bluuebunny/crossref_metadata_2025 huggingface dataset:
Users’ Reaction Time for Improvement of Security and Access Control in Web Services
Authors: Magomedov Shamil , Gusev Alexander , Ilin Dmitry , Nikulchev Evgeny
Published: March 2021

This paper concerns the case of the development of a technology for increasing the efficiency of access control based on the user behavior monitoring built into a software system’s user interface. It is proposed to use the time of user reactions as individual indicators of psychological and psychophysical state. This paper presents the results and interpretation of user reactions collected during a mass web survey of students of the Russian Federation. The total number of users was equal to 22,357. To reveal the patterns in user reactions, both quantitative and qualitative approaches were applied. The analysis of the data demonstrated that the user could be characterized by their psychomotor reactions, collected during the answering of a set of questions. Those reactions reflected the personal skills of the interface interaction, the speed of reading, and the speed of answering. Thus, those observations can be used as a supplement to personal verification in information systems. The collection of the reaction times did not load the data volumes significantly nor transmit confidential information.
Adaptive Multi-View Image Mosaic Method for Conveyor Belt Surface Fault Online Detection
Authors: Gao Rui , Miao Changyun , Li Xianguo
Published: March 2021

In order to improve the accuracy and real-time of image mosaic, realize the multi-view conveyor belt surface fault online detection, and solve the problem of longitudinal tear of conveyor belt, we in this paper propose an adaptive multi-view image mosaic (AMIM) method based on the combination of grayscale and feature. Firstly, the overlapping region of two adjacent images is preliminarily estimated by establishing the overlapping region estimation model, and then the grayscale-based method is used to register the overlapping region. Secondly, the image of interest (IOI) detection algorithm is used to divide the IOI and the non-IOI. Thirdly, only for the IOI, the feature-based partition and block registration method is used to register the images more accurately, the overlapping region is adaptively segmented, the speeded up robust features (SURF) algorithm is used to extract the feature points, and the random sample consensus (RANSAC) algorithm is used to achieve accurate registration. Finally, the improved weighted smoothing algorithm is used to fuse the two adjacent images. The experimental results showed that the registration rate reached 97.67%, and the average time of stitching was less than 500 ms. This method is accurate and fast, and is suitable for conveyor belt surface fault online detection.
Development of Femtosecond Laser-Engineered β-Tricalcium Phosphate (β-TCP) Biomimetic Templates for Orthopaedic Tissue Engineering
Authors: Daskalova Albena , Angelova Liliya , Trifonov Anton , Lasgorceix Marie , Hocquet Stephane , Minne Mendy , Declercq Heidi , Leriche Anne , Aceti Dante , Buchvarov Ivan
Published: March 2021

Reconstruction of bone tissue defects is a problematic area of the modern world. Temporary “platforms” of various materials for improving cell adhesion and proliferation have been extensively researched in recent decades. β-tricalcium phosphate (β-TCP) is a suitable biocompatible, biodegradable material used for bone regeneration. The creation of scaffolds with specifically designed surface structures will enable bone engineering applications that require navigated cell proliferation on a substrate with pre-set geometric limits. In this study, an innovative laser-based technique for surface modification was applied to improve the morphological properties of the surface of β-TCP pellets for proper cell surface environment creation. The obtained topographies with diverse processing parameters were compared. Homogenous microgroove structures, less than 100 µm, without the onset of melting and crack formation, were produced. The contribution from the accumulation effect of a diverse number of laser pulses (N = 1–100) on the final structure dimensions was examined. The microstructured scaffolds were investigated by confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) analyses. We studied the effect of the patterned surface of the material on the mouse calvaria osteoblast (MC3T3) cells’ viability and cytotoxicity from 1 to 7 days. The results indicated that cell behavior was affected by microscale dimensions of the surface.
Evaluating Degradation Coefficients from Existing System Models
Authors: Osara Jude A. , Bryant Michael D.
Published: March 2021

A generalization of the Degradation-Entropy Generation (DEG) theorem to multi-disciplinary multi-physics system-process analysis via a combination with pre-existing system models is presented in this article. Existing models and the DEG methodology are reviewed, and a method for evaluating degradation coefficients Bi is proposed. These coefficients characterize the system’s transformation based on active dissipative mechanisms, including temperature effects. The consistency of entropy generation in characterizing degradation is then inherited by these often-empirical system models, thereby rendering them more robust and applicable to similar systems without the need for numerous tests and measurements for model corrections. The approach applies to all systems and can quickly analyze and predict a system’s performance and degradation, even in the absence of experimental data (using known properties and material constants). Demonstrated applications herein include mechanically loaded systems (frictional wear, grease shearing, fatigue loading), electrochemical energy systems, thermal processes, and others.
Present and Future High-Resolution Climate Forcings over Semiarid Catchments: Case of the Tensift (Morocco)
Authors: Moucha Ahmed , Hanich Lahoucine , Tramblay Yves , Saaidi Amina , Gascoin Simon , Martin Eric , Le Page Michel , Bouras Elhoussaine , Szczypta Camille , Jarlan Lionel
Published: March 2021

