bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Surface Defects and Dimensional Tolerances in Multi-Hole Drilling of AA5083, AA6061, and AA2024
Authors: Aamir Muhammad , Tolouei-Rad Majid , Giasin Khaled , Vafadar Ana , Koklu Ugur , Keeble William
Published: May 2021

Drilling is one of the most performed machining operations for riveting and assembly operations in many industrial sectors. The accuracy of the drilled holes and their surface finish play a vital role in the longevity and performance of the machined components, which, in turn, increase productivity. Therefore, this study investigated the effect of the multi-spindle drilling process on dimensional hole tolerances, such as hole size, circularity, cylindricity, and perpendicularity. In addition, the surface defects formed in the holes were examined using scanning electron microscopy. Three aluminium alloys, AA2024, AA6061, and AA5083, which are commonly used in the aerospace, automotive, and marine sectors, were chosen as the study materials. The results showed that the holes drilled in AA2024 gave less circularity error, cylindricity error, and perpendicularity error. In the case of hole size, the holes drilled in AA6061 were less deviated from the nominal size following holes drilled in AA2024 and AA5083 alloys. Surface damage in the form of metal debris adhesion, smeared material, side flow, and feed marks was found on the inner hole surface. Holes drilled in AA5083 alloy had the worst surface finish and were the most oversized, which was associated with noticeable damage and deformations in their inner surface. The ANOVA results revealed that the spindle speed was more influential than feed and mainly affected the hole size and cylindricity errors. However, in the case of circularity error and perpendicularity error, drilling parameters were found to be insignificant.
Scrophularia buergeriana Extract (Brainon) Improves Scopolamine-Induced Neuronal Impairment and Cholinergic Dysfunction in Mice through CREB-BDNF Signaling Pathway
Authors: Lee Hae-Jin , Kim Hae-Lim , Lee Dae-Young , Lee Dong-Ryung , Choi Bong-Keun , Yang Seung-Hwan
Published: May 2021

We evaluated the effectiveness of Scrophularia buergeriana extract (Brainon) on cognitive dysfunction and determined its underlying mechanisms in a scopolamine (SCO)-treated mouse model of memory impairment. Brainon treatment for 28 days ameliorated the symptoms of memory impairment as indicated by the results of both passive avoidance performance and the Morris water mazes. Brainon lowered acetylcholinesterase activity and raised acetylcholine levels in the hippocampus. The treatment elevated the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding (CREB). Additionally, the excessive generation of SCO-induced reactive oxygen species (ROS) and subsequent oxidative stress were suppressed by the enhancement of superoxide dismutase (SOD)-1 and SOD-2 proteins. mRNA levels of upregulated interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, as well as the apoptotic protein Bcl-2-associated X protein (Bax), cleaved caspase-9, and cleaved poly adenosine diphosphate-ribose polymerase (PARP) expression after SCO injection were downregulated by Brainon treatment. Collectively, these findings suggested that Brainon possesses anti-amnesic effects through the CREB-BDNF pathway. Moreover, it exerted antioxidant, anti-inflammatory, and anti-apoptotic effects in SCO-induced mice exhibiting cognitive impairment and memory loss.
Locally Optimal Subsampling Strategies for Full Matrix Capture Measurements in Pipe Inspection
Authors: Krieg Fabian , Kirchhof Jan , Pérez Eduardo , Schwender Thomas , Römer Florian , Osman Ahmad
Published: May 2021

In ultrasonic non-destructive testing, array and matrix transducers are being employed for applications that require in-field steerability or which benefit from a higher number of insonification angles. Having many transmit channels, on the other hand, increases the measurement time and renders the use of array transducers unfeasible for many applications. In the literature, methods for reducing the number of required channels compared to the full matrix capture scheme have been proposed. Conventionally, these are based on choosing the aperture that is as wide as possible. In this publication, we investigate a scenario from the field of pipe inspection, where cracks have to be detected in specific areas near the weld. Consequently, the width of the aperture has to be chosen according to the region of interest at hand. On the basis of ray-tracing simulations which incorporate a model of the transducer directivity and beam spread at the interface, we derive application specific measures of the energy distribution over the array configuration for given regions of interest. These are used to determine feasible subsampling schemes. For the given scenario, the validity/quality of the derived subsampling schemes are compared on the basis of reconstructions using the conventional total focusing method as well as sparsity driven-reconstructions using the Fast Iterative Shrinkage-Thresholding Algorithm. The results can be used to effectively improve the measurement time for the given application without notable loss in defect detectability.
Safety Evaluation of a RC Structure with Multiple Openings under High Water Depth Inundations
Authors: Endo Yohei , Yasue Takaharu
Published: May 2021

