bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Impedance Estimation: Challenges and Considerations
Authors: de Oliveira Mateus M. , Aleixo Renato R. , Resende Denise F. , Silva Leandro R. M. , Salles Rafael S. , Duque Carlos A. , Ribeiro Paulo F.
Published: January 2021

The objective of this paper was to examine the dynamic impedance estimation of electrical systems from online measurements. The paper makes several considerations and highlights the challenges to obtain a precise estimation. Transducer equalization and harmonic synchrophasor estimation (HSpE) are reviewed and discussed. The use of online and adaptive equalization for transducers proves to be a viable solution for improving voltage transducer’s (VT’s) and current transducer’s (CT’s) frequency response. Additionally, the use of oversampling algorithms can mitigate the effects of noise in the HSpE. Furthermore, methods for harmonic impedance estimation are discussed. The independent component analysis ICA-based dynamic impedance estimation is proposed and results presented, which yields excellent agreement. Finally, harmonic modeling and simulation of injected harmonic currents are used to observe resonances through the amplification and attenuations and, consequently, the opportunity to confirm the system self and transfer impedances of a test system. Dynamic impedance estimation will continue to be a great challenge for the power systems engineer as the system complexity increases with the massive insertion of power electronic inverters and the associated required filtering. Real-time signal processing will be an effective tool to determine the dynamic self or transfer impedance.
Using a Cable-Driven Parallel Robot with Applications in 3D Concrete Printing
Authors: Tho Tuong Phuoc , Thinh Nguyen Truong
Published: January 2021

In construction, a large-scale 3D printing method for construction is used to build houses quickly, based on Computerized Aid Design. Currently, the construction industry is beginning to apply quite a lot of 3D printing technologies to create buildings that require a quick construction time and complex structures that classical methods cannot implement. In this paper, a Cable-Driven Parallel Robot (CDPR) is described for the 3D printing of concrete for building a house. The CDPR structures are designed to be suitable for 3D printing in a large workspace. A linear programming algorithm was used to quickly calculate the inverse kinematic problem with the force equilibrium condition for the moving platform; this method is suitable for the flexible configuration of a CDPR corresponding to the various spaces. Cable sagging was also analyzed by the Trust-Region-Dogleg algorithm to increase the accuracy of the inverse kinematic problem for controlling the robot to perform basic trajectory interpolation movements. The paper also covers the design and analysis of a concrete extruder for the 3D printing method. The analytical results are experimented with based on a prototype of the CDPR to evaluate the work ability and suitability of this design. The results show that this design is suitable for 3D printing in construction, with high precision and a stable trajectory printing. The robot configuration can be easily adjusted and calculated to suit the construction space, while maintaining rigidity as well as an adequate operating space. The actuators are compact, easy to disassemble and move, and capable of accommodating a wide variety of dimensions.
Partial Least Squares Improved Multivariate Adaptive Regression Splines for Visible and Near-Infrared-Based Soil Organic Matter Estimation Considering Spatial Heterogeneity
Authors: Wang Xiaomi , Yang Can , Zhou Mengjie
Published: January 2021

Under the influence of complex environmental conditions, the spatial heterogeneity of soil organic matter (SOM) is inevitable, and the relationship between SOM and visible and near-infrared (VNIR) spectra has the potential to be nonlinear. However, conventional VNIR-based methods for soil organic matter estimation cannot simultaneously consider the potential nonlinear relationship between the explanatory variables and predictors and the spatial heterogeneity of the relationship. Thus, the regional application of existing VNIR spectra-based SOM estimation methods is limited. This study combines the proposed partial least squares–based multivariate adaptive regression spline (PLS–MARS) method and a regional multi-variable associate rule mining and Rank–Kennard-Stone method (MVARC-R-KS) to construct a nonlinear prediction model to realize local optimality considering spatial heterogeneity. First, the MVARC-R-KS method is utilized to select representative samples and alleviate the sample global underrepresentation caused by spatial heterogeneity. Second, the PLS–MARS method is proposed to construct a nonlinear VNIR spectra-based estimation model with local optimization based on selected representative samples. PLS–MARS combined with the MVARC-R-KS method is illustrated and validated through a case study of Jianghan Plain in Hubei Province, China. Results showed that the proposed method far outweighs some available methods in terms of accuracy and robustness, suggesting the reliability of the proposed prediction model.
Risk Identification of FPSO Oil and Gas Processing System Based on an Improved FMEA Approach
Authors: Wang Longting , Sun Liping , Kang Jichuan , Wang Yanfu , Wang Haiqing
Published: January 2021