In semiarid areas, the climate is characterized by strong spatiotemporal variability while the meteorological ground network is often very sparse. In this context, the spatial distribution of meteorological variables is thus a real issue for watershed hydrology, agronomy and the study of surface–atmosphere retroaction in these regions. The aim of this study is twofold: (1) to evaluate and to adapt a reanalysis system “Système d’Analyse Fournissant des Renseignements Adaptés à la Nivologie” (SAFRAN) to map the meteorological variables on the Tensift catchment (Morocco) between 2004 and 2014; (2) to project temperature and precipitation for the 2041–2060 horizon at high-resolution based on the Euro-CORDEX database at 12 km resolution (using two Representative Concentration Pathway -RCPs- scenarios and four Regional Climate Models), on the SAFRAN reanalysis and on a network of meteorological stations. SAFRAN was assessed: (1) based on leave-one-out for a station located in the plain and another in the mountains; (2) by comparison to another re-analysis system named the Meteorological Distribution System for High-Resolution Terrestrial Modeling (MicroMet); (3) by comparison to in situ measurements of snowfall at one station and to the daily Snow Cover Area derived from the Moderate-Resolution Imaging Spectroradiometer (MODIS) product at the catchment scale. The evaluation of the SAFRAN reanalysis showed that an irregular grid up to 1 km resolution is better for reproducing meteorological variables than the regular version of SAFRAN at 8 km, especially in mountains. The projection of the SAFRAN forcing is conducted in three steps corresponding to the three subsections below: (1) disaggregation of the Euro-CORDEX climate scenarios using the Q–Q approach based on stations data; (2) computation of the spatialized delta-change between historical and future Euro-CORDEX runs after Q–Q correction; (3) futurization of SAFRAN using the spatialized delta change values. The mountainous area is expected to face a higher increase in air temperature than the plains, reaching +2.5 °C for RCP8.5 and +1.71 °C for RCP4.5 over 2041–2060. This warming will be accompanied by a marked decrease in precipitation (−16% for RCP8.5). These present and future spatialized data sets should be useful for impact studies, in particular those focusing on water resources.
Stacked Community Prediction: A Distributed Stacking-Based Community Extraction Methodology for Large Scale Social Networks
Authors: Makris Christos , Pispirigos Georgios
Published: March 2021

Nowadays, due to the extensive use of information networks in a broad range of fields, e.g., bio-informatics, sociology, digital marketing, computer science, etc., graph theory applications have attracted significant scientific interest. Due to its apparent abstraction, community detection has become one of the most thoroughly studied graph partitioning problems. However, the existing algorithms principally propose iterative solutions of high polynomial order that repetitively require exhaustive analysis. These methods can undoubtedly be considered resource-wise overdemanding, unscalable, and inapplicable in big data graphs, such as today’s social networks. In this article, a novel, near-linear, and highly scalable community prediction methodology is introduced. Specifically, using a distributed, stacking-based model, which is built on plain network topology characteristics of bootstrap sampled subgraphs, the underlined community hierarchy of any given social network is efficiently extracted in spite of its size and density. The effectiveness of the proposed methodology has diligently been examined on numerous real-life social networks and proven superior to various similar approaches in terms of performance, stability, and accuracy.
Computational Analysis of Self-Expanding and Balloon-Expandable Transcatheter Heart Valves
Authors: Pasta Salvatore , Gandolfo Caterina
Published: March 2021

Bicuspid aortic valve (BAV) patients are usually excluded from transcatheter aortic valve implantation (TAVI) as this valve anatomy likely leads to oval expansion. This study presents a numerical study of TAVI using both self-expanding and balloon expandable transcatheter heart valve (THV) in bicuspid patients with severe stenosis. The simulation framework included a patient-specific anatomy of the aortic root, calcifications and BAV leaflets extracted from medical imaging analysis as well as a realistic crimping and deployment of the THV. Tissue stress analysis highlighted local maxima in the contact area between the inner aortic lumen and the THV stent frame. Flow analysis based on the smoothed particle hydrodynamics (SPH) technique displayed the area at risk of paravalvular leakage (PVL). These findings provide insights on the TAVI in BAV and thus represents a further step towards the use of in-silico for the virtual planning of TAVI, aiming at improving not only the efficacy of the implantation but also the exploration of borderline anatomy as the case of TAVI in BAVs.
Use of Super Paramagnetic Iron Oxide Nanoparticles as Drug Carriers in Brain and Ear: State of the Art and Challenges
Authors: Guigou Caroline , Lalande Alain , Millot Nadine , Belharet Karim , Bozorg Grayeli Alexis
Published: March 2021