Experimental and numerical studies were conducted to examine the resistance of a newly developed residential building to inundations. Natural disasters including inundations have occurred frequently in recent decades. Once inundations submerge urban areas, water may remain there for days. This can cause substantial economic and social costs. Flood hazards have been widely discussed and investigated. However, sufficient research contributions have not been made on the behaviour of individual buildings under inundations. The objective of the research was to develop a prototype residential building in which residents can stay during inundations without the need of evacuation. A 3-m water depth was the target for safety evaluation in this research. This paper dealt with three tasks. First, three-point bending tests were performed on window components. Second, a hydrostatic pressure test was carried out on a full-scale reinforced concrete (RC) specimen. Third, taking advantage of the preceding two tasks, numerical simulations were performed to examine the behaviour of the prototype building under hydrostatic and hydrodynamic pressures. The experiments and numerical analyses showed that the prototype building had sufficient resistance and waterproofness against the inundations of a 3-m water depth. This research contributed to the improvements of the safety of RC structures against inundations and flood-risk reduction in urban areas.
Evaluation of Oak-Specific Consumption, Efficiency, and Losses from an Aesthetic Veneer Factory
Authors: Spirchez Gneorghe Cosmin , Lunguleasa Aurel , Ciobanu Valentina Doina
Published: May 2021

The paper aimed to investigate the losses on the manufacturing flow of an aesthetic veneer factory, in order to know their value and to take measures to limit or use them efficiently. For the analysis, the oak species (Quercus robur) was taken into account, through 25 analyzed logs. Statistical investigation has used the Minitab 18 program, for a 95% confidence interval. Minimum values of losses were obtained for the sectioning-grooming operations with 0.6% and debarking with 4.9%, and the highest values were obtained when cutting veneers with 15.9% and formatting veneers with 22.8%. Based on the losses on the manufacturing flow of 67.3%, the specific consumption index of 2.75 m3/m3 or 1.84 m3/1000 m2 of veneer was determined when the average thickness of the veneers was 0.67 mm. The paper highlights the methodology and the values resulting from the investigation of the technological losses and of the specific consumption from an aesthetic veneer factory.
Color Texture Image Complexity—EEG-Sensed Human Brain Perception vs. Computed Measures
Authors: Nicolae Irina E. , Ivanovici Mihai
Published: May 2021

In practical applications, such as patient brain signals monitoring, a non-invasive recording system with fewer channels for an easy setup and a wireless connection for remotely monitor physiological signals will be beneficial. In this paper, we investigate the feasibility of using such a system in a visual perception scenario. We investigate the complexity perception of color natural and synthetic fractal texture images, by studying the correlations between four types of data: image complexity that is expressed by computed color entropy and color fractal dimension, human subjective evaluation by scoring, and the measured brain EEG responses via Event-Related Potentials. We report on the considerable correlation experimentally observed between the recorded EEG signals and image complexity while considering three complexity levels, as well on the use of an EEG wireless system with few channels for practical applications, with the corresponding electrodes placement in accordance with the type of neural activity recorded.
Effect of Fine Particle Peening Using Hydroxyapatite Particles on Rotating Bending Fatigue Properties of β-Type Titanium Alloy
Authors: Nakamura Yuki , Nambu Koichiro , Akahori Toshikazu , Shimizu Toshihiro , Kikuchi Shoichi
Published: May 2021

Fine particle peening (FPP) using hydroxyapatite (HAp) shot particles was performed to improve the fatigue strength and form a HAp transfer layer on a beta titanium alloy (Ti–22V–4Al). The surface microstructures of the FPP-treated specimen were characterized using scanning electron microscopy, micro-Vickers hardness testing, energy dispersive X-ray spectrometry, X-ray diffraction, and electron backscattered diffraction. A HAp transfer layer with a thickness of 5.5 μm was formed on the surface of the Ti–22V–4Al specimen by FPP. In addition, the surface hardness of the Ti–22V–4Al was increased, and high compressive residual stress was generated on the specimen surface by FPP. Rotating bending fatigue tests were performed at room temperature in laboratory air over a wide cycle-life region (103–109 cycles). In the long cycle-life regime, the fatigue strength at 107 cycles of the FPP-treated specimen became higher than that of the untreated specimen. This result is attributed to the formation of a work-hardened layer with high compressive residual stress by FPP. However, the fatigue strength was not improved by FPP in the short cycle-life regime, because fatigue cracks were initiated at surface defects formed during the FPP process. The fatigue fracture mode of the FPP-treated specimens shifted from surface-initiated fracture to subsurface-initiated fracture at a stress amplitude level of 600 MPa.
Individual Adjustment of Contraction Parameters for Effective Swing Assist Using a Pneumatic Artificial Muscle in the Elderly
Authors: Toda Haruki , Maruyama Tsubasa , Kurita Yuichi , Tada Mitsunori
Published: May 2021

