimentally determined value. The lowest calculated value for linear isotropic polarizability at HF/6-31G* level of theory is [Formula: see text] esu while higher values observed with remaining all methods especially 14% polarizability increases in presence of basis set with diffuse functions and similar trend of variation is also observed in linear anisotropic polarizability. Similarly, the calculated value of frequency dependent second-order polarizability is found to be [Formula: see text] esu at PBE0/6-311+G** level of theory which is quite closer to experimental value of [Formula: see text] esu. A comparison between the calculated and experimental results shows good agreement among geometries, dipole moments and NLO polarizabilities for [Formula: see text]-NA. Moreover, the frontier molecular orbital (FMO) and electron density difference map (EDDM) analysis along with density of state (DOS) plots are also presented to get more physical intuitions into the structure–property relationship and electronic communications between terminal accepter and donor groups through [Formula: see text]-conjugation. The present investigation provides benchmark data including various commonly used functionals and basis sets for the calculation of NLO properties of [Formula: see text]-NA. Thus, the present investigation will put straight several future studies when it comes to comparative NLO study of organic materials.
Extremal unicyclic graphs with respect to the Sanskruti index
Authors: Javaid Muhammad , Amin Umair , Raheem Abdul
Published: October 2019

Sanskruti index of a graph [Formula: see text] with vertex-set [Formula: see text] and edge-set [Formula: see text] is [Formula: see text], where [Formula: see text]. In this paper, the extremal graphs in the class of unicyclic graphs are characterized with respect to the Sanskruti index, where the considered class of unicyclic graphs contains five different large families of graphs.
Investigation of Structural, Dielectric and Electrical Properties of Barium Titanate Ceramics Co-Doped with Bismuth and Yttrium
Authors: Islam Suravi , Satter Syed Abdus , Khatun Nazia , Hossain Mohammad Sajjad , Farhad Syed Farid Uddin , Bala Parimal , Tabassum Samia , Siddika Ayesha
Published: October 2019

Bismuth and Yttrium co-doped Barium Titanate (BaTiO3) ceramics with the general formula (Ba[Formula: see text]BiX) (YxTi[Formula: see text]) O3(where [Formula: see text], 0.01, 0.03, 0.05) have been synthesized at 1300∘C for 3[Formula: see text]h by the standard solid-state reaction method. The prepared samples were characterized by X-ray diffraction (XRD), Scanning Electron Microscope (SEM) and Impedance Analyzer. Temperature-dependent dielectric properties of the samples were also measured. The XRD result revealed perovskite structure for un-doped and co-doped BaTiO3with tetragonal phase. However, with increasing doping concentration, a Pseudo cubic phase occurs also confirmed by the twin peaks (002) and (200) of XRD pattern. From SEM micrograph, submicron size particles were observed for all synthesized BaTiO3samples and exhibit a narrow size distribution with quiet uniform morphology. The crystalline size for un-doped BaTiO3found was 24.26[Formula: see text]nm, the size decreases (minimum 19.59[Formula: see text]nm for [Formula: see text]) for all compositions of co-doped BaTiO3. Dielectric constant values were apparently high and direct current (DC) resistivity follows a decreasing trend at higher doping concentration. The sample doped with [Formula: see text] shows minimum DC resistivity and maximum dielectric constant among the samples investigated.
Water Quality Avoidance Behavior: Bridging the Gap between Perception and Reality
Authors: Kunwar Samrat B. , Bohara Alok K.
Published: October 2019

Water quality remains a significant issue and a source of serious health concern in the developing world. This paper investigates the water averting behavior at the household level by using a primary survey data from Siddharthangar, Nepal. While past studies have generally attributed averting behaviors to risk perception, we place a particular emphasis on the divergence between the household’s perception of their drinking water quality and the actual water quality level in driving the averting behavior. The findings indicate that the perception of the water quality affects a household’s decision to employ water treatment measures. Households that considered their water to be safe were less likely to treat their water. Furthermore, in addition to perception, the result also suggests the deviation between actual and perceived water quality level could also be a crucial element in the decision to employ water treatment measures. Households with divergence between risk perception and the objective water quality levels were less likely to treat their water and this result held across different specifications. In contrast, households with minimal deviation were more likely to employ treatment measures. Findings also suggest the source of drinking water, education level, income and the taste of the drinking water also drives the averting behavior.
Sexual Size Dimorphism: Evolution and Perils of Extreme Phenotypes in Spiders
Authors: Kuntner Matjaž , Coddington Jonathan A.
Published: October 2019

