bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Non-Enzymatic Degradation of Meropenem—Insights from the Bottle to the Body
Authors: Liebchen Uwe , Rakete Sophie , Vogeser Michael , Arend Florian M. , Kinast Christina , Scharf Christina , Zoller Michael , Schönermarck Ulf , Paal Michael
Published: June 2021

Several studies have addressed the poor stability of meropenem in aqueous solutions, though not considering the main degradation product, the open-ring metabolite (ORM) form. In the present work, we elucidate the metabolic fate of meropenem and ORM from continuous infusion to the human bloodstream. We performed in vitro infusate stability tests at ambient temperature with 2% meropenem reconstituted in 0.9% normal saline, and body temperature warmed buffered human serum with 2, 10, and 50 mg/L meropenem, covering the therapeutic range. We also examined meropenem and ORM levels over several days in six critically ill patients receiving continuous infusions. Meropenem exhibited a constant degradation rate of 0.006/h and 0.025/h in normal saline at 22 °C and serum at 37 °C, respectively. Given that 2% meropenem remains stable for 17.5 h in normal saline (≥90% of the initial concentration), we recommend replacement of the infusate every 12 h. Our patients showed inter-individually highly variable, but intra-individually constant molar ORM/(meropenem + ORM) ratios of 0.21–0.52. Applying a population pharmacokinetic approach using the degradation rate in serum, spontaneous degradation accounted for only 6% of the total clearance.
Daptomycin versus Glycopeptides for the Treatment of Enterococcus faecium Bacteraemia: A Cohort Study
Authors: Echeverría-Esnal Daniel , Sorli Luisa , Prim Nuria , Martin-Ontiyuelo Clara , Horcajada Juan Pablo , Grau Santiago
Published: June 2021

Background: Ampicillin resistant and glycopeptide susceptible Enterococcus faecium bloodstream infection (GSEF-BSI) incidence has risen. However, the treatment of choice remains unknown. Daptomycin use for the treatment of enterococcal infections has increased, despite effectiveness and safety concerns. The objective was to compare the effectiveness and safety of daptomycin and glycopeptides in the treatment of GSEF-BSI. Methods: This was a single-centre, retrospective observational cohort study performed at Hospital del Mar (Barcelona, Spain), from January 2006–May 2018. The primary outcome was clinical cure at the end of the therapy, and secondary outcomes included 14-day, 30-day, in-hospital mortality, and length of stay. Results: From a total of 192 patients with GSEF-BSI, 54 (28.1%) were treated with glycopeptides and 17 (8.9%) with daptomycin. Patients treated with daptomycin presented a lower clinical cure than patients treated with glycopeptides (58.8% vs. 83.3%, RR 0.416 (95% CI 0.189–0.915)). After controlling for confounding variables by means of multivariate analysis the significative difference was confirmed (aOR 4.313, 95% CI, 1.053–17.660). The need for treatment discontinuation due to adverse events was similar. Conclusions: Patients with GSEF-BSI treated with glycopeptides showed a higher clinical cure than those treated with daptomycin.
Neuroprotective Effects of Coreopsis lanceolata Flower Extract against Oxidative Stress-Induced Apoptosis in Neuronal Cells and Mice
Authors: Kim Hyung Don , Lee Ji Yeon , Park Jeong-Yong , Kim Dong Hwi , Kang Min Hye , Seong Hyun-A , Seo Kyung Hye , Ji Yun-Jeong
Published: June 2021