Leg swing during walking is controlled by hip and knee flexion motions. This study examined the effect of swing assist using a pneumatic artificial muscle (PAM) driver system on hip and knee motions and gait performance in the elderly. The participants consisted of 10 healthy elderly individuals. Two PAMs were attached to each participant’s left hip joint, and a pressure sensor was inserted under the right heel as the trigger. PAM contraction parameters could be controlled through a smartphone, i.e., the delay from trigger to contraction and the contraction duration. These parameters were randomly changed to 0, 100, or 200 ms for the delay and 100, 200, or 300 ms for the contraction. Four combination patterns of delay and contraction duration were observed as the parameter settings for maximizing the hip flexion angle. During walking with the PAM assistance, the hip and knee flexion angles in the swing phase and hip angular excursion of the elderly were significantly increased without altering the gait performance. The findings show that our PAM driver system can realize effective swing assist through changing temporal parameter settings for the PAM contraction in the elderly.
Analysis of the Effectiveness of Promotion Strategies of Social Platforms for the Elderly with Different Levels of Digital Literacy
Authors: Xu Xiaoyan , Mei Yi , Sun Yanhong , Zhu Xiaoli
Published: May 2021

This paper aimed to examine the effectiveness of social platform promotion strategies for the elderly with different digital literacy. Despite extensive research on the development of youth-oriented social platforms, research on the development of social platforms specifically targeting older adults with varying levels of digital literacy is lacking. The elderly population is divided into passive information receivers (PIRs) and active information seekers (AISs) according to their information seeking expertise, and an empirical study was conducted to assess the behavioral characteristics of PIRs and AISs. Grounded in innovation diffusion research and our empirical results, an agent-based model was developed, and the impact of the proportion of PIRs on the macro result of the social platform adoption (i.e., market penetration) and the impact of promotional strategies on market penetration under different proportions of PIRs were analyzed. The results demonstrate a direct negative effect of the proportion of PIRs on market penetration and a moderating effect on the effectiveness of various promotional strategies.
Selecting Bioassay Test Species at the Screening Level of Soil Ecological Risk Assessments
Authors: Kim Dokyung , Lee Tae-Yang , Kim Lia , Cui Rongxue , Kwak Jin Il , Kim Haemi , Nam Sun-Hwa , Kim Minjin , Hwang Wonjae , Kim Ji-In , Hyun Seunghun , An Youn-Joo
Published: May 2021

For site-specific soil ecological risk assessments (SERAs), an integrated chemical, ecotoxicological, and ecological analysis needs to be performed. The SERA guidelines of international institutions and countries recommend that a SERA be initiated at the screening level to save time and social economic cost; however, they provide no unified test species for this screening level. This study performed SERAs for field soils and confirmed the importance of selecting bioassay test species that reflect the ecotoxicity of field soils at the screening level. To confirm test species that reflect the ecological risk of field soils, correlation analysis was performed on the results of each bioassay with the integrated ecotoxicological risk index (EtoxRI). Our results showed that soil algae, nematodes, and plants were the most representative species in soil assays, with high correlation coefficients with EtoxRI. The results imply the importance of selecting test species that represent ecological risk for the screening level of SERAs. Based on these findings, when using SERAs, species sensitivity, ecological relevance, and economic aspects should be considered when selecting the bioassay test species.
Characterization of Three-Dimensional Internal Structure Evolution in Asphalt Mixtures during Freeze–Thaw Cycles
Authors: Xu Gang , Chen Xianhua , Cai Xing , Yu Yunhong , Yang Jun
Published: May 2021

This paper aims to characterize the three-dimensional (3D) internal structure evolution of asphalt mixtures under freeze–thaw cycles. Asphalt mixtures with three levels of design void content (3%, 5%, and 7%) were prepared in the laboratory. Subsequently, X-ray computed tomography (CT) tests were conducted to capture two-dimensional (2D) images of the internal structure of samples before and after freeze–thaw testing. A set of image processing techniques for reconstructing 3D images of the internal structure were utilized to extract the internal structure properties, which were then used to analyze the changes in the air void distributions and to evaluate the internal structure evolution under freeze–thaw cycles. 3D images reconstructed from X-ray CT images illustrated a dramatic degradation in the internal structure after cyclic freeze–thaw exposure. The change in internal structure occurs mainly in three ways: (1) expansion of existing individual voids, (2) combination of two separated air voids, and (3) generation of new voids. In addition, the parametric analysis of the three-dimensional reconstructed voids revealed that the asphalt mixture void ratio increased with the number of freeze–thaw cycles, while the larger the initial void content, the more pronounced the increase in the specimens. Therefore, asphalt mixture freeze–thaw resistance should be optimized in relation to the design void content.
Segmentation of Brain Tumors from MRI Images Using Convolutional Autoencoder
Authors: Badža Milica M. , Barjaktarović Marko Č.
Published: May 2021

