bluuebunny/crossref_metadata_2025 huggingface dataset:
Beneficial Role of Exercise in the Modulation of mdx Muscle Plastic Remodeling and Oxidative Stress
Authors: Frinchi Monica , Morici Giuseppe , Mudó Giuseppa , Bonsignore Maria , Di Liberto Valentina
Published: April 2021

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive lethal disorder caused by the lack of dystrophin, which determines myofibers mechanical instability, oxidative stress, inflammation, and susceptibility to contraction-induced injuries. Unfortunately, at present, there is no efficient therapy for DMD. Beyond several promising gene- and stem cells-based strategies under investigation, physical activity may represent a valid noninvasive therapeutic approach to slow down the progression of the pathology. However, ethical issues, the limited number of studies in humans and the lack of consistency of the investigated training interventions generate loss of consensus regarding their efficacy, leaving exercise prescription still questionable. By an accurate analysis of data about the effects of different protocol of exercise on muscles of mdx mice, the most widely-used pre-clinical model for DMD research, we found that low intensity exercise, especially in the form of low speed treadmill running, likely represents the most suitable exercise modality associated to beneficial effects on mdx muscle. This protocol of training reduces muscle oxidative stress, inflammation, and fibrosis process, and enhances muscle functionality, muscle regeneration, and hypertrophy. These conclusions can guide the design of appropriate studies on human, thereby providing new insights to translational therapeutic application of exercise to DMD patients.
To Weight or Not to Weight, That Is the Question: The Design of a Composite Indicator of Landscape Fragmentation
Authors: De Montis Andrea , Serra Vittorio , Calia Giovanna , Trogu Daniele , Ledda Antonio
Published: April 2021

Composite indicators (CIs), i.e., combinations of many indicators in a unique synthetizing measure, are useful for disentangling multisector phenomena. Prominent questions concern indicators’ weighting, which implies time-consuming activities and should be properly justified. Landscape fragmentation (LF), the subdivision of habitats in smaller and more isolated patches, has been studied through the composite index of landscape fragmentation (CILF). It was originally proposed by us as an unweighted combination of three LF indicators for the study of the phenomenon in Sardinia, Italy. In this paper, we aim at presenting a weighted release of the CILF and at developing the Hamletian question of whether weighting is worthwhile or not. We focus on the sensitivity of the composite to different algorithms combining three weighting patterns (equalization, extraction by principal component analysis, and expert judgment) and three indicators aggregation rules (weighted average mean, weighted geometric mean, and weighted generalized geometric mean). The exercise provides the reader with meaningful results. Higher sensitivity values signal that the effort of weighting leads to more informative composites. Otherwise, high robustness does not mean that weighting was not worthwhile. Weighting per se can be beneficial for more acceptable and viable decisional processes.
Evaluation of the Coherence of Polish Texts Using Neural Network Models
Authors: Telenyk Sergii , Pogorilyy Sergiy , Kramov Artem
Published: April 2021

Coherence evaluation of texts falls into a category of natural language processing tasks. The evaluation of texts’ coherence implies the estimation of their semantic and logical integrity; such a feature of a text can be utilized during the solving of multidisciplinary tasks (SEO analysis, medicine area, detection of fake texts, etc.). In this paper, different state-of-the-art coherence evaluation methods based on machine learning models have been analyzed. The investigation of the effectiveness of different methods for the coherence estimation of Polish texts has been performed. The impact of text’s features on the output coherence value has been analyzed using different approaches of a semantic similarity graph. Two neural networks based on LSTM layers and a pre-trained BERT model correspondingly have been designed and trained for the coherence estimation of input texts. The results obtained may indicate that both lexical and semantic components should be taken into account during the coherence evaluation of Polish documents; moreover, it is advisable to analyze corresponding documents in a sentence-by-sentence manner taking into account word order. According to the retrieved accuracy of the proposed neural networks, it can be concluded that suggested models may be used in order to solve typical coherence estimation tasks for a Polish corpus.
Perceptions and Resistance to Accept Smart Clothing: Moderating Effect of Consumer Innovativeness
Authors: Ju Naan , Lee Kyu-Hye
Published: April 2021