Coreopsis lanceolata L. is a perennial plant of the family Asteraceae, and its flower is known to contain flavonoids with various bioactivities. We evaluated the effect of Coreopsis lanceolata L. flower (CLF) extracts on H2O2-induced oxidative stress (OS) in neuronal cells and mouse neurons. The flowering part of CL was used as CLF1 (70% ethanol extract) and CLF2 (water extract), and 10 types of phenolic compounds were quantified using high-performance liquid chromatography. To evaluate the neuroprotective effects of CLF, the antioxidant activities of the extracts were measured, and the expression levels of antioxidant enzymes and proteins related to OS-induced apoptosis in neuronal cells and mouse neurons treated with the extracts were investigated. In the in vitro study, CLF ameliorated H2O2-induced oxidative stress and induced the expression of antioxidant enzymes in PC12 cells. Furthermore, CLF1 enhanced the expression of the Bcl-xL protein but reduced the expression of Bax and the cleavage of caspase-3. In the same manner, CLF1 showed neuroprotective effects against OS in vivo. Pretreatment with CLF1 (200 mg/kg) increased the Bcl-2 protein and decreased Bax compared with the 1-methyl-4-phenylpyridinium ion (MPP+)-treated C57BL/6 mice model group. Our results suggest that the protective effects of CLF1 on MPP+-induced apoptosis may be due to its anti-apoptotic activity, through regulating the expression of the Bcl-2 family. CLF1 exerts neuroprotective effects against OS-induced apoptosis in PC12 cells in a Parkinson’s disease model mouse. This effect may be attributable to the upregulation of Bcl-2 protein expression, downregulation of Bax expression, and inhibition of caspase-3 activation. These data indicate that CLF may provide therapeutic value for the treatment of progressive neurodegenerative diseases.
Neonatal Vitamin C and Cysteine Deficiencies Program Adult Hepatic Glutathione and Specific Activities of Glucokinase, Phosphofructokinase, and Acetyl-CoA Carboxylase in Guinea Pigs’ Livers
Authors: Teixeira Vitor , Mohamed Ibrahim , Lavoie Jean-Claude
Published: June 2021

Premature neonates are submitted to an early-life oxidative stress from parenteral nutrition, which is vitamin C (VC) deficient and induces low endogenous levels of glutathione. The oxidative stress caused by these deficiencies may permanently affect liver glycolysis and lipogenesis. This study evaluates the short- and long-term effects of neonatal VC and cysteine deficient diets on redox and energy metabolism. Three-day-old Hartley guinea pigs from both sexes were given a regular or a deficient diet (VC, cysteine, or both) until week 1 of life. Half of the animals were sacrificed at this age, while the other half ate a complete diet until 12 weeks. Liver glutathione and the activity and protein levels of glucokinase, phosphofructokinase, and acetyl-CoA-carboxylase were measured. Statistics: factorial ANOVA (5% threshold). At 1 week, all deficient diets decreased glutathione and the protein levels of glucokinase and phosphofructokinase, while cysteine deficiency decreased acetyl-CoA-carboxylase levels. A similar enzyme level was observed in control animals at 12 weeks. At this age, VC deficiency decreased glutathione, while cysteine increased it. Acetyl-CoA-carboxylase protein levels were increased, which decreased its specific activity. Early-life VC and cysteine deficiencies induce neonatal oxidative stress and an adult-like metabolism, while predisposing to increased lipogenic rates during adulthood.
Femtosecond Optical Nonlinearity of Nanodiamond Suspensions
Authors: Mikheev Gennady M. , Vanyukov Viatcheslav V. , Mogileva Tatyana N. , Mikheev Konstantin G. , Aleksandrovich Alexander N. , Nunn Nicholas A. , Shenderova Olga A.
Published: June 2021

High pressure-high temperature (HP-HT) nanodiamonds and detonation nanodiamonds have unique optical properties and are promising materials for various applications in photonics. In this work, for the first time, comparative studies of the nonlinear optical properties of aqueous suspensions of HP-HT and detonation nanodiamonds under femtosecond laser excitation are performed. Using the z-scan technique, it was found that for the same laser pulse parameters HP-HT nanodiamonds exhibited optical limiting due to two-photon absorption while detonation nanodiamonds exhibited saturable absorption accompanied by short-term optical bleaching, revealing the different electronic-gap structures of the two types of nanodiamonds. The saturable absorption properties of detonation nanodiamonds are characterized by determining the saturable and non-saturable absorption coefficients, the saturation intensity, and the ratio of saturable to non-saturable losses. The nonlinear absorption in HP-HT nanodiamonds is described with the nonlinear absorption coefficient that decreases with decreasing concentration of nanoparticles linearly. The results obtained show the possibility of using aqueous suspensions of nanodiamonds for saturable absorption and optical limiting applications.
A Survey on Machine-Learning Based Security Design for Cyber-Physical Systems
Authors: Kim Sangjun , Park Kyung-Joon
Published: June 2021