Sexual size dimorphism is one of the most striking animal traits, and among terrestrial animals, it is most extreme in certain spider lineages. The most extreme sexual size dimorphism (eSSD) is female biased. eSSD itself is probably an epiphenomenon of gendered evolutionary drivers whose strengths and directions are diverse. We demonstrate that eSSD spider clades are aberrant by sampling randomly across all spiders to establish overall averages for female (6.9 mm) and male (5.6 mm) size. At least 16 spider eSSD clades exist. We explore why the literature does not converge on an overall explanation for eSSD and propose an equilibrium model featuring clade- and context-specific drivers of gender size variation. eSSD affects other traits such as sexual cannibalism, genital damage, emasculation, and monogyny with terminal investment. Coevolution with these extreme sexual phenotypes is termed eSSD mating syndrome. Finally, as costs of female gigantism increase with size, eSSD may represent an evolutionary dead end.
Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes
Authors: Chittezhath Manesh , Gunaseelan Divya , Zheng Xiaofeng , Hasan Riasat , Tay Vanessa S. Y. , Lim Seok Ting , Wang Xiaomeng , Berggren Per-Olof , Bornstein Stefan , Boehm Bernhard , Ruedl Christiane , Ali Yusuf
Published: October 2019

β-Cells respond to peripheral insulin resistance by first increasing circulating insulin during diabetes. Islet remodeling supports this compensation, but its drivers remain poorly understood. Infiltrating macrophages have been implicated in late-stage type 2 diabetes, but relatively little is known on islet resident macrophages, especially during compensatory hyperinsulinemia. We hypothesized that islet resident macrophages would contribute to islet vascular remodeling and hyperinsulinemia during diabetes, the failure of which results in a rapid progression to frank diabetes. We used chemical (clodronate), genetics (CD169-diphtheria toxin receptor mice), or antibody-mediated (colony-stimulating factor 1 receptor α) macrophage ablation methods in diabetic (db/db) and diet-induced models of compensatory hyperinsulinemia to investigate the role of macrophages in islet remodeling. We transplanted islets devoid of macrophages into naïve diabetic mice and assessed the impact on islet vascularization. With the use of the above methods, we showed that macrophage depletion significantly and consistently compromised islet remodeling in terms of size, vascular density, and insulin secretion capacity. Depletion of islet macrophages reduced VEGF-A secretion in both human and mouse islets ex vivo, and this functionally translated to delayed revascularization upon transplantation in vivo. We revealed that islet resident macrophages were associated with islet remodeling and increased insulin secretion during diabetes. This suggests utility in harnessing islet macrophages during this phase to promote islet vascularization, remodeling, and insulin secretion.
A Robust Metatranscriptomic Technology for Population-Scale Studies of Diet, Gut Microbiome, and Human Health
Authors: Hatch Andrew , Horne James , Toma Ryan , Twibell Brittany L. , Somerville Kalie M. , Pelle Benjamin , Canfield Kinga P. , Genkin Matvey , Banavar Guruduth , Perlina Ally , Messier Helen , Klitgord Niels , Vuyisich Momchilo
Published: October 2019

A functional readout of the gut microbiome is necessary to enable precise control of the gut microbiome’s functions, which support human health and prevent or minimize a wide range of chronic diseases. Stool metatranscriptomic analysis offers a comprehensive functional view of the gut microbiome, but despite its usefulness, it has rarely been used in clinical studies due to its complexity, cost, and bioinformatic challenges. This method has also received criticism due to potential intrasample variability, rapid changes, and RNA degradation. Here, we describe a robust and automated stool metatranscriptomic method, called Viomega, which was specifically developed for population-scale studies. Viomega includes sample collection, ambient temperature sample preservation, total RNA extraction, physical removal of ribosomal RNAs (rRNAs), preparation of directional Illumina libraries, Illumina sequencing, taxonomic classification based on a database of >110,000 microbial genomes, and quantitative microbial gene expression analysis using a database of ~100 million microbial genes. We applied this method to 10,000 human stool samples and performed several small-scale studies to demonstrate sample stability and consistency. In summary, Viomega is an inexpensive, high-throughput, automated, and accurate sample-to-result stool metatranscriptomic technology platform for large-scale studies and a wide range of applications.
Nanovectors Design for Theranostic Applications in Colorectal Cancer
Authors: Rampado Riccardo , Crotti Sara , Caliceti Paolo , Pucciarelli Salvatore , Agostini Marco
Published: October 2019

Colorectal cancer (CRC) is a diffused disease with limited therapeutic options, none of which are often curative. Based on the molecular markers and targets expressed by the affected tissues, numerous novel approaches have been developed to study and treat this disease. In particular, the field of nanotechnology offers an astonishingly wide array of innovative nanovectors with high versatility and adaptability for both diagnosis and therapy (the so called “theranostic platforms”). However, such complexity can make the selection of a specific nanocarrier model to study a perplexing endeavour for the biomedical scientist or clinician not familiar with this field of inquiry. This review offers a comprehensive overview of this wide body of knowledge, in order to outline the essential requirements for the clinical viability evaluation of a nanovector model in CRC. In particular, the differences among the foremost designs, their specific advantages, and technological caveats will be treated, never forgetting the ultimate endpoint for these systems development: the clinical practice.
Multiobjective Genetic Algorithms for Reinforcing Equal Population in Congressional Districts
Authors: Lara-Caballero Alejandro , de-los-Cobos-Silva Sergio Gerardo , Mora-Gutiérrez Roman Anselmo , Rincón-García Eric Alfredo , Gutiérrez-Andrade Miguel Ángel , Lara-Velázquez Pedro
Published: October 2019