The use of machine learning algorithms and modern technologies for automatic segmentation of brain tissue increases in everyday clinical diagnostics. One of the most commonly used machine learning algorithms for image processing is convolutional neural networks. We present a new convolutional neural autoencoder for brain tumor segmentation based on semantic segmentation. The developed architecture is small, and it is tested on the largest online image database. The dataset consists of 3064 T1-weighted contrast-enhanced magnetic resonance images. The proposed architecture’s performance is tested using a combination of two different data division methods, and two different evaluation methods, and by training the network with the original and augmented dataset. Using one of these data division methods, the network’s generalization ability in medical diagnostics was also tested. The best results were obtained for record-wise data division, training the network with the augmented dataset. The average accuracy classification of pixels is 99.23% and 99.28% for 5-fold cross-validation and one test, respectively, and the average dice coefficient is 71.68% and 72.87%. Considering the achieved performance results, execution speed, and subject generalization ability, the developed network has great potential for being a decision support system in everyday clinical practice.
Geochemical Mapping, Risk Assessment, and Source Identification of Heavy Metals in Road Dust Using Positive Matrix Factorization (PMF)
Authors: Faisal Muhammad , Wu Zening , Wang Huiliang , Hussain Zafar , Shen Chenyang
Published: May 2021

Heavy metals in road dust pose a significant threat to human health. This study investigated the concentrations, patterns, and sources of eight hazardous heavy metals (Cr, Ni, Cu, Zn, As, Cd, Pb, and Hg) in the street dust of Zhengzhou city of PR China. Fifty-eight samples of road dust were analyzed based on three methods of risk assessment, i.e., Geo-Accumulation Index (Igeo), Potential Ecological Risk Assessment (RI), and Nemerow Synthetic Pollution Index (PIN). The results exhibited higher concentrations of Hg and Cd 14 and 7 times higher than their background values, respectively. Igeo showed the risks of contamination in a range of unpolluted (Cr, Ni) to strongly polluted (Hg and Cd) categories. RI came up with the contamination ranges from low (Cr, Ni, Cu, Zn, As, and Pb) to extreme (Cd and Hg) risk of contamination. The risk of contamination based on PIN was from safe (Cu, As, and Pb) to seriously high (Cd and Hg). The results yielded by PIN indicated the extreme risk of Cd and Hg in the city. Positive Matrix Factorization was used to identify the sources of contamination. Factor 1 (vehicular exhaust), Factor 2 (coal combustion), Factor 3 (metal industry), and Factor 4 (anthropogenic activities), respectively, contributed 14.63%, 35.34%, 36.14%, and 13.87% of total heavy metal pollution. Metal’s presence in the dust is a direct health risk for humans and warrants immediate and effective pollution control and prevention measures in the city.
Analyzing Uncertain Dynamical Systems after State-Space Transformations into Cooperative Form: Verification of Control and Fault Diagnosis
Authors: Kersten Julia , Rauh Andreas , Aschemann Harald
Published: May 2021

When modeling real-life applications, uncertainty appears in the form of, for example, modeling approximations, measurement errors, or simply physical restrictions. Those uncertainties can either be treated as stochastic or as bounded, with known limits in the form of intervals. The latter is considered in this paper for a real-life application in the form of an electrical circuit. This is reasonable because the electrical circuit is subject to uncertainties, mainly due to circuit element tolerances and variable load conditions. Since conservative worst-case limits for such parameters are commonly known, interval methods can be applied. The aim of this paper is to demonstrate a possible overall handling of the given uncertain system. Firstly, this includes a control and a reliable computation of the states’ interval enclosures. On the one hand, this can be used to predict the system’s behavior, and on the other hand to verify the control numerically. Here, the implemented feedback control is based on linear matrix inequalities (LMIs) and the states are predicted using an interval enclosure technique based on cooperativity. Since the original system is not cooperative, a transformation is performed. Finally, an observer is implemented as a diagnosis tool regarding faulty measurements or component failures. Since adding a state-of-the-art observer would destroy this structure, a cooperativity-preserving method is applied. Overall, this paper combines methods from robust control design and interval-based evaluations, and presents a suitable observer technique to show the applicability of the presented methods.
Hide-and-Seek with Tiny Neotenic Beetles in One of the Hottest Biodiversity Hotspots: Towards an Understanding of the Real Diversity of Jurasaidae (Coleoptera: Elateroidea) in the Brazilian Atlantic Forest
Authors: Biffi Gabriel , Rosa Simone Policena , Kundrata Robin
Published: May 2021