Despite positive expectations from different organizations, smart clothing has not spread to the public. This study surveyed 320 adults to identify multiple obstacles arising from the adoption of smart clothing. As a result, perceived risks and unavailability of smart clothes, which are innovative products, have increased innovation resistance to smart clothes. On the other hand, smart clothing improvement expectations have been shown to lower innovation resistance to smart clothing. This suggests that interest and goodwill in a particular technology or function have significant impact on consumers’ willingness to accept it. Next, we validated the moderating effect of consumer characteristics in the relationship between innovative characteristics of smart clothing and innovation resistance. As a result, consumers’ fashion innovativeness has been shown to play a role in strengthening innovation resistance to smart clothing that is affordable. It can be inferred that the more fashion-conscious consumers are, the more burdened they are to continue to purchase relatively expensive smart clothes as the trend changes. In conclusion, to spread smart clothing, it is necessary to decrease the consumers’ perceived risk and improve the performance, durability, and availability of smart clothing.
Nonlinear Dynamics of an Internally Resonant Base-Isolated Beam under Turbulent Wind Flow
Authors: Di Nino Simona , Zulli Daniele , Luongo Angelo
Published: April 2021

A base isolation system, aimed to passively control the nonlinear dynamics of an internally resonant tower, exposed to turbulent wind flow, is studied. A continuous visco-elastic beam, constrained at the bottom end by a nonlinear visco-elastic device and free at the top end, is considered. All the nonlinearities, structural, inertial and aeroelastic, these latter computed via the quasi-static theory, are accounted in the model. The interaction between self- and parametric excitations, triggered by the mean wind velocity and the turbulent component, respectively, are analyzed. The Multiple Scale Method is applied to the partial differential equations of motion, to investigate critical and post-critical behaviors, when two modes in internal 1:3 resonance are involved in the response. The first mode is found to lead the phenomenon, while the second mode is marginally involved. The effectiveness of the visco-elastic nonlinear isolation system is assessed, both in increasing the mean wind bifurcation value and in reducing the limit-cycle amplitude. The contribution of structural nonlinearities is found to weakly affect the response.
Multiple Visual-Semantic Embedding for Video Retrieval from Query Sentence
Authors: Nguyen Huy Manh , Miyazaki Tomo , Sugaya Yoshihiro , Omachi Shinichiro
Published: April 2021

Visual-semantic embedding aims to learn a joint embedding space where related video and sentence instances are located close to each other. Most existing methods put instances in a single embedding space. However, they struggle to embed instances due to the difficulty of matching visual dynamics in videos to textual features in sentences. A single space is not enough to accommodate various videos and sentences. In this paper, we propose a novel framework that maps instances into multiple individual embedding spaces so that we can capture multiple relationships between instances, leading to compelling video retrieval. We propose to produce a final similarity between instances by fusing similarities measured in each embedding space using a weighted sum strategy. We determine the weights according to a sentence. Therefore, we can flexibly emphasize an embedding space. We conducted sentence-to-video retrieval experiments on a benchmark dataset. The proposed method achieved superior performance, and the results are competitive to state-of-the-art methods. These experimental results demonstrated the effectiveness of the proposed multiple embedding approach compared to existing methods.
Fabrication of Eco-Friendly Graphene Nanoplatelet Electrode for Electropolishing and Its Properties
Authors: Jeong Junyoung , Yoon Wanjun , Chung Bongjin , Jeon Giyoung , Ryu Seongwoo
Published: April 2021

Electropolishing is one of the most widely applied metal polishing techniques for passivating and deburring metal parts. Copper is often used as cathode electrode for electropolishing due to its low electrical resistance and low flow values. However, during the electropolishing process, elution of the cathode electrode caused by the electrolyte and remaining oxygen gas also causes critical water pollution and inhibits electropolishing efficiency. Therefore, to achieve an efficient and eco-friendly electropolishing process, development of a highly corrosion resistive and conductive electrode is necessary. We developed a highly oriented graphene nanoplatelet (GNP) electrode that minimizes water pollution in the electropolishing process. We functionalized GNP by a one-step mass-productive ball-milling process and non-covalent melamine functionalization. Melamine is an effective amphiphilic molecule that enhances dispersibility and nematic liquid crystal phase transformation of GNP. The functionalization mechanism and the material interaction were confirmed by Raman spectroscopy after high-speed shear printing. After the electropolishing process by melamine-functionalized GNP electrodes, 304 stainless steel samples were noticeably polished as copper electrodes and elution of carbon was over 50 times less than was the case when using copper electrodes. This electropolishing performance of a highly oriented GNP electrode indicates that melamine-functionalized GNP has great potential for eco-friendly electropolishing applications.
Assessment of AEC Students’ Performance Using BIM-into-VR
Authors: Alizadehsalehi Sepehr , Hadavi Ahmad , Huang Joseph Chuenhuei
Published: April 2021