Redistricting is the process of partitioning a set of basic units into a given number of larger groups for electoral purposes. These groups must follow federal and state requirements to enhance fairness and minimize the impact of manipulating boundaries for political gain. In redistricting tasks, one of the most important criteria is equal population. As a matter of fact, redistricting plans can be rejected when the population deviation exceeds predefined limits. In the literature, there are several methods to balance population among districts. However, further discussion is needed to assess the effectiveness of these strategies. In this paper, we considered two different strategies, mean deviation and overall range. Additionally, a compactness measure is included to design well‐shaped districts. In order to provide a wide set of redistricting plans that achieve good trade‐offs between mean deviation, overall range, and compactness, we propose four multiobjective metaheuristic algorithms based on NSGA‐II and SPEA‐II. The proposed strategies were applied in California, Texas, and New York. Numerical results show that the proposed multiobjective approach can be a very valuable tool in any real redistricting process.
Digital Image Correlation Analysis of Displacement Based on Corrected Three Surface Fitting Algorithm
Authors: Zhao Tong-bin , Zhang Wei , Guo Wei-yao
Published: October 2019

SFA (Surface Fitting Algorithm) for continuous displacement is an important method for digital image correlation with antinoise ability and computational efficiency advantages in practical applications. In order to improve the algorithm accuracy and expand its application range, this paper tries to improve the SFA and studies the modified cubic surface fitting algorithm CTSFA (Corrected Three Surface Fitting Algorithm), which is suitable for solving the initial value of continuous displacement. Bilinear interpolation and adjacent interpolation are used to analyze the gray level at any integer‐pixel position in the displacement matrix and the weight coefficient is given. The distance‐weighted method is used to approximate the true initial displacement value of the continuum, and the algorithm suitable for digital image processing is extended to the continuum displacement solution. The cubic surface expression of the CTSFA programmatic application is solved by the least squares method, and the correlation coefficient of the power basis function is calculated. In the computer simulation of speckle test, the comparison between CTSFA and SFA on the calculation results of linear and nonlinear displacement fields shows that the calculated amount of CTSFA is basically the same as that of SFA, but the calculation accuracy is doubled. The study of analysing the Brazilian splitting test using CTSFA and SFA reveals that CTSFA is better than SFA in observing the development of cracks.
Isolated Pulmonary Hydatid Cyst: A Rare Presentation in a Young Maasai Boy from Northern Tanzania
Authors: Lodhia Jay , Herman Ayesiga , Philemon Rune , Sadiq Adnan , Mchaile Deborah , Chilonga Kondo
Published: October 2019

Introduction. Hydatidosis is a parasitic manifestation caused by Echinococcus granulosus. It is characterized by cystic lesions in the liver and lungs. Diagnosis is based on typical history and radiological measures. Case presentation. A four-year-old boy presented with a one-year history of dry cough and difficulty in breathing which was of gradual progression. Computed tomography of the chest revealed a large 11.7 cm×8.6 cm×11.0 cm cyst in the right hemithorax. The patient underwent thoracotomy and recovered well post procedure. Conclusion. This case report highlights that large hydatid cysts can be surgically removed with good outcome and the importance of realizing that the disease is a burden to the public health and is much neglected.
RFID Double-Loop Tags with Novel Meandering Lines Design for Health Monitoring Application
Authors: Bouhassoune Ibtissame , Saadane Rachid , Minaoui Khalid
Published: October 2019

In this paper, we propose a design of two compact and miniaturized RFID epidermal tags in the UHF band for health monitoring applications. The two conceptions of meandered double-loop antennas with T-match configuration, namely, a double-loop antenna with meandered line in the horizontal direction and a double-loop antenna with meandered lines in two directions, are placed at very close distance from the human body. The proposed tags are composed of bio-silicone substrate, to protect the human skin from the electromagnetic waves, and a copper conductor loaded by T-match configuration, to suit the complex impedance of the antenna to that of the chip. We have performed numerical simulations of these conceptions of two tags using the HFSS and CST solvers. Our results show two optimal sizes with a high communication performance, good matching features, and a large read range. We placed afterwards these two optimized tags in an elliptical environment to test their flexibility and examine their performance on different parts of the human body.
Effect of Common Pavements on Interjoint Coordination of Walking with and without Robotic Exoskeleton
Authors: Wang Jinlei , Qiu Jing , Hou Lei , Zheng Xiaojuan , Yu Suihuai
Published: October 2019