It is increasingly necessary to perform risk analysis in marine structures, to ensure system safety, as they are large and complex. In view of the shortcomings of failure mode and effect analysis (FMEA), a modified fuzzy TOPSIS (Technique for Order Preference by Similarity to an Ideal Solution) approach is proposed that is based on fuzzy evidence reasoning (FER), and considers the risk factor rating and relative weight. The presented method is used to prioritize the risk of equipment failure modes for the floating production storage and offloading system (FPSO) oil and gas processing system. The subjective weights and objective weights of occurrence (O), severity (S), and detectability (D) have been considered comprehensively. The subjective experience of the experts and the objective information reflected by the O, S, and D ratings are all included in the weights, making the ranking results closer to reality. The results can be scientific references for decision-makers in risk identification.
Clinical Study on the Ocular Manifestations in Patients with Obstructive Sleep Apnea Syndrome—Preliminary Results
Authors: Ciuntu Roxana Elena , Anton Nicoleta , Cantemir Alina , Alexa Anisia Iuliana , Bogdanici Camelia Margareta , Boişteanu Daniela , Vasilescu Alin , Danielescu Ciprian , Ghiga Gabriela , Ciuntu Bogdan Mihnea , Chiseliţă Dorin
Published: January 2021

Obstructive sleep apnea syndrome is a multisystemic disorder associated with a series of side effects. Obstructive sleep apnea syndrome (OSAS) includes hypoxemia and is correlated with an increased incidence for various neuronal conditions, including glaucoma, strokes, reduced mental ability, depressive disorders, peripheral neuropathy, and non-arteritic ischemic optic neuropathy. This study’s aims are the evaluation of the degree of ocular surface damage in obstructive sleep apnea patients (in the absence of the continuous positive airway pressure treatment) and the structural changes in the optic nerve, and to establish correlation between the degree of damage to the ocular surface (eye dryness by Schirmer test) and corneal biomechanics by ocular response analyzer. The subjects included in the study will be grouped as follows: a group of patients with glaucoma and obstructive sleep apnea syndrome that will be compared to patients with glaucoma only as well as identifying the evolution of structural changes in patients with glaucoma and sleep apnea syndrome. A prospective study included 65 eyes from 65 subjects diagnosed with obstructive sleep apnea (45 eyes of 45 subjects with glaucoma and OSAS as well as 20 subjects, 20 eyes with dry-eye syndrome and OSAS) who did not follow the continuous positive airway pressure treatment. The control group consisted of 45 subjects (45 eyes) with (mild or moderate) primary open-angle treated glaucoma without obstructive sleep apnea. All patients had ophthalmologic evaluations according to a standardized protocol. Moreover, respiratory functional parameters (apnea–hypopnea index—AHI) and the body mass index were recorded. Within the studied group, patients with mild or moderate primary open-angle glaucoma, with moderate or severe dry-eye syndrome, patients with floppy-eyelid syndrome, with optical non-arteritis ischemic neuropathy, and a patient with retinal central vein occlusion were identified. The increased rate of the apnea syndrome during sleep produces a severe disorder of the ocular surface and a retinal neuro-degenerative disorder. The eyes of patients with sleep apnea syndrome (SAS) and glaucoma have lower mean intraocular pressure than eyes with glaucoma without SAS. However, the mean C/D ratio in eyes with glaucoma correlates with the severity of SAS. There is a positive correlation between the severity of the apnea and the ocular disorder’s degree similar to the studies in the literature review. The joint cooperation between the sleep specialists and ophthalmologists can lead to the improvement of the vascular and ocular status for the obstructive sleep apnea patients.
Past, Present and Future Monitoring at the Vallcebre Landslide (Eastern Pyrenees, Spain)
Authors: Gili Josep A. , Moya Jose , Corominas Jordi , Crosetto Michele , Monserrat Oriol
Published: January 2021