A cyber-physical system (CPS) is the integration of a physical system into the real world and control applications in a computing system, interacting through a communications network. Network technology connecting physical systems and computing systems enables the simultaneous control of many physical systems and provides intelligent applications for them. However, enhancing connectivity leads to extended attack vectors in which attackers can trespass on the network and launch cyber-physical attacks, remotely disrupting the CPS. Therefore, extensive studies into cyber-physical security are being conducted in various domains, such as physical, network, and computing systems. Moreover, large-scale and complex CPSs make it difficult to analyze and detect cyber-physical attacks, and thus, machine learning (ML) techniques have recently been adopted for cyber-physical security. In this survey, we provide an extensive review of the threats and ML-based security designs for CPSs. First, we present a CPS structure that classifies the functions of the CPS into three layers: the physical system, the network, and software applications. Then, we discuss the taxonomy of cyber-physical attacks on each layer, and in particular, we analyze attacks based on the dynamics of the physical system. We review existing studies on detecting cyber-physical attacks with various ML techniques from the perspectives of the physical system, the network, and the computing system. Furthermore, we discuss future research directions for ML-based cyber-physical security research in the context of real-time constraints, resiliency, and dataset generation to learn about the possible attacks.
Virtual Geosite Communication through a WebGIS Platform: A Case Study from Santorini Island (Greece)
Authors: Pasquaré Mariotto Federico , Antoniou Varvara , Drymoni Kyriaki , Bonali Fabio Luca , Nomikou Paraskevi , Fallati Luca , Karatzaferis Odysseas , Vlasopoulos Othonas
Published: June 2021

We document and show a state-of-the-art methodology that could allow geoheritage sites (geosites) to become accessible to scientific and non-scientific audiences through immersive and non-immersive virtual reality applications. This is achieved through a dedicated WebGIS platform, particularly handy in communicating geoscience during the COVID-19 era. For this application, we selected nine volcanic outcrops in Santorini, Greece. The latter are mainly associated with several geological processes (e.g., dyking, explosive, and effusive eruptions). In particular, they have been associated with the famous Late Bronze Age (LBA) eruption, which made them ideal for geoheritage popularization objectives since they combine scientific and educational purposes with geotourism applications. Initially, we transformed these stunning volcanological outcrops into geospatial models—the so called virtual outcrops (VOs) here defined as virtual geosites (VGs)—through UAV-based photogrammetry and 3D modeling. In the next step, we uploaded them on an online platform that is fully accessible for Earth science teaching and communication. The nine VGs are currently accessible on a PC, a smartphone, or a tablet. Each one includes a detailed description and plenty of annotations available for the viewers during 3D exploration. We hope this work will be regarded as a forward model application for Earth sciences’ popularization and make geoheritage open to the scientific community and the lay public.
Artificial Intelligence for Student Assessment: A Systematic Review
Authors: González-Calatayud Víctor , Prendes-Espinosa Paz , Roig-Vila Rosabel
Published: June 2021