Building Information Modeling (BIM) and Virtual reality (VR) have attracted growing attention within the architecture, engineering, and construction (AEC) industry in recent years. Integration of BIM and VR technology can develop workflow efficiency through enhanced common understanding and prepare students in architecture and engineering programs to become leaders of the AEC industry. However, the current shortage of AEC professionals trained in BIM and VR is still a barrier to collaborative working practice in this industry. This paper reviews previous work on the BIM, VR, and BIM-into-VR in AEC education/training to bridge this gap. It also presents an advanced framework to clarify creating and using the BIM model into VR workflow in the AEC industry through the integrated definition function (IDEF0) model. The authors further evaluated the BIM-into-VR applications in literature and real-life by surveying students’ learning performance in terms of eight characteristics relevant to the VR environment and students’ performance within two projects, one involving the “NASA Mars Habitat Project” and the other involving the “Norris Center Project” at Northwestern University. The results confirmed that BIM-into-VR usability and efficiency in improving students’ main learning performance characteristics: Learnability, Interoperability, Visualization, Real-world, Interaction, Creativity, Motivation, and Comfort. This study addresses the advantages of using BIM-into-VR in AEC programs. It also offers suggestions to AEC educators and students in implementing BIM-into-VR in different courses and creating a roadmap for their future as professionals in the AEC industry.
Analysis of Macroscopic Traffic Network Impacted by Structural Damage to Bridges from Earthquakes
Authors: Cho Joongmin , Lee Young-Joo , Lee Seongkwan Mark , Song Ki Han , Suh Wonho
Published: April 2021

Highway systems play a key role in providing mobility to society, especially during emergency situations, including earthquakes. Bridges in highway systems are susceptible to damage from earthquakes, causing traffic capacity loss leading to a serious impact on surrounding areas. To better prepare for such scenarios, it is important to estimate capacity loss and traffic disruptions from earthquakes. For this purpose, a traffic-capacity-analysisbased methodology was developed to model the performance of a transportation network immediately following an earthquake using a macroscopic multi-level urban traffic planning simulation model EMME4. This method employs the second order linear approximation (SOLA) traffic assignment and calculates total system travel time for various capacity loss scenarios due to bridge damage from earthquakes. It has been applied to Pohang City in Korea to evaluate the performance of traffic networks in various situations. The results indicate a significant increase in travel time and a decrease in travel speed as the intensity of an earthquake increases. However, the impact on traffic volume varies depending on the bridges. It is assumed that the location of the bridges and traffic routing patterns might be the main reason. The results are expected to help estimate the impact on transportation networks when earthquakes cause traffic capacity loss on bridges.
A Partially Interpretable Adaptive Softmax Regression for Credit Scoring
Authors: Munkhdalai Lkhagvadorj , Ryu Keun Ho , Namsrai Oyun-Erdene , Theera-Umpon Nipon
Published: April 2021

Credit scoring is a process of determining whether a borrower is successful or unsuccessful in repaying a loan using borrowers’ qualitative and quantitative characteristics. In recent years, machine learning algorithms have become widely studied in the development of credit scoring models. Although efficiently classifying good and bad borrowers is a core objective of the credit scoring model, there is still a need for the model that can explain the relationship between input and output. In this work, we propose a novel partially interpretable adaptive softmax (PIA-Soft) regression model to achieve both state-of-the-art predictive performance and marginally interpretation between input and output. We augment softmax regression by neural networks to make it adaptive for each borrower. Our PIA-Soft model consists of two main components: linear (softmax regression) and non-linear (neural network). The linear part explains the fundamental relationship between input and output variables. The non-linear part serves to improve the prediction performance by identifying the non-linear relationship between features for each borrower. The experimental result on public benchmark datasets shows that our proposed model not only outperformed the machine learning baselines but also showed the explanations that logically related to the real-world.
Identification of Key Genes Related to the Prognosis of Esophageal Squamous Cell Carcinoma Based on Chip Re-Annotation
Authors: Wang Meiqi , Liu Dan , Huang Yunchuanxiang , Jiang Ziyi , Wu Feng , Cen Yu , Ma Lan
Published: April 2021

Esophageal cancer (EC) is one of the deadliest cancers worldwide. However, reliable biomarkers for early diagnosis, or those for the prognosis of therapy, remain unfulfilled goals for its subtype esophageal squamous cell carcinoma (ESCC). The purpose of this study was to identify reliable biomarkers for the diagnosis and prognosis of ESCC by gene chip re-annotation technique and downstream bioinformatics analysis. In our research, the GSE53624 dataset was downloaded from the GEO database. Then, we reannotated the gene expression probe and obtained the gene expression matrix. Differential expressed genes (DEGs) were found by R packages and they were subjected to Gene Ontology enrichment analysis and protein–protein interaction (PPI) network construction. As a result, a total of 28,885 mRNA probes were reannotated, among which 210 down-regulated and 80 up-regulated DEGs were screened out. By combining these genes set in clinical prognosis information and Western blot analysis, we found four genes with diagnostic and prognostic significance, including MMP13, SPP1, MMP10, and COL1A1. Furthermore, markers of infiltrating immune cells exhibited different DEG-related immune infiltration patterns.
Water-Soluble Ions in Atmospheric Aerosol Measured in a Semi-Arid and Chemical-Industrialized City, Northwest China
Authors: Jiang Huimin , Li Zhongqin , Wang Feiteng , Zhou Xi , Wang Fanglong , Ma Shan , Zhang Xin
Published: April 2021