Works carried out to monitor the displacements of the Vallcebre landslide (Pyrenees range, NE of Spain) since 1987 are presented. The landslide, which extends over an area of about 0.8 km2 and affects more than 20 × 106 m3, has experienced displacements of up to one meter per year in some points and periods. It has been periodically monitored since 1987, using a wide range of surface and in-hole techniques: triangulation with theodolite, Terrestrial Photogrammetry, Electronic Distance Measurement, GNSS-GPS, inclinometers, wire extensometers, piezometers, DInSAR (satellite) and GBSAR (terrestrial). The results obtained using new techniques are compared with those obtained with GNSS-GPS and a wire extensometer, and checked against fixed stable points. From this comparison, we conclude that even though wire extensometers and inclinometers may have the highest precision, in practice, all systems play potentially valuable roles in providing meaningful data for monitoring at different study stages. In the near future, we envisage the installation of a Distributed Fiber Optic array to monitor the risk with a certain space and time continuity. After the evaluation of the precision and advantages of the different methods, the complementary use of some of them is strongly recommended.
The Application of a Linear Microphone Array in the Quantitative Evaluation of the Blade Trailing-Edge Noise Reduction
Authors: Chen Weijie , Mao Luqin , Xiang Kangshen , Tong Fan , Qiao Weiyang
Published: January 2021

This paper concerns the application of a linear microphone array in the quantitative evaluation of blade trailing-edge (TE) noise reduction. The noise radiation from the blades with straight and serrated TEs is measured in an indoor open-jet wind tunnel. The array data are processed using the inverse method based on the Clean algorithm based on spatial source coherence (Clean-SC). In order to obtain correct application and achieve the best effect for the microphone array test, the computing software for array data reduction is firstly developed and assessed by Sarradj’s benchmark case. The assessment results show that the present array data processing method has a good accuracy with an error less than 0.5 dB in a wide frequency range. Then, a linear array with 32 microphones is designed to identify the noise source of a NACA65(12)-10 blade. The performance of the Clean-SC algorithm is compared with the Clean algorithm based on point spread functions (Clean-PSF) method for experimentally identifying the noise sources of the blade. The results show that there is about a 2 dB error when using the Clean-PSF algorithm due to the interference of different aerodynamic noise sources. Experimental studies are conducted to study the blade TE noise reduction using serrated TEs. The TE noise for the blade with and without sawtooth configurations is measured with the flow speeds from 20 m/s to 70 m/s, and the corresponding Reynolds numbers based on the chord are from 200,000 to 700,000. Parametric studies of the sawtooth amplitude and wavelength are conducted to understand the noise reduction law. It is observed that the TE noise reduction is sensitive to both the amplitude and wavelength. The flow speed also affects the noise reduction in the serrated TEs. To obtain the best noise suppression effect, the sawtooth configuration should be carefully designed according to the actual working conditions and airflow parameters.
Improving the Strategy of Maintaining Offshore Wind Turbines through Petri Net Modelling
Authors: Yan Rundong , Dunnett Sarah
Published: January 2021

In order to improve the operation and maintenance (O&M) of offshore wind turbines, a new Petri net (PN)-based offshore wind turbine maintenance model is developed in this paper to simulate the O&M activities in an offshore wind farm. With the aid of the PN model developed, three new potential wind turbine maintenance strategies are studied. They are (1) carrying out periodic maintenance of the wind turbine components at different frequencies according to their specific reliability features; (2) conducting a full inspection of the entire wind turbine system following a major repair; and (3) equipping the wind turbine with a condition monitoring system (CMS) that has powerful fault detection capability. From the research results, it is found that periodic maintenance is essential, but in order to ensure that the turbine is operated economically, this maintenance needs to be carried out at an optimal frequency. Conducting a full inspection of the entire wind turbine system following a major repair enables efficient utilisation of the maintenance resources. If periodic maintenance is performed infrequently, this measure leads to less unexpected shutdowns, lower downtime, and lower maintenance costs. It has been shown that to install the wind turbine with a CMS is helpful to relieve the burden of periodic maintenance. Moreover, the higher the quality of the CMS, the more the downtime and maintenance costs can be reduced. However, the cost of the CMS needs to be considered, as a high cost may make the operation of the offshore wind turbine uneconomical.
Experimental Parameter Study on Synthesis Gas Production by Steam-Oxygen Fluidized Bed Gasification of Sewage Sludge
Authors: Schmid Max , Hafner Selina , Scheffknecht Günter
Published: January 2021