Drug delivery and distribution in the central nervous system (CNS) and the inner ear represent a challenge for the medical and scientific world, especially because of the blood–brain and the blood–perilymph barriers. Solutions are being studied to circumvent or to facilitate drug diffusion across these structures. Using superparamagnetic iron oxide nanoparticles (SPIONs), which can be coated to change their properties and ensure biocompatibility, represents a promising tool as a drug carrier. They can act as nanocarriers and can be driven with precision by magnetic forces. The aim of this study was to systematically review the use of SPIONs in the CNS and the inner ear. A systematic PubMed search between 1999 and 2019 yielded 97 studies. In this review, we describe the applications of the SPIONS, their design, their administration, their pharmacokinetic, their toxicity and the methods used for targeted delivery of drugs into the ear and the CNS.
Effects of Betahistine on the Development of Vestibular Compensation after Unilateral Labyrinthectomy in Rats
Authors: Fukuda Junya , Matsuda Kazunori , Sato Go , Kitahara Tadashi , Matsuoka Momoyo , Azuma Takahiro , Kitamura Yoshiaki , Tomita Koichi , Takeda Noriaki
Published: March 2021

Background: Vestibular compensation (VC) after unilateral labyrinthectomy (UL) consists of the initial and late processes. These processes can be evaluated based on the decline in the frequency of spontaneous nystagmus (SN) and the number of MK801-induced Fos-positive neurons in the contralateral medial vestibular nucleus (contra-MVe) in rats. Histamine H3 receptors (H3R) are reported to be involved in the development of VC. Objective: We examined the effects of betahistine, an H3R antagonist, on the initial and late processes of VC in UL rats. Methods: Betahistine dihydrochloride was continuously administered to the UL rats at doses of 100 and 200 mg/kg/day using an osmotic minipump. MK801 (1.0 mg/kg) was intraperitoneally administered on days 7, 10, 12, and 14 after UL, while Fos-positive neurons were immunohistochemically stained in the contra-MVe. Results: The SN disappeared after 42 h, and continuous infusion of betahistine did not change the decline in the frequency of SN. The number of MK801-induced Fos-positive neurons in contra-MVe significantly decreased on days 7, 10, and 12 after UL in a dose-dependent manner in the betahistine-treated rats, more so than in the saline-treated rats. Conclusion: These findings suggest that betahistine facilitated the late, but not the initial, process of VC in UL rats.
Interactions of COMT and ALDH2 Genetic Polymorphisms on Symptoms of Parkinson’s Disease
Authors: Yu Rwei-Ling , Tu Shao-Ching , Wu Ruey-Meei , Lu Pei-An , Tan Chun-Hsiang
Published: March 2021

(1) Background: Monoamine neurotransmitters play essential roles in the normal functioning of our nervous system. However, the metabolism of monoamine neurotransmitters is accompanied by the production of neurotoxic metabolites, and inefficient removal of the metabolites has been suggested to cause neurodegeneration. (2) Methods: To examine the effect of reduced activity of catechol-O-methyltransferase (COMT) and aldehyde dehydrogenase 2 (ALDH2) conferred by single nucleotide polymorphisms COMT rs4680(A) and ALDH2 rs671(A) on the symptoms of patients with Parkinson’s disease (PD), a total of 114 PD patients were recruited cross-sectionally and received genotyping for rs4680 and rs671 along with MDS-UPDRS evaluation. (3) Results: We found that patients carrying rs4680(A) had more severe bradykinesia in the upper extremity and rest tremor. Besides, patients carrying rs671(A) had more difficulty maintaining personal hygiene, while patients with genotype rs671(GG) had higher scores in the item “depressed mood.” More importantly, we found the effect of rs4680 to be moderated by rs671 SNP for the symptom of “hand movements.” The detrimental impact of rs4680(A) is more pronounced in the presence of genotype rs671(GG). (4) Conclusions: This study facilitates a deeper understanding of the detrimental effect of reduced activity of COMT and ALDH2 conferred by genetic variation and provides novel insight into the interactions between enzymes metabolizing monoamine neurotransmitters in the pathogenesis of PD.
Gender Differences in Complete Blood Count and Inflammatory Ratios among Patients with Bipolar Disorder
Authors: Fusar-Poli Laura , Amerio Andrea , Cimpoesu Patriciu , Grimaldi Filioli Pietro , Natale Antimo , Zappa Guendalina , Aguglia Eugenio , Amore Mario , Serafini Gianluca , Aguglia Andrea
Published: March 2021