Jurasaidae are a family of neotenic elateroid beetles which was described recently from the Brazilian Atlantic Forest biodiversity hotspot based on three species in two genera. All life stages live in the soil, including the larviform females, and only adult males are able to fly. Here, we report the discovery of two new species, Jurasai miraculum sp. nov. and J. vanini sp. nov., and a new, morphologically remarkable population of J. digitusdei Rosa et al., 2020. Our discovery sheds further light on the diversity and biogeography of the group. Most species of Jurasaidae are known from the rainforest remnants of the Atlantic Forest, but here for the first time we report a jurasaid species from the relatively drier Atlantic Forest/Caatinga transitional zone. Considering our recent findings, minute body size and cryptic lifestyle of all jurasaids, together with potentially high numbers of yet undescribed species of this family from the Atlantic Forest and possibly also other surrounding ecoregions, we call for both field research in potentially suitable localities as well as for a detailed investigation of a massive amount of already collected but still unprocessed materials deposited in a number of Brazilian institutes, laboratories and collections.
Expression Analysis of FGF/FGFR and FOX Family Proteins in Mucosal Tissue Obtained from Orofacial Cleft-Affected Children
Authors: Pilmane Māra , Jain Nityanand , Vitenberga-Verza Zane
Published: May 2021

Orofacial clefts affect hundreds of thousands of children worldwide annually and are usually corrected by a series of surgeries extending to childhood. The underlying mechanisms that lead to clefts are still unknown, mainly because of the multifactorial etiology and the myriad of interactions between genes and environmental factors. In the present study, we investigated the role and expression of candidate genes belonging to the FGF/FGFR signaling pathway and FOX family in tissue material obtained from 12 pediatric patients undergoing cleft correction surgery. The expression was investigated using immunohistochemistry (IHC) and chromogenic in-situ hybridization (CISH) in three cell/tissue types—epithelial cells, connective tissue, and endothelial cells. We found elevated expression of FGFR1 in epithelial cells while no expression was observed in endothelial cells. Further, our results elucidate the potential pathogenetic role of FGFR1 in cellular proliferation, local site inflammation, and fibrosis in cleft patients. Along with bFGF (also called FGF2), FGFR1 could play a pro-inflammatory role in clefts. Over-amplification of FGFR2 in some patients, along with bFGF, could potentially suggest roles for these genes in angiogenesis. Additionally, increased expression of FOXE1 (also called TTF2) contributes to local site inflammation. Finally, zero to low amplification of FOXO1 could suggest its potential role in inducing oxidative stress in the endothelium along with reduced epithelial apoptosis.
Into the Deep: New Data on the Lipid and Fatty Acid Profile of Redfish Sebastes mentella Inhabiting Different Depths in the Irminger Sea
Authors: Voronin Viktor P. , Nemova Nina N. , Ruokolainen Tatjana R. , Artemenkov Dmitrii V. , Rolskii Aleksei Y. , Orlov Alexei M. , Murzina Svetlana A.
Published: May 2021

New data on lipid and fatty acid profiles are presented, and the dynamics of the studied components in muscles in the males and females of the beaked redfish, Sebastes mentella, in the depth gradient of the Irminger Sea (North Atlantic) is discussed. The contents of the total lipids (TLs), total phospholipids (PLs), monoacylglycerols (MAGs), diacylglycerols (DAGs), triacylglycerols (TAGs), cholesterol (Chol), Chol esters, non-esterified fatty acids (NEFAs), and wax esters were determined by HPTLC; the phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylcholine (PC), and lysophosphatidylcholine (LPC) were determined by HPLC; and fatty acids of total lipids were determined using GC. The Chol esters prevailed in muscles over the storage TAGs, and the wax ester content was high, which is a characteristic trait of vertically migrating species. Specific dynamics in certain PL in redfish were found to be depended on depth, suggesting that PLs are involved in the re-arrangement of the membrane physicochemical state and the maintenance of motor activity under high hydrostatic pressure. The high contents of DHA and EPA were observed in beaked redfish muscles is the species’ characteristic trait. The MUFAs in muscles include dietary markers of zooplankton (copepods)—20:1(n-9) and 22:1(n-11), whose content was found to be lower in fish sampled from greater depths.
α-Difluoromethylornithine-Induced Cytostasis is Reversed by Exogenous Polyamines, Not by Thymidine Supplementation
Authors: Hyvönen Mervi T. , Khomutov Maxim , Vepsäläinen Jouko , Khomutov Alex R. , Keinänen Tuomo A.
Published: May 2021