Artificial Intelligence (AI) is being implemented in more and more fields, including education. The main uses of AI in education are related to tutoring and assessment. This paper analyzes the use of AI for student assessment based on a systematic review. For this purpose, a search was carried out in two databases: Scopus and Web of Science. A total of 454 papers were found and, after analyzing them according to the PRISMA Statement, a total of 22 papers were selected. It is clear from the studies analyzed that, in most of them, the pedagogy underlying the educational action is not reflected. Similarly, formative evaluation seems to be the main use of AI. Another of the main functionalities of AI in assessment is for the automatic grading of students. Several studies analyze the differences between the use of AI and its non-use. We discuss the results and conclude the need for teacher training and further research to understand the possibilities of AI in educational assessment, mainly in other educational levels than higher education. Moreover, it is necessary to increase the wealth of research which focuses on educational aspects more than technical development around AI.
Code Calibration of the Eurocodes
Authors: Poutanen Tuomo
Published: June 2021

This article addresses the process to optimally select safety factors and characteristic values for the Eurocodes. Five amendments to the present codes are proposed: (1) The load factors are fixed, γG = γQ, by making the characteristic load of the variable load changeable, it simplifies the codes and lessens the calculation work. (2) Currently, the characteristic load of the variable load is the same for all variable loads. It creates excess safety and material waste for the variable loads with low variation. This deficiency can be avoided by applying the same amendment as above. (3) Various materials fit with different accuracy in the reliability model. This article explains two options to reduce this difficulty. (4) A method to avoid rounding errors in the safety factors is explained. (5) The current safety factors are usually set by minimizing the reliability indexes regarding the target when the obtained codes include considerable safe and unsafe design cases with the variability ratio (high reliability/low) of about 1.4. The proposed three code models match the target β50 = 3.2 with high accuracy, no unsafe design cases and insignificant safe design cases with the variability ratio 1.07, 1.03 and 1.04.
Fatigue Life Prediction of Radial Tire Bead Using a Maximum Strain Energy Density Range Method
Authors: Wang Guolin , Wang Weibin , Liang Chen , Cao Leitian
Published: June 2021

The damage that occurs around the tire bead region is one of the critical failure forms of a tire. Generally, the prediction of tire durability is carried out by the experimental method. However, it takes a lot of money and time to conduct experiments. Therefore, to determine the fatigue life of radial tire bead, a reasonable prediction method is proposed in this paper. Fatigue testing of bead rubber compounds to determine the ΔSED-number of the cycle (Nf) was applied. The maximum strain energy density range (ΔSEDmax) of several bead compounds was obtained by steady-state rolling analysis with a finite element method. This quantity is then inserted into a fatigue life equation to estimate the fatigue life. The experimental results of the 175/75R14 tire were compared with the estimated value, which showed a good correlation. It is concluded that the method can be effectively applied to the fatigue life prediction of the tire bead.
Detecting Social Media Bots with Variational AutoEncoder and k-Nearest Neighbor
Authors: Wang Xiujuan , Zheng Qianqian , Zheng Kangfeng , Sui Yi , Cao Siwei , Shi Yutong
Published: June 2021

Malicious social media bots are disseminators of malicious information on social networks and seriously affect information security and the network environment. Efficient and reliable classification of social media bots is crucial for detecting information manipulation in social networks. Aiming to correct the defects of high-cost labeling and unbalanced positive and negative samples in the existing methods of social media bot detection, and to reduce the training of abnormal samples in the model, we propose an anomaly detection framework based on a combination of a Variational AutoEncoder and an anomaly detection algorithm. The purpose is to use Variational AutoEncoder to automatically encode and decode sample features. The normal sample features are more similar to the initial features after decoding; however, there is a difference between the abnormal samples and the initial features. The decoding representation and the original features are combined, and then the anomaly detection method is used for detection. The results show that the area under the curve of the proposed model for identifying social media bots reaches 98% through the experiments on public datasets, which can effectively distinguish bots from common users and further verify the performance of the proposed model.
Development of a Fuzzy Logic Controller for Small-Scale Solar Organic Rankine Cycle Cogeneration Plants
Authors: Cioccolanti Luca , De Grandis Simone , Tascioni Roberto , Pirro Matteo , Freddi Alessandro
Published: June 2021