Background: Evidence suggested that inflammation may be involved in the etiopathogenesis of bipolar disorder (BD), a chronic psychiatric condition affecting around 2–3% of the general population. However, little is known regarding potential gender differences in peripheral biomarkers of BD, such as neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and monocyte-to-lymphocyte (MLR) ratios. Methods: In total, 197 females and 174 males with BD in different phases (i.e., (hypo)mania, depression, euthymia) were recruited. A blood sample was drawn to perform a complete blood count (CBC). NLR, PLR, and MLR were subsequently calculated, and differences were computed according to the illness phase and gender. Results: PLR was consistently higher in (hypo)manic than depressed patients, in both males and females. No significant gender differences in PLR value were found when considering only (hypo)mania. Conversely, NLR was increased in (hypo)mania only among males, and gender differences were retrieved in the (hypo)manic subgroup. The findings related to MLR were only marginally significant. Higher platelets values were associated with (hypo)mania only in the female group. Basophils and eosinophils appeared gender- but not state-dependent. Conclusions: Our findings provide further evidence that increased PLR levels may be associated with (hypo)mania in bipolar patients, regardless of gender. Moreover, the usefulness of NLR as a peripheral biomarker of BD appeared limited to males while the role of platelets to females. As CBC represents a low-cost and easily accessible test, researchers should investigate in-depth its potential usefulness as a biomarker of BD and other psychiatric disorders.
Computational Simulation of Wind Microclimate in Complex Urban Models and Mitigation Using Trees
Authors: Hosseinzadeh Azin , Keshmiri Amir
Published: March 2021

Due to a rapid increase in urbanisation, accurate wind microclimate assessment is of crucial importance. Evaluating wind flows around buildings is part of the planning application process in the design of new developments. In this study, computational fluid dynamics (CFD) simulations are carried out for a case study, representing the East Village in the London Olympic Park. Following a validation test against experimental data for a simpler urban configuration, the key input parameters, including appropriate boundary conditions, mesh setting and type of turbulence model, are selected for the Olympic Park model. All the simulations are conducted using the commercial code STARCCM+ under steady-state conditions with the Reynolds-averaged Navier–Stokes (RANS) method. The turbulence is modelled using different common variants of eddy-viscosity models (EVMs) including standard k-ε, realizable k-ε and standard and shear stress transport (SST) k-ω. The results demonstrate that standard and realisable k-ε models correlate very well with the experimental data, while some discrepancies are found with standard and SST k-ω. Following the determination of areas of high velocity, appropriate tree planting is proposed to overcome the effect of corner and downwash acceleration. With the optimised arrangement of trees and using specific types of tree (e.g., birch), wind speeds at the pedestrian level are reduced by 3.5, 25 and 66% in three main regions of interest. Moreover, we investigate the effects of tree heights. The obtained results illustrate that the wind velocity reduces when the crowns of the trees are located closer to the buildings and the ground. Our high-resolution CFD simulation and results offer a quantitative tool for wind microclimate assessment and optimised design and arrangement of trees around buildings to improve pedestrian comfort.
Relationship between Energy and Atmosphere (EA) Credits and Project Size in the LEED-NC Version 3 (v3) and 4 (v4) Projects
Authors: Pushkar Svetlana
Published: March 2021

This study aims to explore the influence of project size on the Energy and Atmosphere (EA) credits in the Leadership in Energy and Environmental Design for New Construction and Major Renovations (LEED-NC) version 3 (v3) in California and version 4 (v4) in the United States (US) in office-type projects. If the relationship between the ordinal data of EA credits and project size changed monotonically, then Spearman’s correlation coefficient was used. If the relationship between the EA credits ordinal data and project size did not change monotonically, then the EA credit data were divided into below and above the median project size groups, and, as a consequence, the Cliff′s δ effect size and exact Wilcoxon–Mann–Whitney tests were used. If the EA credits were binary or dichotomous data, then the natural logarithm of the odds ratio and Fisher’s exact 2 × 2 test with Lancaster’s mid-p-value were used. The results showed that the performance of operational energy, enhanced the refrigerant management and that the renewable energy credits in LEED-NC v3/v4 Certified, Silver, and Gold projects depended on the project size. We concluded that the LEED project size is an important variable for developing LEED-NC strategies for office-type projects.
Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells
Authors: Rad S. M. Ali Hosseini , Halpin Joshua Colin , Mollaei Mojtaba , Smith Bell Samuel W. J. , Hirankarn Nattiya , McLellan Alexander D.
Published: March 2021