Polyamine spermidine is essential for the proliferation of eukaryotic cells. Administration of polyamine biosynthesis inhibitor α-difluoromethylornithine (DFMO) induces cytostasis that occurs in two phases; the early phase which can be reversed by spermidine, spermine, and some of their analogs, and the late phase which is characterized by practically complete depletion of cellular spermidine pool. The growth of cells at the late phase can be reversed by spermidine and by very few of its analogs, including (S)-1-methylspermidine. It was reported previously (Witherspoon et al. Cancer Discovery 3(9); 1072–81, 2013) that DFMO treatment leads to depletion of cellular thymidine pools, and that exogenous thymidine supplementation partially prevents DFMO-induced cytostasis without affecting intracellular polyamine pools in HT-29, SW480, and LoVo colorectal cancer cells. Here we show that thymidine did not prevent DFMO-induced cytostasis in DU145, LNCaP, MCF7, CaCo2, BT4C, SV40MES13, HepG2, HEK293, NIH3T3, ARPE19 or HT-29 cell lines, whereas administration of functionally active mimetic of spermidine, (S)-1-methylspermidine, did. Thus, the effect of thymidine seems to be specific only for certain cell lines. We conclude that decreased polyamine levels and possibly also distorted pools of folate-dependent metabolites mediate the anti-proliferative actions of DFMO. However, polyamines are necessary and sufficient to overcome DFMO-induced cytostasis, while thymidine is generally not.
Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide
Authors: Socher Eileen , Conrad Marcus , Heger Lukas , Paulsen Friedrich , Sticht Heinrich , Zunke Friederike , Arnold Philipp
Published: May 2021

The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD–ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD–ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.
NRG1 Genetic Variant Influences the Efficacy of Androgen-Deprivation Therapy in Men with Prostate Cancer
Authors: Huang Shu-Pin , Chen Yei-Tsung , Chen Lih-Chyang , Lee Cheng-Hsueh , Huang Chao-Yuan , Yu Chia-Cheng , Lin Victor C. , Lu Te-Ling , Bao Bo-Ying
Published: May 2021

Neuregulins (NRGs) activate receptor tyrosine kinases of the ErbB family, and play essential roles in the proliferation, survival, and differentiation of normal and malignant tissue cells. We hypothesized that genetic variants of NRG signalling pathway genes may influence treatment outcomes in prostate cancer. To test this hypothesis, we performed a comprehensive analysis to evaluate the associations of 459 single-nucleotide polymorphisms in 19 NRG pathway genes with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in 630 patients with prostate cancer receiving androgen-deprivation therapy (ADT). After multivariate Cox regression and multiple testing correction, we found that NRG1 rs144160282 C > T is significantly associated with worsening CSS, OS, and PFS during ADT. Further analysis showed that low expression of NRG1 is closely related to prostate cancer, as indicated by a high Gleason score, an advanced stage, and a shorter PFS rate. Meta-analysis of 16 gene expression datasets of 1,081 prostate cancer samples and 294 adjacent normal samples indicate lower NRG1 expression in the former compared with the latter (p < 0.001). These results suggest that NRG1 rs144160282 might be a prognostic predictor of the efficacy of ADT. Further studies are required to confirm the significance of NRG1 as a biomarker and therapeutic target for prostate cancer.
Data Processing in Functional Near-Infrared Spectroscopy (fNIRS) Motor Control Research
Authors: Dans Patrick W. , Foglia Stevie D. , Nelson Aimee J.
Published: May 2021

FNIRS pre-processing and processing methodologies are very important—how a researcher chooses to process their data can change the outcome of an experiment. The purpose of this review is to provide a guide on fNIRS pre-processing and processing techniques pertinent to the field of human motor control research. One hundred and twenty-three articles were selected from the motor control field and were examined on the basis of their fNIRS pre-processing and processing methodologies. Information was gathered about the most frequently used techniques in the field, which included frequency cutoff filters, wavelet filters, smoothing filters, and the general linear model (GLM). We discuss the methodologies of and considerations for these frequently used techniques, as well as those for some alternative techniques. Additionally, general considerations for processing are discussed.
Adjuvant Hormonotherapy and Cardiovascular Risk in Post-Menopausal Women with Breast Cancer: A Large Population-Based Cohort Study
Authors: Franchi Matteo , Tritto Roberta , Tarantini Luigi , Navazio Alessandro , Corrao Giovanni
Published: May 2021