We investigated water-soluble ions (WSIs) of aerosol samples collected from 2016 to 2017 in Lanzhou, a typical semi-arid and chemical-industrialized city in Northwest China. WSIs concentration was higher in the heating period (35.68 ± 19.17 μg/m3) and lower in the non-heating period (12.45 ± 4.21 μg/m3). NO3−, SO42−, NH4+ and Ca2+ were dominant WSIs. The concentration of SO42− has decreased in recent years, while the NO3− level was increasing. WSIs concentration was affected by meteorological factors. The sulfur oxidation and nitrogen oxidation ratios (SOR and NOR) exceeded 0.1, inferring the vital contribution of secondary transformation. Meanwhile higher O3 concentration and temperature promoted the homogeneous reaction of SO2. Lower temperature and high relative humidity (RH) were more suitable for heterogeneous reactions of NO2. Three-phase cluster analysis illustrated that the anthropogenic source ions and natural source ions were dominant WSIs during the heating and non-heating periods, respectively. The backward trajectory analysis and the potential source contribution function model indicated that Lanzhou was strongly influenced by the Hexi Corridor, northeastern Qinghai–Tibetan Plateau, northern Qinghai province, Inner Mongolia Plateau and its surrounding cities. This research will improve our understanding of the air quality and pollutant sources in the industrial environment.
A Spherical Fuzzy Analytic Hierarchy Process (SF-AHP) and Combined Compromise Solution (CoCoSo) Algorithm in Distribution Center Location Selection: A Case Study in Agricultural Supply Chain
Authors: Kieu Phan Thuy , Nguyen Van Thanh , Nguyen Viet Tinh , Ho Thanh Phong
Published: April 2021

Logistics is an important service sector, contributing to improving the competitiveness of the economy. Therefore, along with increasing the application of technology and effective business models, it is necessary to increase the connectivity of the infrastructure systems of industrial parks, roads, and seaports of regions and the country. Over the past decades, Vietnamese businesses have been step-by-step going through many stages from production, packaging, quality, hygiene, and safety to grasping new stages in the domestic and global value chain. In many industries, businesses are increasing the content of their own designs, exploiting brands, and approaching consumption networks in the target market. The role of the distribution center is becoming more and more important in ensuring a seamless and flawless supply chain. In particular, the distribution center is the most sensitive contact point between supply and demand in each enterprise. Therefore, the key mission of a distribution center is to reconcile supply and demand requirements. Distribution center location selection problems usually involve multiple quantitative and qualitative criteria that the decision maker must take into account for assessing the symmetrical impact of the criteria to reach the most accurate result. In this study, the authors propose a hybrid MCDM model based on Spherical Fuzzy Analytic Hierarchy Process (SF-AHP) and Combined Compromise Solution (CoCoSo) Algorithm to support the distribution location selection problem of perishable agricultural products. The proposed model is then applied to the numerical case study of the sweet potato product of the Mekong Delta region of Vietnam to demonstrate the feasibility of the model. The contribution of this research is to propose an MCDM model for improving the efficiency of the agricultural supply chain through selecting a location distribution center. This proposed model can be applied to the agricultural supply chain around the world.
Octreotide-Targeted Lcn2 siRNA PEGylated Liposomes as a Treatment for Metastatic Breast Cancer
Authors: Gote Vrinda , Pal Dhananjay
Published: April 2021