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.
AKT3 Is a Novel Regulator of Cancer-Associated Fibroblasts in Head and Neck Squamous Cell Carcinoma
Authors: Takahashi Hideyuki , Rokudai Susumu , Kawabata-Iwakawa Reika , Sakakura Koichi , Oyama Tetsunari , Nishiyama Masahiko , Chikamatsu Kazuaki
Published: March 2021

Cancer-associated fibroblasts (CAFs) play vital roles in tumor progression by promoting epithelial-to-mesenchymal transition, angiogenesis, and immunosuppression. In the present study, we sought to identify the key regulators of the pro-tumoral functions of CAFs in head and neck squamous cell carcinoma (HNSCC). mRNA expression data obtained from The Cancer Genome Atlas revealed that CAF-specific mRNA expression correlated with genes that relate to an immunosuppressive microenvironment in a HNSCC cohort. RNA sequencing of CAFs and normal fibroblasts isolated from HNSCC specimens identified 1127 differentially expressed genes (DEGs) and several upregulated pathways in CAFs. Among the 1127 DEGs, we identified 13 immune function-related genes and focused on AKT3 as a potential regulator of CAFs. The targeted depletion of AKT3 in CAFs revealed that AKT3 promotes their myofibroblastic phenotype. AKT3-transduced CAFs exhibited downregulated the expression of immunosuppressive cytokine genes, impairing T-cell suppression and pro-tumoral macrophage induction. The immunohistochemistry of 72 HNSCC patients showed that AKT3 expression in CAFs positively correlated with tumor infiltration by CAFs, tumor-associated macrophages, dendritic cells, and T cells. Moreover, AKT3 expression in CAFs was an independent prognostic factor for overall survival. In conclusion, AKT3 is a potential target for cancer therapy that inhibits the pro-tumoral function of CAFs and reverses CAF-mediated immunosuppression.
Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features
Authors: Raffenne Jérôme , Martin Fernando A. , Nicolle Rémy , Konta Marina , Blum Yuna , Torrisani Jérôme , Puleo Francesco , Bachet Jean Baptiste , Svrcek Magali , Bardier-Dupas Armel , Emile Jean Francois , Demetter Peter , Radman Miroslav , Van Laethem Jean Luc , Hammel Pascal , Rebours Vinciane , Paradis Valérie , Couvelard Anne , Cros Jérôme
Published: March 2021

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.
Isoliquiritigenin Reverses Epithelial-Mesenchymal Transition Through Modulation of the TGF-β/Smad Signaling Pathway in Endometrial Cancer
Authors: Chen Hsin-Yuan , Chiang Yi-Fen , Huang Jia-Syuan , Huang Tsui-Chin , Shih Yin-Hwa , Wang Kai-Lee , Ali Mohamed , Hong Yong-Han , Shieh Tzong-Ming , Hsia Shih-Min
Published: March 2021

Endometrial cancer is a common gynecological cancer with a poor prognosis, mostly attributed to tumor metastasis. Epithelial–mesenchymal transition (EMT) can be mediated via transforming growth factor beta (TGF-β) signaling pathway, facilitating the ability of cancer cell invasion and migration. Isoliquiritigenin (ISL) is a flavonoid derived from licorice with reported antineoplastic activities. This study aims to investigate the anti-metastatic potential of ISL on endometrial cancer both in vitro and in vivo. First, human endometrial cancer cell lines (HEC-1A, Ishikawa, and RL95-2) were treated with ISL and then subjected to functional assays such as migration assay as well as molecular analyses including immunoblotting, immunofluorescence and RT-qPCR. In addition, HEC-1A-LUC cells were implanted into female nude mice and treated with ISL by intraperitoneal injection for four weeks. Results showed that ISL inhibited cell migration and reversed the effect of TGF-β on the expression of E-cadherin, N-cadherin, vimentin, α-SMA, p-Smad3, and TWIST1/2 In vitro. Interestingly, In vivo study revealed that ISL reduced peritoneal dissemination and serum level of TGF-β1, as well as decreased the expression levels of N-cadherin, p-Smad2/3, TWIST1/2, while increased E-cadherin. Overall, ISL reverses the EMT through targeting the TGF-β/Smad signaling pathway and features a potential therapeutic treatment for metastatic endometrial cancer.
Cancer during Pregnancy: A Review of Preclinical and Clinical Transplacental Transfer of Anticancer Agents
Authors: Benoit Laure , Mir Olivier , Vialard François , Berveiller Paul
Published: March 2021