The conversion of biogenic residues to fuels and chemicals via gasification and synthesis processes is a promising pathway to replace fossil carbon. In this study, the focus is set on sewage sludge gasification for syngas production. Experiments were carried out in a 20 kW fuel input bubbling fluidized bed facility with steam and oxygen as gasification agent. In-situ produced sewage sludge ash was used as bed material. The sensitivity of the key operation parameters gasifier temperature, oxygen ratio, steam to carbon ratio, and the space velocity on the syngas composition (H2, CO, CO2, CH4, CxHy, H2S, COS, NH3, and tars) was determined. The results show that the produced syngas has high H2 and CO concentrations of up to 0.37 m3 m−3 and 0.18 m3 m−3, respectively, and is thus suitable for synthesis of fuels and chemicals. By adjusting the steam to carbon ratio, the syngas’ H2 to CO ratio can be purposely tailored by the water gas shift reaction for various synthesis products, e.g., synthetic natural gas (H2/CO = 3) or Fischer–Tropsch products (H2/CO = 2). Also, the composition and yields of fly ash and bed ash are presented. Through the gasification process, the cadmium and mercury contents of the bed ash were drastically reduced. The ash is suitable as secondary raw material for phosphorous or phosphate fertilizer production. Overall, a broad database was generated that can be used for process simulation and process design.
Biomonitoring of Heavy Metals: The Unexplored Role of Marine Sessile Taxa
Authors: Roveta Camilla , Annibaldi Anna , Afghan Afghan , Calcinai Barbara , Di Camillo Cristina , Gregorin Chiara , Illuminati Silvia , Pulido Mantas Torcuato , Truzzi Cristina , Puce Stefania
Published: January 2021

Coastal areas are known to receive significant anthropogenic inputs, mainly deriving from metropolitan areas, industries, and activities related to tourism. Among these inputs, some trace elements are listed as priority pollutants in the European Water Framework Directive, due to their ability to bioaccumulate in organisms. Many studies have been conducted on heavy metals (HMs) accumulation and on their possible effects on different edible marine species. While the most studied sessile organisms are bivalves, in the current review, we focus our attention on other sessile taxa (sponges, cnidarians, bryozoans, polychaetes, cirripeds, and tunicates), proposed as bioindicators in coastal shallow waters. Although their potential as bioindicator tools has been repeatedly highlighted in the literature, these organisms are still poorly investigated and considered for monitoring. In this context, we analyze the available literature about this topic, in order to summarize the current knowledge and identify possible applications of these organisms in a bioremediation scenario.
Co-Seismic Ionospheric Disturbance with Alaska Strike-Slip Mw7.9 Earthquake on 23 January 2018 Monitored by GPS
Authors: Zhang Yongming , Liu Xin , Guo Jinyun , Shi Kunpeng , Zhou Maosheng , Wang Fangjian
Published: January 2021

The Mw7.9 Alaska earthquake at 09:31:40 UTC on 23 January 2018 occurred as the result of strike slip faulting within the shallow lithosphere of the Pacific plate. Global positioning system (GPS) data were used to calculate the slant total electron contents above the epicenter. The singular spectrum analysis (SSA) method was used to extract detailed ionospheric disturbance information, and to monitor the co-seismic ionospheric disturbances (CIDs) of the Alaska earthquake. The results show that the near-field CIDs were detected 8–12 min after the main shock, and the typical compression-rarefaction wave (N-shaped wave) appeared. The ionospheric disturbances propagate to the southwest at a horizontal velocity of 2.61 km/s within 500 km from the epicenter. The maximum amplitude of CIDs appears about 0.16 TECU (1TECU = 1016 el m−2) near the epicenter, and gradually decreases with the location of sub-ionospheric points (SIPs) far away from the epicenter. The attenuation rate of amplitude slows down as the distance between the SIPs and the epicenter increases. The direction of the CIDs caused by strike-slip faults may be affected by the horizontal direction of fault slip. The propagation characteristics of the ionospheric disturbance in the Alaska earthquake may be related to the complex conditions of focal mechanisms and fault location.
Role of Transportome in the Gills of Chinese Mitten Crabs in Response to Salinity Change: A Meta-Analysis of RNA-Seq Datasets
Authors: Malik Adeel , Kim Chang-Bae
Published: January 2021