Background. The analysis and comprehension of the coordination control of a human gait on common grounds benefit the development of robotic exoskeleton for motor recovery. Objective. This study investigated whether the common grounds effect the interjoint coordination of healthy participants with/without exoskeletons in walking. Methods. The knee-ankle coordination and hip-knee coordination of 8 healthy participants in a sagittal plane were measured on five kinds of pavements (tiled, carpet, wooden, concrete, and pebbled) with/without exoskeletons, using the continuous relative phase (CRP). The root mean square of CRP (CRPRMS) over each phase of the gait cycle is used to analyze the magnitude of dephasing between joints, and the standard deviation of CRP (CRPSD) in the full gait cycle is used to assess the variability of coordination patterns between joints. Results. The CRPHip-Knee/RMS of the carpet pavement with exoskeleton is different from that of other pavements (except the tiled pavement) in the midstance phase. The CRPHip-Knee/RMS on the pebble pavement without exoskeleton is less than that on the other pavements in all phases. The CRPHip-Knee/SD of the pebble pavement without exoskeleton is smaller than that of other pavements. The CRPKnee-Ankle/SD with/without exoskeleton is similar across all pavements. Conclusion. The compressive capacity of the pavement and the unevenness of the pavement are important factors that influence interjoint coordination, which can be used as key control elements of gait to adapt different pavements for robotic exoskeleton. Novelty. We provide a basis of parameter change of kinematics on different common grounds for the design and optimization of robotic exoskeleton for motor recovery.
Antibacterial Effect of Curcumin against Clinically Isolated Porphyromonas gingivalis and Connective Tissue Reactions to Curcumin Gel in the Subcutaneous Tissue of Rats
Authors: Sha Aram Mohammed , Garib Balkees Taha
Published: October 2019

The aim of this study was to find the antibacterial potential of curcumin against Porphyromonas gingivalis and connective tissue responses to curcumin gel in the subcutaneous tissue of rats. The sample consisted of subgingival plaque collected from patients with chronic periodontitis. The P. gingivalis clinically isolated strain was confirmed by anaerobic culture, morphology, biochemical tests (Vitek ANC Kit), and PCR (16S rDNA). Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined by incubation of twofold serial dilution of broth media containing curcumin (from 100 to 0.05 µg/ml) for 48 h at 37°C. Fifteen adult Wistar rats (3-4 months old) were used and randomly divided into three groups (negative control, positive control, and experimental groups). Tubes were implanted on the back skin (45 tubes). Rats were euthanized at 7, 30, and 60 days after surgical processes, and then the samples were taken and processed to achieve conventional hematoxylin and eosin-stained slides. The MIC and MBC of curcumin against clinically isolated P. gingivalis were 12 µg/ml. Curcumin gel caused moderate inflammatory reactions at 7 and 30 days, while at 60 days, it caused dramatic decline and resulted in a nonsignificant response. Besides, curcumin gel stimulated quick reepithelialization, fibroblast proliferation, and scarring through the formation of thick bundles of well-organized collagen fibers. Curcumin has an effective antibacterial action against clinically isolated P. gingivalis at low concentration (12 µg/ml), and it was regarded as the biocompatible material in the subcutaneous tissues.
Creep Investigation on Shale‐Like Material with Preexisting Fissure under Coupling Temperatures and Confining Pressures
Authors: Wang Yongyan , Wang Hongwei , Shi Xiao
Published: October 2019

In order to investigate the influence of temperature, confining pressure, and preexisting fissure on creep characteristics of rock mass, multistage creep experiments were performed on shale‐like material, with preexisting fissure under different temperatures and confining pressures. The results showed that new microcracks generated and propagated with the increase of temperature in both uniaxial and triaxial creep experiments, and the generation and propagation were most pronounced at 60°C and least at 20∼50°C in uniaxial creep experiments. The generation and propagation were restricted by confining pressure. Temperature had less influence on the creep strain rate in triaxial creep experiment, whereas it had a significant influence on the steady‐state creep rate in uniaxial creep experiment. The influence of confining pressure on the steady‐state creep rate was slight when confining pressure was 1 MPa, whereas it was obvious when confining pressure was 3∼7 MPa. The closure of preexisting fissure promoted the creep strain rate, and the closure was incomplete when confining pressure was below 3 MPa, whereas it was complete when confining pressure at 5 and 7 MPa.
A Pilot Study of Parameter-Optimized Low-Intensity Pulsed Ultrasound Stimulation for the Bone Marrow Mesenchymal Stem Cells Viability Improvement
Authors: Yang Xiuzhi , Wu Yu , Li Jiqing , Yin Wuliang , An Yang , Wang Yanfen , Wang Man , Wu Qiuli , Qu Zhigang , Ning Guangzhi , Feng Shiqing
Published: October 2019