The occurrence of cancer during pregnancy is observed in 1 in 1000 pregnancies and is expected to increase given the trend of delaying childbearing. While breast cancer is the most common, the incidence of other cancers, such as cervical, ovarian, and lung cancers as well as hemopathies and melanomas, is also increasing. Thus, cancer occurrence in pregnant women raises questions of management during pregnancy and, especially, assessment of the treatment benefit–risk ratio to ensure optimal management for the mother while ensuring the safety of the fetus. Chemotherapy remains a cornerstone of cancer management. If the use of anticancer agents appears possible during pregnancy, while avoiding the first trimester, the extent of placental transfer of different anticancer agents varies considerably thereafter. Furthermore, the significant physiological pharmacokinetic variations observed in pregnant women may have an impact on the placental transfer of anticancer agents. Given the complexity of predicting placental transfer of anticancer agents, preclinical studies are therefore mandatory. The aim of this review was to provide updated data on in vivo and ex vivo transplacental transfer of anticancer agents used in the management of the most common pregnancy-associated cancers to better manage these highly complex cases.
Hyperthermia-Based Anti-Cancer Treatments
Authors: Crezee Johannes , Franken Nicolaas A. P. , Oei Arlene L.
Published: March 2021

Hyperthermia is an adjuvant local anti-cancer treatment using temperatures exceeding the physiologically optimal level, typically 40–43 °C for approximately one hour [...]
Preclinical Evaluation of the Association of the Cyclin-Dependent Kinase 4/6 Inhibitor, Ribociclib, and Cetuximab in Squamous Cell Carcinoma of the Head and Neck
Authors: van Caloen Gabrielle , Schmitz Sandra , van Marcke Cédric , Caignet Xavier , Mendola Antonella , Pyr dit Ruys Sébastien , Roger Pierre P. , Vertommen Didier , Machiels Jean-Pascal
Published: March 2021

Epidermal growth factor receptor (EGFR) overexpression is observed in 90% of human papillomavirus (HPV)-negative squamous cell carcinomas of the head and neck (SCCHN). Cell cycle pathway impairments resulting in cyclin-dependent kinase (CDK) 4 and 6 activation, are frequently observed in SCCHN. We investigated the efficacy of ribociclib, a CDK4/6 inhibitor, in combination with cetuximab, a monoclonal antibody targeting the EGFR, in HPV-negative SCCHN patient-derived tumor xenograft (PDTX) models. The combination of cetuximab and ribociclib was not significantly more active than cetuximab monotherapy in all models investigated. In addition, the combination of cetuximab and ribociclib was less active than ribociclib monotherapy in the cetuximab-resistant PDTX models. In these models, a significant downregulation of the retinoblastoma (Rb) protein was observed in cetuximab-treated mice. We also observed Rb downregulation in the SCCHN cell lines chronically exposed and resistant to cetuximab. In addition, Rb downregulation induced interleukin 6 (Il-6) secretion and the Janus kinase family member/signal transducer and activator of transcription (JAK/STAT) pathway activation that might be implicated in the cetuximab resistance of these cell lines. To conclude, cetuximab is not an appropriate partner for ribociclib in cetuximab-resistant SCCHN models. Our work has significant clinical implications since the combination of anti-EGFR therapy with CDK4/6 inhibitors is currently being investigated in clinical trials.
Autophagy Triggers Tamoxifen Resistance in Human Breast Cancer Cells by Preventing Drug-Induced Lysosomal Damage
Authors: Actis Chiara , Muzio Giuliana , Autelli Riccardo
Published: March 2021

Endocrine resistance is a major complication during treatment of estrogen receptor-positive breast cancer. Although autophagy has recently gained increasing consideration among the causative factors, the link between autophagy and endocrine resistance remains elusive. Here, we investigate the autophagy-based mechanisms of tamoxifen resistance in MCF7 cells. Tamoxifen (Tam) triggers autophagy and affects the lysosomal compartment of MCF7 cells, such that activated autophagy supports disposal of tamoxifen-damaged lysosomes by lysophagy. MCF7 cells resistant to 5 µM tamoxifen (MCF7-TamR) have a higher autophagic flux and an enhanced resistance to Tam-induced lysosomal alterations compared to parental cells, which suggests a correlation between the two events. MCF7-TamR cells overexpress messenger RNAs (mRNAs) for metallothionein 2A and ferritin heavy chain, and they are re-sensitized to Tam by inhibition of autophagy. Overexpressing these proteins in parental MCF7 cells protects lysosomes from Tam-induced damage and preserves viability, while inhibiting autophagy abrogates lysosome protection. Consistently, we also demonstrate that other breast cancer cells that overexpress selected mRNAs encoding iron-binding proteins are less sensitive to Tam-induced lysosomal damage when autophagy is activated. Collectively, our data demonstrate that autophagy triggers Tam resistance in breast cancer cells by favoring the lysosomal relocation of overexpressed factors that restrain tamoxifen-induced lysosomal damage.
Prognostic Significance of Interim Response Evaluation during Definitive Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma
Authors: Yeom Jun Gi , Kim Jie-Hyun , Kim Jun Won , Cho Yeona , Lee Ik Jae , Lee Chang Geol , Chun Jaeyoung , Youn Young Hoon , Park Hyojin
Published: March 2021