Chinese mitten crab (CMC) or Eriocheir sinensis is a strong osmoregulator that can keep rigorous cellular homeostasis. CMC can flourish in freshwater, as well as seawater, habitats and represents the most important species for freshwater aquaculture. Salt stress can have direct effects on several stages (e.g., reproduction, molting, growth, etc.) of the CMC life cycle. To get a better overview of the genes involved in the gills of CMC under different salinity conditions, we conducted an RNA-Seq meta-analysis on the transcriptomes of four publicly available datasets. The meta-analysis identified 405 differentially expressed transcripts (DETs), of which 40% were classified into various transporter classes, including accessory factors and primary active transporters as the major transport classes. A network analysis of the DETs revealed that adaptation to salinity is a highly regulated mechanism in which different functional modules play essential roles. To the best of our knowledge, this study is the first to conduct a transcriptome meta-analysis of gills from crab RNA-Seq datasets under salinity. Additionally, this study is also the first to focus on the differential expression of diverse transporters and channels (transportome) in CMC. Our meta-analysis opens new avenues for a better understanding of the osmoregulation mechanism and the selection of potential transporters associated with salinity change.
Different Modulatory Effects of Four Methicillin-Resistant Staphylococcus aureus Clones on MG-63 Osteoblast-Like Cells
Authors: Musso Nicolò , Caruso Giuseppe , Bongiorno Dafne , Grasso Margherita , Bivona Dalida A. , Campanile Floriana , Caraci Filippo , Stefani Stefania
Published: January 2021

Staphylococcus aureus is a Gram-positive bacterium responsible for a variety of mild to life-threatening infections including bone infections such as osteomyelitis. This bacterium is able to invade and persist within non-professional phagocytic cells such as osteoblasts. In the present study, four different S. aureus strains, namely, 2SA-ST239-III (ST239), 5SA-ST5-II (ST5), 10SA-ST228-I (ST228), and 14SA-ST22-IVh (ST22), were tested for their ability to modulate cell viability in MG-63 osteoblast-like cells following successful invasion and persistence. Methicillin-sensitive S. aureus (MSSA) ATCC-12598-ST30 (ST30) was used as control strain. Despite being proven that ST30, ST239, and ST22 have a similar ability to internalize and persist in MG-63 osteoblast-like cells under our experimental conditions, we demonstrated that the observed decrease in cell viability was due to the different behavior of the considered strains, rather than the number of intracellular bacteria. We focused our attention on different biochemical cell functions related to inflammation, cell metabolism, and oxidative stress during osteoblast infections. We were able to show the following: (1) ST30 and ST239 were the only two clones able to persist and maintain their number in the hostile environment of the cell during the entire period of infection; (2) ST239 was the only clone able to significantly increase gene expression (3 and 24 h post-infection (p.i.)) and protein secretion (24 h p.i.) of both interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in MG-63 osteoblast-like cells; (3) the same clone determined a significant up-regulation of the transforming growth factorbeta 1 (TGF-β1) and of the metabolic marker glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNAs at 24 h p.i.; and (4) neither the MSSA nor the four methicillin-resistant S. aureus (MRSA) strains induced oxidative stress phenomena in MG-63 cells, although a high degree of variability was observed for the different clones with regard to the expression pattern of nuclear factor E2-related factor 2 (Nrf2) and its downstream gene heme oxygenase 1 (HO-1) activation. Our results may pave the way for an approach to S. aureus-induced damage, moving towards individualized therapeutic strategies that take into account the differences between MSSA and MRSA as well as the distinctive features of the different clones. This approach is based on a change of paradigm in antibiotic therapy involving a case-based use of molecules able to counteract pro-inflammatory cytokines activity such as selective cytokine signaling inhibitors (IL-6, TNF-α).
Changes in Resurgent Sodium Current Contribute to the Hyperexcitability of Muscles in Patients with Paramyotonia Congenita
Authors: Huang Chiung-Wei , Lai Hsing-Jung , Lin Pi-Chen , Lee Ming-Jen
Published: January 2021