Solar energy is widely recognized as one of the most attractive renewable energy sources to support the transition toward a decarbonized society. Use of low- and medium-temperature concentrated solar technologies makes decentralized power production of combined heating and power (CHP) an alternative to conventional energy conversion systems. However, because of the changes in solar radiation and the inertia of the different subsystems, the operation control of concentrated solar power (CSP) plants is fundamental to increasing their overall conversion efficiency and improving reliability. Therefore, in this study, the operation control of a micro-scale CHP plant consisting of a linear Fresnel reflector solar field, an organic Rankine cycle unit, and a phase change material thermal energy storage tank, as designed and built under the EU-funded Innova Microsolar project by a consortium of universities and companies, is investigated. In particular, a fuzzy logic control is developed in MATLAB/Simulink by the authors in order to (i) initially recognize the type of user according to the related energy consumption profile by means of a neural network and (ii) optimize the thermal-load-following approach by introducing a set of fuzzy rules to switch among the different operation modes. Annual simulations are performed by combining the plant with different thermal load profiles. In general, the analysis shows that that the proposed fuzzy logic control increases the contribution of the TES unit in supplying the ORC unit, while reducing the number of switches between the different OMs. Furthermore, when connected with a residential user load profile, the overall electrical and thermal energy production of the plant increases. Hence, the developed control logic proves to have good potential in increasing the energy efficiency of low- and medium-temperature concentrated solar ORC systems when integrated into the built environment.
Multi-Organ Protective Effects of Curcumin Nanoparticles on Drug-Induced Acute Myocardial Infarction in Rats with Type 1 Diabetes Mellitus
Authors: Boarescu Paul-Mihai , Boarescu Ioana , Bulboacă Adriana Elena , Bocșan Ioana Corina , Pop Raluca Maria , Gheban Dan , Râjnoveanu Ruxandra-Mioara , Râjnoveanu Armand , Roşian Ştefan Horia , Buzoianu Anca Dana , Bolboacă Sorana D.
Published: June 2021

The objectives of this study were to investigate the cardio-protective, hepatoprotective and nephroprotective effects of curcumin nanoparticle (NC) pretreatment compared to conventional curcumin (CC) on acute myocardial infarction (AMI) in rats with type 1 diabetes mellitus (T1DM). Fifty-six Wister Bratislava rats were divided into eight groups. The first four groups—C (control group), AMI (group with AMI), T1DM (group with T1DM), and T1DM-AMI (group with T1DM and AMI)—received only saline (S) during the whole experiment. Two groups—S-T1DM-CC-AMI and S-T1DM-NC-AMI—were pretreated with S before T1DM induction. The S-T1DM-CC-AMI group received CC (200 mg/Kg bw (bw—body weight)) after T1DM induction, while the S-T1DM-NC-AMI group received NC (200 mg/Kg bw) after T1DM induction. the CC-T1DM-CC-AMI group received CC (200 mg/Kg bw) during the whole experiment. Similarly, the NC-T1DM-NC-AMI group received NC (200 mg/Kg bw) over the entire experiment. T1DM was induced on day 7 using a single dose of streptozotocin (STZ). AMI was induced with isoproterenol (ISO) on day 22. Both curcumin formulations, CC and NC, prevented the following electrocardiographic changes: prolongation of the QRS complex, enlargement of QT and QTc intervals, and ST-segment elevation. Glucose levels and lipid profile parameters were reduced up to 1.9 times, while C-peptide serum levels were increased up to 1.6 times in groups that received CC or NC. Liver function parameters (aspartate transaminase, alanine transaminase) and kidney function parameters (creatinine, urea) were reduced 4.8 times, and histological changes of liver and kidney tissue were improved by CC or NC administration. Pretreatment with NC proved significantly higher cardioprotective, hepatoprotective and nephroprotective effects in the case of AMI in T1DM.
A Systematic Deep Learning Based Overhead Tracking and Counting System Using RGB-D Remote Cameras
Authors: Gochoo Munkhjargal , Rizwan Syeda Amna , Ghadi Yazeed Yasin , Jalal Ahmad , Kim Kibum
Published: June 2021