Background: Whether aromatase inhibitors (AIs) increase the risk of cardiovascular (CV) events, compared to tamoxifen, in women with breast cancer is still debated. We evaluated the association between AI and CV outcomes in a large population-based cohort of breast cancer women. Methods: By using healthcare utilization databases of Lombardy (Italy), we identified women ≥50 years, with new diagnosis of breast cancer between 2009 and 2015, who started adjuvant therapy with either AI or tamoxifen. We estimated the association between exposure to AI and CV outcomes (including myocardial infarction, ischemic stroke, heart failure or any CV event) by a Cox proportional hazard model with inverse probability of treatment and censoring weighting. Results: The study cohort included 26,009 women starting treatment with AI and 7937 with tamoxifen. Over a median follow-up of 5.8 years, a positive association was found between AI and heart failure (Hazard Ratio = 1.20, 95% CI: 1.02 to 1.42) and any CV event (1.14, 1.00 to 1.29). The CV risk increased in women with previous CV risk factors, including hypertension, diabetes and dyslipidemia. Conclusions: Adjuvant therapy with AI in breast cancer women aged more than 50 years is associated with increased risk of heart failure and combined CV events.
Radiomics-Based Differentiation between Glioblastoma, CNS Lymphoma, and Brain Metastases: Comparing Performance across MRI Sequences and Machine Learning Models
Authors: Priya Sarv , Liu Yanan , Ward Caitlin , Le Nam H. , Soni Neetu , Pillenahalli Maheshwarappa Ravishankar , Monga Varun , Zhang Honghai , Sonka Milan , Bathla Girish
Published: May 2021

Prior radiomics studies have focused on two-class brain tumor classification, which limits generalizability. The performance of radiomics in differentiating the three most common malignant brain tumors (glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic disease) is assessed; factors affecting the model performance and usefulness of a single sequence versus multiparametric MRI (MP-MRI) remain largely unaddressed. This retrospective study included 253 patients (120 metastatic (lung and brain), 40 PCNSL, and 93 GBM). Radiomic features were extracted for whole a tumor mask (enhancing plus necrotic) and an edema mask (first pipeline), as well as for separate enhancing and necrotic and edema masks (second pipeline). Model performance was evaluated using MP-MRI, individual sequences, and the T1 contrast enhanced (T1-CE) sequence without the edema mask across 45 model/feature selection combinations. The second pipeline showed significantly high performance across all combinations (Brier score: 0.311–0.325). GBRM fit using the full feature set from the T1-CE sequence was the best model. The majority of the top models were built using a full feature set and inbuilt feature selection. No significant difference was seen between the top-performing models for MP-MRI (AUC 0.910) and T1-CE sequence with (AUC 0.908) and without edema masks (AUC 0.894). T1-CE is the single best sequence with comparable performance to that of multiparametric MRI (MP-MRI). Model performance varies based on tumor subregion and the combination of model/feature selection methods.
Small High-Risk Uveal Melanomas Have a Lower Mortality Rate
Authors: Hussain Rumana N. , Coupland Sarah E. , Kalirai Helen , Taktak Azzam F. G. , Eleuteri Antonio , Damato Bertil E. , Groenewald Carl , Heimann Heinrich
Published: May 2021

Our aim was to determine whether size impacts on the difference in metastatic mortality of genetically high-risk (monosomy 3) uveal melanomas (UM). We undertook a retrospective analysis of data from a patient cohort with genetically characterized UM. All patients treated for UM in the Liverpool Ocular Oncology Centre between 2007 and 2014, who had a prognostic genetic tumor analysis. Patients were subdivided into those with small (≤2.5 mm thickness) and large (>2.5 mm thickness) tumors. Survival analyses were performed using Gray rank statistics to calculate absolute probabilities of dying as a result of metastatic UM. The 5-year absolute risk of metastatic mortality of those with small monosomy 3 UM was significantly lower (23%) compared to the larger tumor group (50%) (p = 0.003). Small disomy 3 UM also had a lower absolute risk of metastatic mortality (0.8%) than large disomy 3 UM (6.4%) (p = 0.007). Hazard rates showed similar differences even with lead time bias correction estimates. We therefore conclude that earlier treatment of all small UM, particularly monosomy 3 UM, reduces the risk of metastatic disease and death. Our results would support molecular studies of even small UM, rather than ‘watch-and-wait strategies’.
Intra-Tumoral Genomic Heterogeneity in Rectal Cancer: Mutational Status Is Dependent on Preoperative Biopsy Depth and Location
Authors: Vuijk Floris A. , van de Water Carlijn , Lent-van Vliet Shannon , van der Valk Maxime J. M. , Simmer Femke , van de Velde Cornelis J. H. , Vahrmeijer Alexander L. , Nagtegaal Iris D. , Hilling Denise E.
Published: May 2021