To investigate how a back propagation neural network based on genetic algorithm (GA-BPNN) optimizes the low-intensity pulsed ultrasound (LIPUS) stimulation parameters to improve the bone marrow mesenchymal stem cells (BMSCs) viability further. The LIPUS parameters were set at various frequencies (0.6, 0.8, 1.0, and 1.2 MHz), voltages (5, 6, 7, and 8 V), and stimulation durations (3, 6, and 9 minutes). As only some discrete points can be set up in the experiments, the optimal LIPUS stimulation parameter may not be in the value of these settings. The GA-BPNN algorithm is used to optimize parameters of LIPUS to increase the BMSCs viability further. The BMSCs viability of the LIPUS-treated group was improved up to 19.57% (P<0.01). With the optimization via the GA-BPNN algorithm, the viability of BMSCs was further improved by about 5.36% (P<0.01) under the optimized condition of 6.92 V, 1.02 MHz, and 7.3 min. LIPUS is able to improve the BMSCs viability, which can be improved further by LIPUS with parameter optimization via GA-BPNN algorithm.
Evaluation of Tobacco Smoke and Diet as Sources of Exposure to Two Heterocyclic Aromatic Amines for the U.S. Population: NHANES 2013–2014
Authors: Zhang Li , Wang Lanqing , Li Yao , Xia Yang , Chang Cindy M. , Xia Baoyun , Sosnoff Connie S. , Pine Brittany N. , deCastro B. Rey , Blount Benjamin C.
Published: October 2019

Background:

Heterocyclic aromatic amines (HAA) are a group of hazardous substances produced during combustion of tobacco or high-temperature cooking of meats. 2-Amino-9H-pyrido[2,3-b]indole (AαC) is a major carcinogenic HAA in tobacco smoke.

Methods:

Urinary AαC, used as a marker of AαC exposure, was analyzed on spot urine samples from adult participants of the 2013–2014 cycle of the National Health and Nutrition Examination Survey (N = 1,792). AαC was measured using isotope-dilution liquid chromatography–tandem mass spectrometry. Exclusive combusted tobacco smokers were differentiated from nonusers of tobacco products through both self-report and serum cotinine data.

Results:

Among exclusive smokers, sample-weighted median urinary AαC was 40 times higher than nonusers. Sample-weighted regression models showed that urinary AαC increased significantly with serum cotinine among both exclusive tobacco users and nonusers with secondhand smoke exposure. Among nonusers, eating beef cooked at high temperature was associated with a significant increase in urinary AαC, whereas consuming vegetables was associated with decreased AαC. In addition, smoking one-half pack of cigarettes per day was associated with a significant increase of 23.6 pg AαC/mL calculated at geometric mean of AαC, controlling for potential confounders. In comparison, increase in AαC attributable to consuming the 99th percentile of beef cooked at high temperature was 0.99 pg AαC/mL.

Conclusions:

Both exclusive smokers and nonusers of tobacco in the general U.S. population are exposed to AαC from tobacco smoke, with additional, lesser contributions from certain dietary components.

Impact:

AαC is an important biomarker that is associated with tobacco smoke exposure.
High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers
Authors: Anderhub Simon J. , Mak Grace Wing-Yan , Gurden Mark D. , Faisal Amir , Drosopoulos Konstantinos , Walsh Katie , Woodward Hannah L. , Innocenti Paolo , Westwood Isaac M. , Naud Sébastien , Hayes Angela , Theofani Efthymia , Filosto Simone , Saville Harry , Burke Rosemary , van Montfort Rob L.M. , Raynaud Florence I. , Blagg Julian , Hoelder Swen , Eccles Suzanne A. , Linardopoulos Spiros
Published: October 2019

BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor–mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel.
Molecular Inhibitor of QSOX1 Suppresses Tumor GrowthIn Vivo
Authors: Fifield Amber L. , Hanavan Paul D. , Faigel Douglas O. , Sergienko Eduard , Bobkov Andrey , Meurice Nathalie , Petit Joachim L. , Polito Alysia , Caulfield Thomas R. , Castle Erik P. , Copland John A. , Mukhopadhyay Debabrata , Pal Krishnendu , Dutta Shamit K. , Luo Huijun , Ho Thai H. , Lake Douglas F.
Published: October 2019

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion in vitro and in vivo, we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis. High throughput screening using a QSOX1-based enzymatic assay revealed multiple potential QSOX1 inhibitors. One of the inhibitors, known as “SBI-183,” suppresses tumor cell growth in a Matrigel-based spheroid assay and inhibits invasion in a modified Boyden chamber, but does not affect viability of nonmalignant cells. Oral administration of SBI-183 inhibits tumor growth in 2 independent human xenograft mouse models of renal cell carcinoma. We conclude that SBI-183 warrants further exploration as a useful tool for understanding QSOX1 biology and as a potential novel anticancer agent in tumors that overexpress QSOX1.
Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2
Authors: Wang Rui , Liu Hongwei , Shao Yingying , Wang Kailong , Yin Shuangshuang , Qiu Yuling , Wu Honghua , Liu Erwei , Wang Tao , Gao Xiumei , Yu Haiyang
Published: October 2019