Lcn2 overexpression in metastatic breast cancer (MBC) can lead to cancer progression by inducing the epithelial-to-mesenchymal transition and enhancing tumor angiogenesis. In this study, we engineered a PEGylated liposomal system encapsulating lipocalin 2 (Lcn2) small interfering RNA (Lcn2 siRNA) for selective targeting MBC cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. The PEGylated liposomes were decorated with octreotide (OCT) peptide. OCT is an octapeptide analog of somatostatin growth hormone, having affinity for somatostatin receptors, overexpressed on breast cancer cells. Optimized OCT-targeted Lcn2 siRNA encapsulated PEGylated liposomes (OCT-Lcn2-Lipo) had a mean size of 152.00 nm, PDI, 0.13, zeta potential 4.10 mV and entrapment and loading efficiencies of 69.5% and 7.8%, respectively. In vitro uptake and intracellular distribution of OCT-Lcn2-Lipo in MCF-7 and MDA-MB-231 and MCF-12A cells demonstrated higher uptake for the OCT-targeted liposomes at 6 h by flow cytometry and confocal microscopy. OCT-Lcn2-lipo could achieve approximately 55−60% silencing of Lcn2 mRNA in MCF-7 and MDA-MB-231 cells. OCT-Lcn2-Lipo also demonstrated in vitro anti-angiogenic effects in MCF-7 and MDA-MB-231 cells by reducing VEGF-A and reducing the endothelial cells (HUVEC) migration levels. This approach may be useful in inhibiting angiogenesis in MBC.
A Uremic Goat Model Created by Subtotal Renal Artery Embolization and Gentamicin
Authors: van Gelder Maaike K. , de Vries Joost C. , Ahmed Sabbir , Monninkhof Anneke S. , de Kort Gérard A. P. , Vonken Evert-Jan P. A. , Hazenbrink Diënty H. M. , Vaessen Koen R. D. , Nguyen Tri Q. , Verhaar Marianne C. , Joles Jaap A. , Gerritsen Karin G. F.
Published: April 2021

A large animal model of (end-stage) kidney disease (ESKD) is needed for the preclinical testing of novel renal replacement therapies. This study aimed to create stable uremia via subtotal renal artery embolization in goats and induce a temporary further decline in kidney function by administration of gentamicin. Renal artery embolization was performed in five Dutch white goats by infusing polyvinyl alcohol particles in branches of the renal artery, aiming for the embolization of ~80% of one kidney and complete embolization of the contralateral kidney. Gentamicin was administered to temporarily further increase the plasma concentrations of uremic toxins. After initial acute kidney injury, urea and creatinine plasma concentrations stabilized 1.5 ± 0.7 months post-embolization and remained elevated (12 ± 1.4 vs. 5.6 ± 0.8 mmol/L and 174 ± 45 vs. 65 ± 5.6 µmol/L, resp.) during follow-up (16 ± 6 months). Gentamicin induced temporary acute-on-chronic kidney injury with a variable increase in plasma concentrations of small solutes (urea 29 ± 15 mmol/L, creatinine 841 ± 584 µmol/L, phosphate 2.2 ± 0.3 mmol/L and potassium 5.0 ± 0.6 mmol/L) and protein-bound uremic toxins representative of patients with ESKD. A uremic goat model characterized by stable moderate uremia was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by the administration of gentamicin, allowing preclinical in vivo validation of novel renal replacement technologies.
Lymphatic Senescence: Current Updates and Perspectives
Authors: Filelfi Sebastian Lucio , Onorato Alberto , Brix Bianca , Goswami Nandu
Published: April 2021

Lymphatic flow is necessary for maintenance of vital physiological functions in humans and animals. To carry out optimal lymphatic flow, adequate contractile activity of the lymphatic collectors is necessary. Like in all body systems, aging has also an effect on the lymphatic system. However, limited knowledge is available on how aging directly affects the lymphatic system anatomy, physiology and function. We investigated how senescence leads to alterations in morphology and function of the lymphatic vessels. We used the strategy of a review to summarize the scientific literature of studies that have been published in the area of lymphatic senescence. Searches were carried out on PubMed and Web of Science using predefined search queries. We obtained an initial set of 1060 publications. They were filtered to 114 publications based on strict inclusion and exclusion criteria. Finally, the most appropriate 57 studies that specifically addressed lymphatic senescence have been selected for the preparation of this review. Analysis of the literature showed that lymphatic senescence is associated with alterations in lymphatic muscles and nerve fibers, lymphatic glycocalyx function of lymphatic endothelial cells, effects of chronic ultraviolet light exposure and oxidative stress as well as changes in lymphatic pump, acute inflammation responses and immune function. The current review underscores the relevance of the understudied area of lymphatic senescence. Continued research on the impact of aging on the structure and function of the lymphatic vasculature is needed to provide further insights to develop innovative clinical diagnostic—and treatment—modalities as well as to reduce the morbidity associated with diseases related to the lymphatic system.
Effects of A6E Mutation on Protein Expression and Supramolecular Assembly of Yeast Asparagine Synthetase
Authors: Surasiang Thunyarat , Noree Chalongrat
Published: April 2021