Paramyotonia congenita (PMC) is a rare hereditary skeletal muscle disorder. The major symptom, muscle stiffness, is frequently induced by cold exposure and repetitive exercise. Mutations in human SCN4A gene, which encodes the α-subunit of Nav1.4 channel, are responsible for PMC. Mutation screening of SCN4A gene from two PMC families identified two missense mutations, p.T1313M and p.R1448H. To elucidate the electrophysiological abnormalities caused by the mutations, the p.T1313M, p.R1448H, and wild-type (WT) SCN4A genes were transient expressed on Chinese hamster ovary (CHO-K1) cells. The detailed study on the gating defects of the mutant channels using the whole-cell patch clamping technique was performed. The mutant Nav1.4 channels impaired the basic gating properties with increasing sustained and window currents during membrane depolarization and facilitated the genesis of resurgent currents during repolarization. The mutations caused a hyperpolarization shift in the fast inactivation and slightly enhanced the slow inactivation with an increase in half-maximal inactivation voltage. No differences were found in the decay kinetics of the tail current between mutant and WT channels. In addition to generating the larger resurgent sodium current, the time to peak in the mutant channels was longer than that in the WT channels. In conclusion, our results demonstrated that the mutations p.T1313M and p.R1448H in Nav1.4 channels can enhance fast inactivation, slow inactivation, and resurgent current, revealing that subtle changes in gating processes can influence the clinical phenotype.
Aptamer–Target–Gold Nanoparticle Conjugates for the Quantification of Fumonisin B1
Authors: Mirón-Mérida Vicente Antonio , González-Espinosa Yadira , Collado-González Mar , Gong Yun Yun , Guo Yuan , Goycoolea Francisco M.
Published: January 2021

Fumonisin B1 (FB1), a mycotoxin classified as group 2B hazard, is of high importance due to its abundance and occurrence in varied crops. Conventional methods for detection are sensitive and selective; however, they also convey disadvantages such as long assay times, expensive equipment and instrumentation, complex procedures, sample pretreatment and unfeasibility for on-site analysis. Therefore, there is a need for quick, simple and affordable quantification methods. On that note, aptamers (ssDNA) are a good alternative for designing specific and sensitive biosensing techniques. In this work, the assessment of the performance of two aptamers (40 and 96 nt) on the colorimetric quantification of FB1 was determined by conducting an aptamer–target incubation step, followed by the addition of gold nanoparticles (AuNPs) and NaCl. Although MgCl2 and Tris-HCl were, respectively, essential for aptamer 96 and 40 nt, the latter was not specific for FB1. Alternatively, the formation of Aptamer (96 nt)–FB1–AuNP conjugates in MgCl2 exhibited stabilization to NaCl-induced aggregation at increasing FB1 concentrations. The application of asymmetric flow field-flow fractionation (AF4) allowed their size separation and characterization by a multidetection system (UV-VIS, MALS and DLS online), with a reduction in the limit of detection from 0.002 µg/mL to 56 fg/mL.
Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent
Authors: Shang Chuquan , Hassan Bardes , Haque Moinul , Song Yuqi , Li Jing , Liu Dongzhe , Lipke Eva , Chen Will , Giuriato Sylvie , Lai Raymond
Published: January 2021

Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.
Bromamine T (BAT) Exerts Stronger Anti-Cancer Properties than Taurine (Tau)
Authors: Baliou Stella , Goulielmaki Maria , Ioannou Petros , Cheimonidi Christina , Trougakos Ioannis P. , Nagl Markus , Kyriakopoulos Anthony M. , Zoumpourlis Vassilis
Published: January 2021

Background: Taurine (Tau) ameliorates cancer pathogenesis. Researchers have focused on the functional properties of bromamine T (BAT), a stable active bromine molecule. Both N-bromotaurine (TauNHBr) and BAT exert potent anti-inflammatory properties, but the landscape remains obscure concerning the anti-cancer effect of BAT. Methods: We used Crystal Violet, colony formation, flow cytometry and Western blot experiments to evaluate the effect of BAT and Tau on the apoptosis and autophagy of cancer cells. Xenograft experiments were used to determine the in vivo cytotoxicity of either agent. Results: We demonstrated that both BAT and Tau inhibited the growth of human colon, breast, cervical and skin cancer cell lines. Among them, BAT exerted the greatest cytotoxic effect on both RKO and MDA-MB-468 cells. In particular, BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK½), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK½), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. In contrast, Tau exerted its cytotoxic effect by upregulating JNK½ forms, thus triggering mitochondrial apoptosis in RKO cells. Accordingly, colon cancer growth was impaired in vivo. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities.
Fibroblast Subsets in Intestinal Homeostasis, Carcinogenesis, Tumor Progression, and Metastasis
Authors: Dang Hao , Harryvan Tom J. , Hawinkels Lukas J. A. C.
Published: January 2021