Radian Sophorae flavescentis is a traditional Chinese medicine commonly used to treat cancer in China. However, its active components and underlying mechanism remain ambiguous. In this study, we have screened the pharmacokinetic parameters of the main chemical constituents of Radian Sophorae flavescentis by Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform and have found that Sophoridine is one of the best antitumor active ingredients. We have found that MAPKAPK2 is a potential target for Sophoridine by the PharmMapper and KEGG databXase analysis. Moreover, we have found that Sophoridine selectively inactivates phospho-MAPKAPK2 (Thr222) and directly binds into the ATP site of MAPKAPK2 by molecular docking. Furthermore, we have found out a direct binding between MAPKAPK2 and Sophoridine by cellular thermal shift assay and drug affinity responsive targets stability assay. The inhibition effects are further confirmed by Western blot: Sophoridine significantly decreases phospho-MAPKAPK2 (Thr222) in a time-dependent manner, but there is no obvious change in its total expression in colorectal cancer cells. Clinical studies have shown that a higher level of MAPKAPK2 is associated with a poorer percent survival rate (prognosis). Furthermore, a higher level of MAPKAPK2 is positively associated with the enrichment of downregulation of apoptosis and autophagy by gene set enrichment analysis, as well as upregulation of proliferation and cell-cycle arrest. Taken together, our results suggest that the MAPKAPK2 plays a key role in Sophoridine-inhibited growth and invasion in colorectal cancers.

Implications:

These studies show that Sophoridine may be a promising therapeutic strategy that blocks tumorigenesis in colorectal cancers.
Temozolomide plus PARP Inhibition in Small-Cell Lung Cancer: Could Patient-Derived Xenografts Accelerate Discovery of Biomarker Candidates?
Authors: Pacheco Jose M. , Byers Lauren Averett
Published: October 2019

Effective options are limited for patients with small-cell lung cancer who develop progressive disease during or after etoposide plus platinum-based therapy. In this issue of Cancer Discovery, Farago and colleagues highlight the data for temozolomide plus olaparib in this patient population and demonstrate the potential to accelerate biomarker discovery through co-clinical trials utilizing patient-derived xenografts.

See related article by Farago et al., p. 1372.
Fitts’ Law in Tongue Movements of Repetitive Speech
Authors: Kuberski Stephan R. , Gafos Adamantios I.
Published: October 2019

Fitts’ law, perhaps the most celebrated law of human motor control, expresses a relation between the kinematic property of speed and the non-kinematic, task-specific property of accuracy. We aimed to assess whether speech movements obey this law using a metronome-driven speech elicitation paradigm with a systematic speech rate control. Specifically, using the paradigm of repetitive speech, we recorded via electromagnetic articulometry speech movement data in sequences of the form /CV…/ from 6 adult speakers. These sequences were spoken at 8 distinct rates ranging from extremely slow to extremely fast. Our results demonstrate, first, that the present paradigm of extensive metronome-driven manipulations satisfies the crucial prerequisites for evaluating Fitts’ law in a subset of our elicited rates. Second, we uncover for the first time in speech evidence for Fitts’ law at the faster rates and specifically beyond a participant-specific critical rate. We find no evidence for Fitts’ law at the slowest metronome rates. Finally, we discuss implications of these results for models of speech.
Clinical Significance of Galactose-Deficient IgA1 by KM55 in Patients with IgA Nephropathy
Authors: Zhang Kai , Li Qiongqiong , Zhang Yaru , Shang Wenya , Wei Li , Li Hongfen , Gao Shan , Yan Tiekun , Jia Junya , Liu Youxia , Lin Shan
Published: October 2019

Background: Aberrant galactose-deficient IgA1 molecules (Gd-IgA1) are important causal factors in IgA nephropathy (IgAN); however, the detection of Gd-IgA1 in IgAN is complicated and instable. A monoclonal antibody, KM55, which specifically recognizes Gd-IgA1 has been developed. In the present study, we further explored the clinical significance of Gd-IgA1 using KM55. Methods: In this study, we enrolled 75 patients with IgAN and 80 healthy controls and detected the plasma Gd-IgA1 levels using the KM55 ELISA method. We also stained ­mesangial Gd-IgA1 deposition using KM55. Results: We observed that the levels of plasma Gd-IgA1 in IgAN patients were elevated compared to the corresponding levels of healthy controls. Patients were divided into 2 groups based on the median of Gd-IgA1. Patients with high Gd-IgA1 levels had significantly higher levels of uric acid (UA) and IgA. The other clinical manifestations demonstrated that there were no differences in age, sex, blood pressure, initial proteinuria, hematuria, estimated glomerular filtration rate and Oxford pathological classification between the 2 groups of patients. In addition, positive correlations were observed between Gd-IgA1 and Bb, C3a, C4d and MAC. Mesangial Gd-IgA1 was positive in IgAN but negative in the normal renal tissue adjacent to neoplasm. We next analyzed the correlation between plasma Gd-IgA1 and mesangial Gd-IgA1 deposition. The results showed that a high level of plasma Gd-IgA1 was related to the deposition of mesangial Gd-IgA1, although the difference was not significant. Conclusion: We verified the elevated level of plasma and ­mesangial Gd-IgA1 in patients with IgAN by KM55, which provided an alternative, easy, and reliable tool for diagnosis and activity assessment of IgAN. The level of plasma Gd-IgA1 positively correlated with levels of UA, total IgA levels, and complement activation products.
GALP Qualifier Scale: Initial Considerations to Classify a Voice Problem
Authors: Englert Marina , Mendoza Viviana , Behlau Mara , De Bodt Marc
Published: October 2019