The study aimed to investigate the clinical significance of interim response evaluation during definitive chemoradiotherapy (dCRT) in predicting overall treatment response and survival of patients with locally advanced esophageal squamous cell carcinoma (LAESCC). We reviewed 194 consecutive patients treated with dCRT for biopsy-confirmed LAESCC. A total of 51 patients met the inclusion criteria. Interim response was assessed by defining a region of interest in initial and adaptive computed tomography (CT) images and subsequently examined against the overall treatment response assessed three months after dCRT, treatment failure pattern, overall survival (OS), and progression-free survival (PFS) estimates. Reductions in both the area and maximal diameter of the primary lesion (p < 0.001; p < 0.001, respectively) and those of the metastatic lymph nodes (LN) (p = 0.002; p < 0.001, respectively) in interim analysis were significantly higher among patients who achieved complete response (CR) than among those who did not. OS was significantly longer among patients who showed ≥30% interim reduction in the area and maximal diameter of the primary lesion and among those who showed such reduction in both the primary lesion and LN. PFS was significantly longer in the patients with ≥30% interim reduction in the area of the primary lesion. In addition, the proportion of cases with locoregional failure began decreasing at interim response of 20% or higher, while the proportion of cases with outfield failure followed the opposite pattern, increasing at interim response of 20% or higher. Among patients treated with dCRT for LAESCC, interim response assessed using adaptive CT images correlated with overall CR and OS rates. The evaluation of tumor burden reduction during dCRT may help predict patient prognosis.
Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study
Authors: Terpos Evangelos , Ntanasis-Stathopoulos Ioannis , Katodritou Eirini , Kyrtsonis Marie-Christine , Douka Vassiliki , Spanoudakis Emmanouil , Papatheodorou Athanasios , Eleutherakis-Papaiakovou Evangelos , Kanellias Nikolaos , Gavriatopoulou Maria , Makras Polyzois , Kastritis Efstathios , Dimopoulos Meletios A
Published: March 2021

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.
Managing Difficulties of Microsatellite Instability Testing in Endometrial Cancer-Limitations and Advantages of Four Different PCR-Based Approaches
Authors: Siemanowski Janna , Schömig-Markiefka Birgid , Buhl Theresa , Haak Anja , Siebolts Udo , Dietmaier Wolfgang , Arens Norbert , Pauly Nina , Ataseven Beyhan , Büttner Reinhard , Merkelbach-Bruse Sabine
Published: March 2021

Microsatellite instability (MSI), a common alteration in endometrial cancers (EC) is known as a biomarker for immune checkpoint therapy response alongside screening for Lynch Syndrome (LS). However, former studies described challenging MSI profiles in EC hindering analysis by using MSI testing methods intensively validated for colorectal cancer (CRC) only. In order to reduce false negatives, this study examined four different PCR-based approaches for MSI testing using 25 EC samples already tested for mismatch repair deficiency (dMMR). In a follow up validation set of 75 EC samples previously tested both for MMR and MSI, the efficiency of a seven-marker system corresponding to the Idylla system was further analyzed. Both Bethesda and Promega marker panels require trained operators to overcome interpretation complexities caused by either hardly visible additional peaks of one and two nucleotides, or small shifts in microsatellite repeat length. Using parallel sequencing adjustment of bioinformatics is needed. Applying the Idylla MSI assay, an evaluation of input material is more crucial for reliable results and is indispensable. Following MMR deficiency testing as a first-line screening procedure, additional testing with a PCR-based method is necessary if inconclusive staining of immunohistochemistry (IHC) must be clarified.
Ionic Liquids in Catalysis
Authors: Maciejewski Hieronim
Published: March 2021

Ionic liquids play a larger and larger as well as more and more diversified role in catalysis [...]
Combined Iron-Loaded Zeolites and Ozone-Based Process for the Purification of Drinking Water in a Novel Hybrid Reactor: Removal of Faecal Coliforms and Arsenic
Authors: Ikhlaq Amir , Fatima Rida , Qazi Umair Yaqub , Javaid Rahat , Akram Asia , Ibn Shamsah Sami , Qi Fei
Published: March 2021