In intestinal homeostasis, continuous renewal of the epithelium is crucial to withstand the plethora of stimuli which can damage the structural integrity of the intestines. Fibroblasts contribute to this renewal by facilitating epithelial cell differentiation as well as providing the structural framework in which epithelial cells can regenerate. Upon dysregulation of intestinal homeostasis, (pre-) malignant neoplasms develop, a process which is accompanied by (epi) genetic alterations in epithelial cells as well as phenotypic changes in fibroblast populations. In the context of invasive carcinomas, these fibroblast populations are termed cancer-associated fibroblasts (CAFs). CAFs are the most abundant cell type in the tumor microenvironment of colorectal cancer (CRC) and consist of various functionally heterogeneous subsets which can promote or restrain cancer progression. Although most previous research has focused on the biology of epithelial cells, accumulating evidence shows that certain fibroblast subsets can also importantly contribute to tumor initiation and progression, thereby possibly providing avenues for improvement of clinical care for CRC patients. In this review, we summarized the current literature on the emerging role of fibroblasts in various stages of CRC development, ranging from adenoma initiation to the metastatic spread of cancer cells. In addition, we highlighted translational and therapeutic perspectives of fibroblasts in the different stages of intestinal tumor progression.
Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia
Authors: K. Bhanumathy Kalpana , Balagopal Amrutha , Vizeacoumar Frederick S. , Vizeacoumar Franco J. , Freywald Andrew , Giambra Vincenzo
Published: January 2021

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.
Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination
Authors: Pérez-Romasanta Luis A. , González-Del Portillo Elisabet , Rodríguez-Gutiérrez Ana , Matías-Pérez Ángela
Published: January 2021

Stereotactic body radiotherapy (SBRT) is an emerging ablative modality for hepatocellular carcinoma (HCC). Most patients with HCC have advanced disease at the time of diagnosis, and therefore, are not candidates for definitive-intent therapies such as resection or transplantation. For this reason, various alternative local and regional therapies have been used to prevent disease progression, palliate symptoms, and delay liver failure. Stereotactic body radiation therapy is a non-invasive technique of delivering ablative doses of radiation to tumors while sparing normal or non-tumor hepatic tissue. Incorporation of SBRT in multidisciplinary HCC management is gradual, initially applied when other liver-directed therapies have failed or are contraindicated, and tried in combination with other locoregional or systemic therapies for more unfavorable conditions by more experienced teams. In order to improve SBRT therapeutic ratio, there has been much interest in augmenting the effect of radiation on tumors by combining it with chemotherapy, molecularly targeted therapeutics, nanoparticles, and immunotherapy. This review aims to synthesize available evidence to evaluate the clinical feasibility and efficacy of SBRT for HCC, and to explore novel radio-potentiation concepts by combining SBRT with novel therapeutics. It is expected that those approaches would result in improved therapeutic outcomes, even though many questions remain with regard to the optimal way to assemble treatments. Further trials are needed to evaluate and consolidate these promising therapies for HCC.
Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma
Authors: Fountzilas Elena , Eliades Alexia , Koliou Georgia-Angeliki , Achilleos Achilleas , Loizides Charalambos , Tsangaras Kyriakos , Pectasides Dimitrios , Sgouros Joseph , Papakostas Pavlos , Rallis Grigorios , Psyrri Amanda , Papadimitriou Christos , Oikonomopoulos Georgios , Ferentinos Konstantinos , Koumarianou Anna , Zarkavelis George , Dervenis Christos , Aravantinos Gerasimos , Bafaloukos Dimitrios , Kosmidis Paris , Papaxoinis George , Theochari Maria , Varthalitis Ioannis , Kentepozidis Nikolaos , Rigakos Georgios , Saridaki Zacharenia , Nikolaidi Adamantia , Christopoulou Athina , Fostira Florentia , Samantas Epaminontas , Kypri Elena , Ioannides Marios , Koumbaris George , Fountzilas George , Patsalis Philippos C.
Published: January 2021

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.
Fertility Preservation and Long-Term Monitoring of Gonadotoxicity in Girls, Adolescents and Young Adults Undergoing Cancer Treatment
Authors: Michalczyk Kaja , Cymbaluk-Płoska Aneta
Published: January 2021