Objective: To propose a single qualifier scale for voice problems based on the International Classification of Functioning, Disability, and Health (ICF) that classifies a voice problem considering its multidimensionality. Method: A multicultural database was analyzed (280 subjects). The analyzed information was: the perceptual judgment of the overall voice quality (G); the acoustic analysis (A) with the Acoustic Voice Quality Index; the laryngeal diagnosis (L) and the patient self-assessment (P) using the Voice Handicap Index. The variables were categorized. A 2-step cluster analysis was performed to define groups with common characteristics. Results: A 7-point qualifier scale, the GALP, was defined to generally classify levels of voice problems considering 4 dimensions of the voice evaluation. Each level of voice problem, that is, no problem, mild, moderate, severe, or complete voice problem, has its own possible outcome for G, A, L, and P that will change, or not, the overall level of voice problem. The extremes of the scale represent “no problem” at all when all parameters are normal, and “complete problem” when all parameters are altered. The 3 levels in between were defined by the cluster analysis (mild, moderate, and severe problem) and change according to the outcome of each evaluation (G, A, L, and P). Thus, changes in one parameter alone may or not contribute to the change of the level of voice problem. Also, there are 2 categories for cases that do not fit the classification (not specified) and for which some of the variables are missing (not applicable). Conclusion: The GALP scale was proposed to classify the level of voice problem. This approach considers important dimensions of voice evaluation according to the ICF. It is a potential tool to be used by different professionals, with different assessment procedures, and among different populations, clinicians, and study centers.
DNA Methylation-Based Regulation of Human Bone Marrow-Derived Mesenchymal Stem/Progenitor Cell Chondrogenic Differentiation
Authors: Nomura Yu , Hara Emilio Satoshi , Yoshioka Yuya , Nguyen Há Thi , Nosho Shuji , Komori Taishi , Ishibashi Kei , Oohashi Toshitaka , Ono Mitsuaki , Kuboki Takuo
Published: October 2019

Stem cells have essential applications in in vitro tissue engineering or regenerative medicine. However, there is still a need to understand more deeply the mechanisms of stem cell differentiation and to optimize the methods to control stem cell function. In this study, we first investigated the activity of DNA methyltransferases (DNMTs) during chondrogenic differentiation of human bone marrow-derived mesenchymal stem/progenitor cells (hBMSCs) and found that DNMT3A and DNMT3B were markedly upregulated during hBMSC chondrogenic differentiation. In an attempt to understand the effect of DNMT3A and DNMT3B on the chondrogenic differentiation of hBMSCs, we transiently transfected the cells with expression vectors for the two enzymes. Interestingly, DNMT3A overexpression strongly enhanced the chondrogenesis of hBMSCs, by increasing the gene expression of the mature chondrocyte marker, collagen type II, more than 200-fold. Analysis of the methylation condition in the cells revealed that DNMT3A and DNMT3B methylated the promoter sequence of early stem cell markers, NANOG and POU5F1(OCT-4). Conversely, the suppression of chondrogenic differentiation and the increase in stem cell markers of hBMSCs were obtained by chemical stimulation with the demethylating agent, 5-azacitidine. Loss-of-function assays with siRNAs targeting DNMT3A also significantly suppressed the chondrogenic differentiation of hBMSCs. Together, these results not only show the critical roles of DNMTs in regulating the chondrogenic differentiation of hBMSCs, but also suggest that manipulation of DNMT activity can be important tools to enhance the differentiation of hBMSCs towards chondrogenesis for potential application in cartilage tissue engineering or cartilage regeneration.
Meta-Analysis of Changes in Sleep Quality of Women with Breast Cancer before and after Therapy
Authors: Chang Wen-Pei , Chang Yu-Pei
Published: October 2019

Cancer treatments may affect the sleep quality and even future quality of life of women with breast cancer. A meta-analysis was performed to understand the changes in the sleep quality of women with breast cancer during their treatment period. In a systematic literature review in compliance with the PRISMA guidelines, we searched for articles published between 2000 and 2018 in databases. A total of 12 study articles were included. The standardized mean differences of the pooling effect size of sleep quality between the period before treatment and 1–8 weeks, 9–16 weeks, 17–24 weeks, and 25–56 weeks after the commencement of treatment were –0.020, –0.162, 0.075, and 0.216, respectively. Although the differences were not statistically significant, in view of the heterogeneity among the studies, we conducted further analysis using a linear mixed effect model. The overall results indicated poorer sleep quality as time passed from the start of the first treatment (p = 0.014). The results of this study revealed that patients experienced better sleep quality in the initial months after the beginning of treatment; however, their sleep quality became poorer between 4 months to approximately 1 year after the beginning of treatment, compared with the sleep quality before treatment, and continued to decline rather than improve during the follow-up period.
Is there any relationship between Neuroscience and Psychiatry
Authors: Farhat Luis C. , Hoexter Marcelo Q. , Miguel Euripedes C.
Published: October 2019