Automatic head tracking and counting using depth imagery has various practical applications in security, logistics, queue management, space utilization and visitor counting. However, no currently available system can clearly distinguish between a human head and other objects in order to track and count people accurately. For this reason, we propose a novel system that can track people by monitoring their heads and shoulders in complex environments and also count the number of people entering and exiting the scene. Our system is split into six phases; at first, preprocessing is done by converting videos of a scene into frames and removing the background from the video frames. Second, heads are detected using Hough Circular Gradient Transform, and shoulders are detected by HOG based symmetry methods. Third, three robust features, namely, fused joint HOG-LBP, Energy based Point clouds and Fused intra-inter trajectories are extracted. Fourth, the Apriori-Association is implemented to select the best features. Fifth, deep learning is used for accurate people tracking. Finally, heads are counted using Cross-line judgment. The system was tested on three benchmark datasets: the PCDS dataset, the MICC people counting dataset and the GOTPD dataset and counting accuracy of 98.40%, 98%, and 99% respectively was achieved. Our system obtained remarkable results.
Ship Model Identification with Genetic Algorithm Tuning
Authors: Miller Anna
Published: June 2021

Modeling is the most important component in predictive controller design. It should predict outputs precisely and fast. Thus, it must be adequate for the ship dynamics while having as simple a structure as possible. In a good ship model the standard deviation of a particular coefficient should not exceed 10% of its value. Fitting the validation data to 80% for short-term prediction and 65% for long-term prediction is treated as a declared benchmark for model usage in ship course predictive controller. Regularization was proposed to ensure better state-space models to fit the real ship dynamics and more accurate standard deviation value control. Usage of the simulation results and real-time trials, as model estimation and validation data, respectively, during the identification procedure is proposed. In the first step a predictive linear model is identified conventionally, and then coefficients are regularized, based on the validation data, using a genetic algorithm. Particular linearized model coefficient standard deviations were decreased from more than 100% of their values to approximately 5% of them using genetic algorithm tuning. Moreover, the proposed method eliminated model output signal oscillations, which were observed during the validation process based on experimental data, gained during ship trials. Improved mapping of ship dynamics was achieved. Fit to validation data increased from 71% and 54% to 89% and 76%, respectively, for short-term and long-term prediction. The proposed method, which may be applied to real applications, is easily applicable and reliable. The tuned model is sufficiently suited to plant dynamics and may be used for future predictive control purposes.
Analysis of the Loading on an Articulated Flat Wagon of Circular Pipes Loaded with Tank Containers
Authors: Fomin Oleksij , Gerlici Juraj , Lovska Alyona , Kravchenko Kateryna
Published: June 2021

This research is concerned with the use of double walls filled with foam aluminum for an open wagon to decrease loading during operational modes. The research presents the strength calculation for the frame of a wagon with a consideration of the engineering solutions proposed. It was found that the maximum equivalent stresses appeared in the bottom section of the center sill behind the back support; they amounted to about 290 MPa and did not exceed the allowable values. The maximum displacements were in the middle parts of the main longitudinal beams of a section, and they amounted to 8.8 mm. The research also presents the strength calculation for a weld joint in the maximum loaded zones of the frame of a wagon and reports the results of the modal analysis of the frame of the improved wagon. It was found that the oscillation frequencies did not exceed the allowable values. The results of the research may be useful for those who are concerned about designing innovative rolling stock units and improving the operational efficiency of railway transport.
Experimenting with Odour Proficiency Tests Implementation Using Synthetic Bench Loops
Authors: Cipriano Domenico , Cefalì Amedeo M. , Allegrini Marco
Published: June 2021