Asparagine synthetase deficiency (ASD) has been found to be caused by certain mutations in the gene encoding human asparagine synthetase (ASNS). Among reported mutations, A6E mutation showed the greatest reduction in ASNS abundance. However, the effect of A6E mutation has not yet been tested with yeast asparagine synthetase (Asn1/2p). Here, we constructed a yeast strain by deleting ASN2 from its genome, introducing the A6E mutation codon to ASN1, along with GFP downstream of ASN1. Our mutant yeast construct showed a noticeable decrease of Asn1p(A6E)-GFP levels as compared to the control yeast expressing Asn1p(WT)-GFP. At the stationary phase, the A6E mutation also markedly lowered the assembly frequency of the enzyme. In contrast to Asn1p(WT)-GFP, Asn1p(A6E)-GFP was insensitive to changes in the intracellular energy levels upon treatment with sodium azide during the log phase or fresh glucose at the stationary phase. Our study has confirmed that the effect of A6E mutation on protein expression levels of asparagine synthetase is common in both unicellular and multicellular eukaryotes, suggesting that yeast could be a model of ASD. Furthermore, A6E mutation could be introduced to the ASNS gene of acute lymphoblastic leukemia patients to inhibit the upregulation of ASNS by cancer cells, reducing the risk of developing resistance to the asparaginase treatment.
The Myokine Irisin Promotes Osteogenic Differentiation of Dental Bud-Derived MSCs
Authors: Posa Francesca , Colaianni Graziana , Di Cosola Michele , Dicarlo Manuela , Gaccione Francesco , Colucci Silvia , Grano Maria , Mori Giorgio
Published: April 2021

The myokine irisin, well known for its anabolic effect on bone tissue, has been demonstrated to positively act on osteoblastic differentiation processes in vitro. Mesenchymal stem cells (MSCs) have captured great attention in precision medicine and translational research for several decades due to their differentiation capacity, potent immunomodulatory properties, and their ability to be easily cultured and manipulated. Dental bud stem cells (DBSCs) are MSCs, isolated from dental tissues, that can effectively undergo osteoblastic differentiation. In this study, we analyzed, for the first time, the effects of irisin on DBSC osteogenic differentiation in vitro. Our results indicated that DBSCs were responsive to irisin, showed an enhanced expression of osteocalcin (OCN), a late marker of osteoblast differentiation, and displayed a greater mineral matrix deposition. These findings lead to deepening the mechanism of action of this promising molecule, as part of osteoblastogenesis process. Considering the in vivo studies of the effects of irisin on skeleton, irisin could improve bone tissue metabolism in MSC regenerative procedures.
Structure and Dynamics of an Archeal Monoglyceride Lipase from Palaeococcus ferrophilus as Revealed by Crystallography and In Silico Analysis
Authors: Labar Geoffray , Brandt Nathalie , Flaba Amaury , Wouters Johan , Leherte Laurence
Published: April 2021

The crystallographic analysis of a lipase from Palaeococcus ferrophilus (PFL) previously annotated as a lysophospholipase revealed high structural conservation with other monoglyceride lipases, in particular in the lid domain and substrate binding pockets. In agreement with this observation, PFL was shown to be active on various monoacylglycerols. Molecular Dynamics (MD) studies performed in the absence and in the presence of ligands further allowed characterization of the dynamics of this system and led to a systematic closure of the lid compared to the crystal structure. However, the presence of ligands in the acyl-binding pocket stabilizes intermediate conformations compared to the crystal and totally closed structures. Several lid-stabilizing or closure elements were highlighted, i.e., hydrogen bonds between Ser117 and Ile204 or Asn142 and its facing amino acid lid residues, as well as Phe123. Thus, based on this complementary crystallographic and MD approach, we suggest that the crystal structure reported herein represents an open conformation, at least partially, of the PFL, which is likely stabilized by the ligand, and it brings to light several key structural features prone to participate in the closure of the lid.
The Most Competent Plant-Derived Natural Products for Targeting Apoptosis in Cancer Therapy
Authors: Rajabi Sadegh , Maresca Marc , Yumashev Alexei Valerievich , Choopani Rasool , Hajimehdipoor Homa
Published: April 2021

Cancer is a challenging problem for the global health community, and its increasing burden necessitates seeking novel and alternative therapies. Most cancers share six basic characteristics known as “cancer hallmarks”, including uncontrolled proliferation, refractoriness to proliferation blockers, escaping apoptosis, unlimited proliferation, enhanced angiogenesis, and metastatic spread. Apoptosis, as one of the best-known programmed cell death processes, is generally promoted through two signaling pathways, including the intrinsic and extrinsic cascades. These pathways comprise several components that their alterations can render an apoptosis-resistance phenotype to the cell. Therefore, targeting more than one molecule in apoptotic pathways can be a novel and efficient approach for both identifying new anticancer therapeutics and preventing resistance to therapy. The main purpose of this review is to summarize data showing that various plant extracts and plant-derived molecules can activate both intrinsic and extrinsic apoptosis pathways in human cancer cells, making them attractive candidates in cancer treatment.
Imaging of Inflammation in Spinal Cord Injury: Novel Insights on the Usage of PFC-Based Contrast Agents
Authors: Garello Francesca , Boido Marina , Miglietti Martina , Bitonto Valeria , Zenzola Marco , Filippi Miriam , Arena Francesca , Consolino Lorena , Ghibaudi Matilde , Terreno Enzo
Published: April 2021