This study was carried out to provide a novel solution to treat drinking water at household levels, specifically removing arsenic (As) and faecal coliforms (microbes). In the current investigation, a synergistic iron-loaded zeolites and ozonation process (O3/Fe-ZA) was used for the first time in a modified batch reactor to remove coliform bacteria and arsenic in tap water. Moreover, the study utilizes the human health risk assessment model to confirm the health risk due to As intake in drinking water. The risk assessment study revealed a health risk threat among the residents suffering from the adverse effects of As through its intake in drinking water. Furthermore, the results also suggested that the O3/Fe-ZA process significantly removes faecal coliforms and As, when compared with single ozonation processes. Additionally, the ozone dose 0.2 mg/min and Fe-ZA dose of 10 g (in the O3/Fe-ZA process) gives the maximum removal efficiency of 100% within 15 min for faecal coliform removal. In 30 min, the removal efficiency of 88.4% was achieved at the ozone dose of 0.5 mg/min and 93% removal efficiency was achieved using 10 g Fe-ZA for the removal of As in the O3/Fe-ZA process. Hence, it was concluded that the O3/Fe-ZA process may be regarded as an effective method for removing faecal coliforms and As from drinking water compared to the single ozonation processes.
Effect of Time, Temperature and Stirring Rate Used in the First Step of the Synthesis of SBA-15 on Its Application as Reductor of Tars in Tobacco Smoke
Authors: Juárez-Serrano Nerea , Asensio Javier , Blasco Inmaculada , Beltrán Maribel , Marcilla Antonio
Published: March 2021

SBA-15 has been employed as a tobacco additive with the objective of reducing the toxic and carcinogenic components in tobacco smoke. The effect of the synthesis conditions (temperature, time, and stirring rate) on this application was studied in this paper. The SBA-15 was characterized (RDX, N2 adsorption isotherms, SEM and apparent density), mixed with the 3R4F reference tobacco, and smoked under standard conditions. The composition of the gas and condensed fractions also was analyzed. The morphology of the material plays an important role on this application and is highly influenced by the three variables studied. Long fibers show improved efficiency compared to short fibers. The tar reduction effect was improved when increasing the time of synthesis. Nevertheless, a maximum was observed with temperature (40 °C) and stirring rate (700 rpm). The optimal synthesis conditions obtained were 24 h, 40 °C and 700 rpm, yielding reductions as high as 68% for tar, 67% for nicotine, and 31% for CO. The scaling-up process has only been reported in terms of grams but never in a preindustrial scale (around 4 kg), and thus the results of this analysis show a promising material with properties and behavior similar with respect to the sample synthesized at laboratory scale.
Rab27a-Dependent Paracrine Communication Controls Dendritic Spine Formation and Sensory Responses in the Barrel Cortex
Authors: Zhang Longbo , Zhang Xiaobing , Hsieh Lawrence S. , Lin Tiffany V. , Bordey Angélique
Published: March 2021

Rab27a is an evolutionarily conserved small GTPase that regulates vesicle trafficking, and copy number variants of RAB27a are associated with increased risk of autism. However, the function of Rab27a on brain development is unknown. Here, we identified a form of paracrine communication that regulates spine development between distinct populations of developing cortical neurons. In the developing somatosensory cortex of mice, we show that decreasing Rab27a levels in late-born pyramidal neurons destined for layer (L) 2/3 had no cell-autonomous effect on their synaptic integration but increased excitatory synaptic transmission onto L4 neurons that receive somatosensory information. This effect resulted in an increased number of L4 neurons activated by whisker stimulation in juvenile mice. In addition, we found that Rab27a, the level of which decreases as neurons mature, regulates the release of small extracellular vesicles (sEVs) in developing neurons in vitro and decreasing Rab27a levels led to the accumulation of CD63-positive vesicular compartments in L2/3 neurons in vivo. Together, our study reveals that Rab27a-mediated paracrine communication regulates the development of synaptic connectivity, ultimately tuning responses to sensory stimulation, possibly via controlling the release of sEVs.
PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells
Authors: Rasmussen Marit , Tan Susanna , Somisetty Venkata S. , Hutin David , Olafsen Ninni Elise , Moen Anders , Anonsen Jan H. , Grant Denis M. , Matthews Jason
Published: March 2021

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.
Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly
Authors: Wang Weikan , Thomas Rachel , Oh Jiyoung , Su Dong-Ming
Published: March 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.