Psychiatry has always been considered a separate field of medicine among other medical specialties. Unlike Cardiology or Oncology, diagnoses of psychiatric disorders are made entirely based on patients’ presenting signs and symptoms. There are no sources of external validity (e.g. laboratory exam, imaging findings) that can be employed reliably to identify individuals with psychiatric disorders. [...]
Benefit of Endovascular Thrombectomy by Mode of Onset
Authors: Jadhav Ashutosh P. , Aghaebrahim Amin , Jankowitz Brian T. , Haussen Diogo C. , Budzik Ronald F. , Bonafe Alain , Bhuva Parita , Yavagal Dileep R. , Hanel Ricardo A. , Hassan Ameer E. , Ribo Marc , Cognard Christophe , Sila Cathy A. , Zhang Yanchang , Smith Wade S. , Saver Jeffrey L. , Liebeskind David S. , Nogueira Raul G. , Jovin Tudor G.
Published: October 2019

Background and Purpose—

It is unknown whether the benefit of thrombectomy in late presenting acute stroke patients with imaging evidence of clinical-infarct mismatch is different in patients presenting with wake-up stroke compared with those presenting with witnessed onset or unwitnessed onset.

Methods—

Prespecified secondary analysis was performed from DAWN (Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention), a multicenter, prospective, randomized clinical trial with blinded end point assessment comparing thrombectomy with the Trevo device against standard medical therapy in patients with acute stroke and clinical-infarct mismatch presenting 6 to 24 hour after the time last seen well. For the purposes of this study, the primary outcome was the proportion of modified Rankin Scale score 0 to 2 at 90 days. Univariable analysis and multivariable logistic regression was used to assess the relationship between outcome and mode of onset.

Results—

All 206 enrolled patients were included in the study. Mode of onset was: wake-up stroke (55.3%, n=114), witnessed onset (12.1%, n=25), and unwitnessed onset (32.5%, n=67) with median time last seen well to randomization (13.4±3.7, 10.0±3.7, 14.1±4.9 hours) respectively. Rates of 90-day modified Rankin Scale score of 0 to 2 and symptomatic intracerebral hemorrhage in the thrombectomy arm were not statistically different across patient onset subtypes (
P
=0.79 and
P
=0.40, respectively). The benefit of thrombectomy compared with best medical therapy was maintained across all 3 onset modes (rates of 90-day modified Rankin Scale score of 0 to 2 in patients allocated to thrombectomy versus control: wake-up stroke—49.3% versus 10.6%, witnessed onset—63.6% versus 21.4%, UW—41.4% versus 13.2%;
P
×interaction=0.79). In univariable and multivariable analyses, mode of onset was not identified as a significant predictor of modified Rankin Scale score 0 to 2 at 90 days.

Conclusions—

In patients with acute ischemic stroke presenting between 6 and 24 hours from time last seen well and harboring clinical-infarct mismatch, the benefit of thrombectomy was similar regardless of the wake-up, unwitnessed, or witnessed mode of onset.
One-Year Home-Time and Mortality After Thrombolysis Compared With Nontreated Patients in a Propensity-Matched Analysis
Authors: Yu Amy Y.X. , Fang Jiming , Kapral Moira K.
Published: October 2019

Background and Purpose—

Intravenous thrombolysis with r-tPA (recombinant tissue-type plasminogen activator) is associated with improved early functional outcome after stroke, but its long-term effects are less understood. We aimed to determine the association between r-tPA and 1-year outcomes after stroke.

Methods—

We used the Ontario Stroke Registry to identify patients diagnosed with ischemic stroke between 2002 and 2013 in Ontario, Canada, their baseline characteristics, and whether they received r-tPA. We used propensity score methods to match patients treated with r-tPA to nontreated patients. The primary outcome was 1-year home-time, defined as the number of days spent outside of any healthcare institutions in the first 365 days after the index date of admission. Secondary outcomes were admission to a nursing home and all-cause mortality in the first year. Outcomes were determined using linked administrative data. We used paired
t
tests to compare mean home-time days and Cox proportional hazards models for mortality and nursing home admission to estimate hazard ratios and 95% CI.

Results—

All 4449 patients treated with r-tPA in the registry were matched to nontreated patients. Compared with nontreated patients, those treated with r-tPA experienced more time at home in the first year (mean±SD was 248.9 days±137.2 treated versus 239.4 days±139.0 nontreated,
P
=0.005) and were less likely to be admitted to nursing homes (9.4% treated versus 12.2% nontreated; hazard ratio, 0.84; 95% CI, 0.78–0.91). One-year all-cause mortality was similar between the 2 groups (13.2% treated versus 12.4% nontreated; hazard ratio, 1.07; 95% CI, 0.96–1.20).

Conclusions—

Despite similar mortality, patients who received r-tPA spent more time at home and were less likely to require nursing home admission in the first year after stroke compared with nontreated patients, suggesting long-term benefits and safety of this treatment.