Labeling of macrophages with perfluorocarbon (PFC)-based compounds allows the visualization of inflammatory processes by 19F-magnetic resonance imaging (19F-MRI), due to the absence of endogenous background. Even if PFC-labeling of monocytes/macrophages has been largely investigated and used, information is lacking about the impact of these agents over the polarization towards one of their cell subsets and on the best way to image them. In the present work, a PFC-based nanoemulsion was developed to monitor the course of inflammation in a model of spinal cord injury (SCI), a pathology in which the understanding of immunological events is of utmost importance to select the optimal therapeutic strategies. The effects of PFC over macrophage polarization were studied in vitro, on cultured macrophages, and in vivo, in a mouse SCI model, by testing and comparing various cell tracking protocols, including single and multiple administrations, the use of MRI or Point Resolved Spectroscopy (PRESS), and application of pre-saturation of Kupffer cells. The blood half-life of nanoemulsion was also investigated by 19F Magnetic Resonance Spectroscopy (MRS). In vitro and in vivo results indicate the occurrence of a switch towards the M2 (anti-inflammatory) phenotype, suggesting a possible theranostic function of these nanoparticles. The comparative work presented here allows the reader to select the most appropriate protocol according to the research objectives (quantitative data acquisition, visual monitoring of macrophage recruitment, theranostic purpose, rapid MRI acquisition, etc.). Finally, the method developed here to determine the blood half-life of the PFC nanoemulsion can be extended to other fluorinated compounds.
A Sensor Designed to Record Underwater Irradiance with Concern for a Shark’s Spectral Sensitivity
Authors: Klimley A. Peter
Published: April 2021

To ascertain how scalloped hammerhead sharks make nightly migrations to their feeding grounds as many as 20 km from their daytime abode, a seamount, a sensor was developed that measured irradiance intensity within the spectral range and sensitivity of the vision of the species. Could the sharks guide their movements by sensing the polarity of irradiation energy radiated from the sun or moon that penetrated into the oceanic depths? Two sensory receptors, cones and rods, are present in the retina of sharks to enable them to see both during daytime and nighttime. The peak sensitivity of the cones is red-shifted due to the presence of these wavelengths during the former period, while their response is linear under the range of the high light levels also present at this time; the peak sensitivity of rods is blue-shifted due to the presence of these wavelengths during dawn, dusk, and nighttime and is linear over the complementary range of low light levels. Spectral response curves for these two receptors were determined for sharks, and an attempt was made to match those of the sensors to the shark’s wavelength perception. The first sensor was matched to the photopic range using a photocell covered with a red-shifted gel filter; the second was matched to the scotopic range using a blue-shifted gel filter.
Renal Cell Carcinoma with or without Tumor Thrombus Invading the Liver, Pancreas and Duodenum
Authors: González Javier , Gaynor Jeffrey J. , Ciancio Gaetano
Published: April 2021

Background: The purpose of this study is to report the outcomes of a series of patients with locally advanced renal cell carcinoma (RCC) who underwent radical nephrectomy, tumor thrombectomy, and visceral resection. Patients and methods: 18 consecutive patients who underwent surgical treatment in the period 2003-2019 were included. Neoplastic extension was found extending into the pancreas, duodenum, and liver in 9(50%), 2(11.1%), and 7(38.8%) patients, respectively. Seven patients (38.8%) presented also inferior vena cava tumor thrombus level I (n = 3), II (n = 2), or III (n = 2). The resection was tailored according to the degree of invasiveness. Demographics, clinical presentation, disease characteristics, surgical details, 30-day postoperative complications, and overall survival (OS) were analyzed. Results: Median age was 56 years (range: 40–76). Median tumor size was 14.5 cm (range, 8.8–22), and 10 cm (range: 4–15) for those cases with pancreatico-duodenal and liver involvement, respectively. Median estimated blood loss (EBL) was 475 mL (range: 100–4000) and resulted higher for those cases requiring thrombectomy (300 mL vs. 750 mL). Nine patients (50%) required transfusions with a median requirement of 4 units (range: 2–8). No perioperative deaths were registered in the first 30 days. Overall complication rate was 44.4%. Major complications were detected in 6/18 patients (33.3%). Overall median follow-up was 24 months (range: 0–108). Five-year OS (actuarial) rate was 89.9% and 75%, for 9/11 patients with pancreatico-duodenal involvement and 6/7 patients with liver invasion, respectively. Conclusion: Our series establishes the technical feasibility of this procedure with acceptable complication rates, no deaths, and potential for durable response.
Pharmacological Regulation of Tumor Hypoxia in Model Murine Tumors and Spontaneous Canine Tumors
Authors: Benej Martin , Wu Jinghai , Kreamer McKenzie , Kery Martin , Corrales-Guerrero Sergio , Papandreou Ioanna , Williams Terence M. , Li Zihai , Graves Edward E. , Selmic Laura E. , Denko Nicholas C.
Published: April 2021