Chemo- and radio-therapy can often affect reproductive organs impairing hormonal regulation, fertility, and sexual function. As cancer treatments become more effective and many patients have long term survival, concerns related to patient’s quality of life and reproductive health become relevant. It is especially important for girls and young females facing cancer therapy who have not yet started family planning. Chemotherapy protocols using alkylating agents and abdominal radiotherapy, which are frequently used in the treatment of childhood and adolescent cancer, can cause gonadal injury. The most common clinical manifests are ovarian hormone insufficiency, premature ovarian insufficiency, early menopause and infertility. In this review we assess current literature and summarize current recommendations on the reproductive function of girls and young females undergoing cancer treatment and their follow-up. Fertility preservation methods are discussed, including psychological and ethical considerations and barriers. Improvement of reproductive health and quality of life of adolescents and young adults (AYA) undergoing cancer treatment is an important issue. Further research should be continued to develop efficient and accessible methods for fertility preservation in young patients. An expert panel including oncologists, radiation oncologists, endocrinologists and gynecologists should always consider fertility preservation in pediatric, adolescent and AYA cancer patients, minding patients’ medical condition, cancer staging and potential risk of treatment-related gonadotoxicity.
Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican
Authors: Brunn David , Turkowski Kati , Günther Stefan , Weigert Andreas , Muley Thomas , Kriegsmann Mark , Winter Hauke , Dammann Reinhard H. , Stathopoulos Georgios T. , Thomas Michael , Guenther Andreas , Grimminger Friedrich , Pullamsetti Soni S. , Seeger Werner , Savai Rajkumar
Published: January 2021

Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
Heterogeneity of Response and Immune System Activity during Treatment with Nivolumab in Hepatocellular Carcinoma: Results from a Single-Institution Retrospective Analysis
Authors: Rapposelli Ilario Giovanni , De Matteis Serena , Lanuti Paola , Valgiusti Martina , Bartolini Giulia , Ulivi Paola , Marisi Giorgia , Pedica Federica , Burgio Valentina , Frassineti Giovanni Luca , Cascinu Stefano , Casadei-Gardini Andrea
Published: January 2021

Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options; in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite these promising results, an important limitation is the lack of prognostic and predictive factors that prevent provision of a tool for patient stratification in order to select the most appropriate strategy. Furthermore, response assessment can be challenging with IT due to peculiar patterns such as mixed responses or pseudoprogression. We analyzed biological and clinical features from the first 10 HCC patients treated with nivolumab in our institution. Analysis of patterns of response in CT assessment revealed complete response in pulmonary lesions, along with heterogeneous behavior in the liver and other organ lesions. Peripheral blood mononuclear cells (PBMC) analysis in the first four patients showed unique alterations in a patient with poor prognosis, both at baseline (lower percentage of effector T cells, higher percentage of natural killer T [NK/T] cells) and during treatment with nivolumab (decrease in nonclassical monocytes, increase in monocytic myeloid-derived suppressor cells [MO-MDSC]), suggesting a possible prognostic role for these features. Although obtained in a small cohort of patients, our results open a new perspective for understanding mechanisms underlying IT outcomes in HCC patients.
Immune-Checkpoint Inhibitors in B-Cell Lymphoma
Authors: Armengol Marc , Santos Juliana Carvalho , Fernández-Serrano Miranda , Profitós-Pelejà Núria , Ribeiro Marcelo Lima , Roué Gaël
Published: January 2021

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.
Enhancing Capsid Proteins Capacity in Plant Virus-Vector Interactions and Virus Transmission
Authors: Agranovsky Alexey
Published: January 2021

Vector transmission of plant viruses is basically of two types that depend on the virus helper component proteins or the capsid proteins. A number of plant viruses belonging to disparate groups have developed unusual capsid proteins providing for interactions with the vector. Thus, cauliflower mosaic virus, a plant pararetrovirus, employs a virion associated p3 protein, the major capsid protein, and a helper component for the semi-persistent transmission by aphids. Benyviruses encode a capsid protein readthrough domain (CP-RTD) located at one end of the rod-like helical particle, which serves for the virus transmission by soil fungal zoospores. Likewise, the CP-RTD, being a minor component of the luteovirus icosahedral virions, provides for persistent, circulative aphid transmission. Closteroviruses encode several CPs and virion-associated proteins that form the filamentous helical particles and mediate transmission by aphid, whitefly, or mealybug vectors. The variable strategies of transmission and evolutionary ‘inventions’ of the unusual capsid proteins of plant RNA viruses are discussed.