Neoadjuvant therapy before surgical resection is indicated for patients with locally advanced rectal cancer. However, a significant number of patients show minimal or no response to neoadjuvant therapy. Unfortunately, we are currently unable to predict response and identify non-responding patients before neoadjuvant treatment is given. Genomic mutational status might provide valuable prognostic information. However, it is unclear whether predictions based on genomic mutational status in single preoperative biopsies are reliable due to intra-tumoral heterogeneity. In this study we aim to investigate the reliability of genomic mutations found in single pre-operative biopsies by comparing genomic mutations to four other locations within the same tumor using next generation sequencing. Rectal cancer patients undergoing primary resection without neoadjuvant therapy were included. From each patient, one biopsy, two deep and two superficial samples were obtained and sequenced using a targeted next generation sequencing gene panel. Concordance between these five samples was assessed. In this feasibility study we included 11 patients. In 7 out of 11 (64%) patients, all 5 samples showed concordant mutations. In 4 out of 11 patients (36%) discordant mutations were observed. In conclusion, assessment of mutational status on a single pre-operative biopsy shows discordance with tumor tissue from other locations in 36% of cases. These results warrant careful interpretation of biopsy material analysis, as these might be influenced by tumor heterogeneity.
Allogenic Stem Cell Transplantation Abrogates Negative Impact on Outcome of AML Patients with KMT2A Partial Tandem Duplication
Authors: Antherieu Gabriel , Bidet Audrey , Huet Sarah , Hayette Sandrine , Migeon Marina , Boureau Lisa , Sujobert Pierre , Thomas Xavier , Ghesquières Hervé , Pigneux Arnaud , Heiblig Mael
Published: May 2021

Recently, a new subset of acute myeloid leukemia (AML) presenting a direct partial tandem duplication (PTD) of the KMT2A gene was described. The consequences of this alteration in terms of outcome and response to treatment remain unclear. We analyzed retrospectively a cohort of KMT2A-PTD-mutated patients with newly diagnosed AML. With a median follow-up of 3.6 years, the median overall survival was 12.1 months. KMT2A-PTD-mutated patients were highly enriched in mutations affecting epigenetic actors and the RTK/RAS signaling pathway. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In the multivariate analysis, only HSCT at any time in complete remission (HR = 2.35; p = 0.034) and FLT3-ITD status (HR = 0.29; p = 0.014) were independent variables associated with overall survival, whereas age was not. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor. However, as KMT2A-PTD-mutated patients are usually considered an intermediate risk group, upfront HSCT should be considered in first CR due to the high relapse rate observed in this subset of patients.
Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now?
Authors: Pelizzaro Filippo , Cardin Romilda , Penzo Barbara , Pinto Elisa , Vitale Alessandro , Cillo Umberto , Russo Francesco Paolo , Farinati Fabio
Published: May 2021

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.
Neuroendocrine Factors in Melanoma Pathogenesis
Authors: Scheau Cristian , Draghici Carmen , Ilie Mihaela Adriana , Lupu Mihai , Solomon Iulia , Tampa Mircea , Georgescu Simona Roxana , Caruntu Ana , Constantin Carolina , Neagu Monica , Caruntu Constantin
Published: May 2021

Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects.
Primary Ovarian Mesothelioma: A Case Series with Electron Microscopy Examination and Review of the Literature
Authors: Vimercati Luigi , Cavone Domenica , Delfino Maria Celeste , Bruni Biagio , De Maria Luigi , Caputi Antonio , Sponselli Stefania , Rossi Roberta , Resta Leonardo , Fortarezza Francesco , Pezzuto Federica , Serio Gabriella
Published: May 2021

Primary ovarian mesothelioma is a rare, aggressive neoplastic disease with a poor prognosis. At onset, the tumor is only rarely limited to the ovaries and usually already widespread in the peritoneum. The rarity of this entity and the difficulties differentiating it from either ovarian carcinoma or peritoneal mesothelioma may lead to frequent misdiagnoses and may raise some concerns about its histogenesis. Thus, reporting such rare cases is fundamental to gain greater awareness of this neoplasm and try to answer unsolved questions. Herein, we described four cases of histological diagnoses of ovarian mesothelioma extrapolated by the regional mesothelioma register of Apulia (southern Italy). In all cases, a detailed medical history was collected according to national mesothelioma register guidelines. A broad panel of antibodies was used for immunohistochemistry to confirm the diagnoses. Moreover, ovarian tissue samples were also examined by transmission and scanning electron microscopy, detecting asbestos fibers and talc crystals in two cases. Because of the few cases described, we reviewed the English literature in the Medline database, focusing on articles about ovarian mesothelioma “misclassification”, “misdiagnosis”, “diagnostic challenge” or “diagnostic pitfall” and on unsolved questions about its histogenesis and possible risk factors.
Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients
Authors: Zhou Sarah , Sikorski Daniel , Xu Honghao , Zubarev Andrei , Chergui May , Lagacé François , Miller Wilson H. , Redpath Margaret , Ghazal Stephanie , Butler Marcus O. , Petrella Teresa M. , Claveau Joël , Nessim Carolyn , Salopek Thomas G. , Gniadecki Robert , Litvinov Ivan V.
Published: May 2021

Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III–IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.