Background: Hypoxia is found in many solid tumors and is associated with increased disease aggressiveness and resistance to therapy. Reducing oxygen demand by targeting mitochondrial oxidative metabolism is an emerging concept in translational cancer research aimed at reducing hypoxia. We have shown that the U.S. Food and Drug Administration (FDA)-approved drug papaverine and its novel derivative SMV-32 are potent mitochondrial complex I inhibitors. Methods: We used a dynamic in vivo luciferase reporter system, pODD-Luc, to evaluate the impact of pharmacological manipulation of mitochondrial metabolism on the levels of tumor hypoxia in transplanted mouse tumors. We also imaged canine patients with blood oxygen level-dependent (BOLD) MRI at baseline and one hour after a dose of 1 or 2 mg/kg papaverine. Results: We showed that the pharmacological suppression of mitochondrial oxygen consumption (OCR) in tumor-bearing mice increases tumor oxygenation, while the stimulation of mitochondrial OCR decreases tumor oxygenation. In parallel experiments in a small series of spontaneous canine sarcomas treated at The Ohio State University (OSU) Veterinary Medical Center, we observed a significant increase in BOLD signals indicative of an increase in tumor oxygenation of up to 10–50 mm HgO2. Conclusion: In both transplanted murine tumors and spontaneous canine tumors we found that decreasing mitochondrial metabolism can decrease tumor hypoxia, potentially offering a therapeutic advantage.
Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis
Authors: Bartlett Alexandra Q. , Pennock Nathan D. , Klug Alex , Schedin Pepper
Published: April 2021

In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.
The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma
Authors: Chalada Melissa , Ramlogan-Steel Charmaine A. , Dhungel Bijay P. , Layton Christopher J. , Steel Jason C.
Published: April 2021

Uveal melanoma (UM) is currently classified by the World Health Organisation as a melanoma caused by risk factors other than cumulative solar damage. However, factors relating to ultraviolet radiation (UVR) susceptibility such as light-coloured skin and eyes, propensity to burn, and proximity to the equator, frequently correlate with higher risk of UM. These risk factors echo those of the far more common cutaneous melanoma (CM), which is widely accepted to be caused by excessive UVR exposure, suggesting a role of UVR in the development and progression of a proportion of UM. Indeed, this could mean that countries, such as Australia, with high UVR exposure and the highest incidences of CM would represent a similarly high incidence of UM if UVR exposure is truly involved. Most cases of UM lack the typical genetic mutations that are related to UVR damage, although recent evidence in a small minority of cases has shown otherwise. This review therefore reassesses statistical, environmental, anatomical, and physiological evidence for and against the role of UVR in the aetiology of UM.
Targeted Cancer Therapy: What’s New in the Field of Neuroendocrine Neoplasms?
Authors: La Salvia Anna , Espinosa-Olarte Paula , Riesco-Martinez Maria Del Carmen , Anton-Pascual Beatriz , Garcia-Carbonero Rocío
Published: April 2021

Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients.
B-Cell Regeneration Profile and Minimal Residual Disease Status in Bone Marrow of Treated Multiple Myeloma Patients
Authors: Mendonça de Pontes Robéria , Flores-Montero Juan , Sanoja-Flores Luzalba , Puig Noemi , Pessoa de Magalhães Roberto J. , Corral-Mateos Alba , Salgado Anna Beatriz , García-Sánchez Omar , Pérez-Morán José , Mateos Maria-Victoria , Burgos Leire , Paiva Bruno , te Marvelde Jeroen , van der Velden Vincent H. J. , Aguilar Carlos , Bárez Abelardo , García-Mateo Aranzazú , Labrador Jorge , Leoz Pilar , Aguilera-Sanz Carmen , Durie Brian , van Dongen Jacques J. M. , Maiolino Angelo , Sobral da Costa Elaine , Orfao Alberto
Published: April 2021

B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (≥50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naïve B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19− nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome.
IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm
Authors: De Mattia Elena , Polesel Jerry , Roncato Rossana , Labriet Adrien , Bignucolo Alessia , Gagno Sara , Buonadonna Angela , D’Andrea Mario , Lévesque Eric , Jonker Derek , Couture Félix , Guillemette Chantal , Cecchin Erika , Toffoli Giuseppe
Published: April 2021

A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR: 1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR: 0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.