Uncertainty in the quantification of odour measurements is a difficult (but needed) task. Critical aspects include panel selection (required by dynamic olfactometry), sampling, and stability of the samples. Proficiency tests (PTs) can help evaluate such contributions; however, the classical approach to PTs, in which laboratories analyse real samples taken from the field, are not as applicable in this field, and are often implemented by only using dry gas cylinders containing stable compounds. Consequently, uncertainties related to the sampling activity cannot be assessed. In particular, high odour levels and the presence of water vapour in emission sources can create significative biases due to sampling techniques used and chemical reactions that can occur before analysis. In this work, we present experimental notes, developed using the experimental facility ‘LOOP’, realised at the RSE research centre in Italy, in order to “help” the definition, in an upgraded protocol for implementing PTs for odour determinations. Using this bench loop is advantageous as it involves the possibility of implementing samples in conditions very similar to reality (i.e., high temperatures, high water content, and the presence of chemical interferents).
Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair
Authors: Thompson Marlo K. , Sobol Robert W. , Prakash Aishwarya
Published: June 2021

The earliest methods of genome editing, such as zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENs), utilize customizable DNA-binding motifs to target the genome at specific loci. While these approaches provided sequence-specific gene-editing capacity, the laborious process of designing and synthesizing recombinant nucleases to recognize a specific target sequence, combined with limited target choices and poor editing efficiency, ultimately minimized the broad utility of these systems. The discovery of clustered regularly interspaced short palindromic repeat sequences (CRISPR) in Escherichia coli dates to 1987, yet it was another 20 years before CRISPR and the CRISPR-associated (Cas) proteins were identified as part of the microbial adaptive immune system, by targeting phage DNA, to fight bacteriophage reinfection. By 2013, CRISPR/Cas9 systems had been engineered to allow gene editing in mammalian cells. The ease of design, low cytotoxicity, and increased efficiency have made CRISPR/Cas9 and its related systems the designer nucleases of choice for many. In this review, we discuss the various CRISPR systems and their broad utility in genome manipulation. We will explore how CRISPR-controlled modifications have advanced our understanding of the mechanisms of genome stability, using the modulation of DNA repair genes as examples.
Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”
Authors: Trzyna Anna , Banaś-Ząbczyk Agnieszka
Published: June 2021

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides cytokines, proteins, and growth factors, the therapeutic effect of secretome is hidden in non-coding RNAs such as miR-21, miR-24, and miR-26 carried via exosomes secreted by adequate cells. The whole secretome, including ASC-derived exosomes (ASC-exos) has been proven in many studies to have immunomodulatory, proangiogenic, neurotrophic, and epithelization activity and can potentially be used for neurodegenerative, cardiovascular, respiratory, inflammatory, and autoimmune diseases as well as wound healing treatment. Due to limitations in the use of stem cells in cell-based therapy, its secretome with emphasis on exosomes seems to be a reasonable and safer alternative with increased effectiveness and fewer side effects. Moreover, the great advantage of cell-free therapy is the possibility of biobanking the ASCs secretome. In this review, we focus on the current state of knowledge on the use of the ASCs secretome in stem cell-free therapy.
Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression
Authors: St-Pierre Yves
Published: June 2021

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial origin (carcinoma) are among the most frequent and deadly cancer subtypes. Initially described as a p53-induced gene and associated with apoptosis, galectin-7 is now recognized as having a protumorigenic role in many cancer types. Several studies have indeed shown that galectin-7 is associated with aggressive behavior of cancer cells and induces expression of MMP-9, a member of the matrix metalloproteinases (MMP) family known to confer invasive behavior to cancer cells. It is therefore not surprising that many studies have examined its relationships with p53 and MMP-9. However, the relationships between galectin-7 and p53 and MMP-9 are not always clear. This is largely because p53 is often mutated in cancer cells and such mutations drastically change its functions and, consequently, its association with galectin-7. In this review, we discuss the functional relationships between galectin-7, p53 and MMP-9 and reconcile some apparently contradictory observations. A better understanding of these relationships will help to develop a working hypothesis and model that will provide the basis for further research in the hope of establishing a new paradigm for tackling the role of galectin-7 in cancer.
Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer
Authors: Culig Zoran
Published: June 2021

Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways.
Characterization of Circulating T Cell Receptor Repertoire Provides Information about Clinical Outcome after PD-1 Blockade in Advanced Non-Small Cell Lung Cancer Patients
Authors: Dong Ning , Moreno-Manuel Andrea , Calabuig-Fariñas Silvia , Gallach Sandra , Zhang Feiyu , Blasco Ana , Aparisi Francisco , Meri-Abad Marina , Guijarro Ricardo , Sirera Rafael , Camps Carlos , Jantus-Lewintre Eloísa
Published: June 2021

Despite the success of immunotherapies in lung cancer, development of new biomarkers for patient selection is urgently needed. This study aims to explore minimally invasive approaches to characterize circulating T cell receptor beta chain (TCR-β) repertoire in a cohort of advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. Peripheral blood samples were obtained at two time points: i) pretreatment (PRE) and ii) first response assessment (FR). Next-generation sequencing (NGS) was used to analyze the hypervariable complementary determining region 3 (CDR3) of TCR-β chain. Richness, evenness, convergence, and Jaccard similarity indexes plus variable (V) and joining (J)-gene usage were studied. Our results revealed that increased richness during treatment was associated with durable clinical benefit (DCB; p = 0.046), longer progression-free survival (PFS; p = 0.007) and overall survival (OS; p = 0.05). Patients with Jaccard similarity index ≥0.0605 between PRE and FR samples showed improved PFS (p = 0.021). Higher TRBV20-1 PRE usage was associated with DCB (p = 0.027). TRBV20-1 levels ≥9.14% in PRE and ≥9.02% in FR significantly increased PFS (p = 0.025 and p = 0.016) and OS (p = 0.035 and p = 0.018). Overall, analysis of circulating TCR-β repertoire may provide information about the immune response in anti-PD-1 treated NSCLC patients; in this scenario, it can also offer important information about the clinical outcome.
Differentiating Glioblastomas from Solitary Brain Metastases: An Update on the Current Literature of Advanced Imaging Modalities
Authors: Fordham Austin-John , Hacherl Caitlin-Craft , Patel Neal , Jones Keri , Myers Brandon , Abraham Mickey , Gendreau Julian
Published: June 2021

Differentiating between glioblastomas and solitary brain metastases proves to be a challenging diagnosis for neuroradiologists, as both present with imaging patterns consisting of peritumoral hyperintensities with similar intratumoral texture on traditional magnetic resonance imaging sequences. Early diagnosis is paramount, as each pathology has completely different methods of clinical assessment. In the past decade, recent developments in advanced imaging modalities enabled providers to acquire a more accurate diagnosis earlier in the patient’s clinical assessment, thus optimizing clinical outcome. Dynamic susceptibility contrast has been optimized for detecting relative cerebral blood flow and relative cerebral blood volume. Diffusion tensor imaging can be used to detect changes in mean diffusivity. Neurite orientation dispersion and density imaging is an innovative modality detecting changes in intracellular volume fraction, isotropic volume fraction, and extracellular volume fraction. Magnetic resonance spectroscopy is able to assist by providing a metabolic descriptor while detecting variable ratios of choline/N-acetylaspartate, choline/creatine, and N-acetylaspartate/creatine. Finally, radiomics and machine learning algorithms have been devised to assist in improving diagnostic accuracy while often utilizing more than one advanced imaging protocol per patient. In this review, we provide an update on all the current evidence regarding the identification and differentiation of glioblastomas from solitary brain metastases.
The Importance of Clinical Examination under General Anesthesia: Improving Parametrial Assessment in Cervical Cancer Patients
Authors: Sodeikat Paulina , Lia Massimiliano , Martin Mireille , Horn Lars-Christian , Höckel Michael , Aktas Bahriye , Wolf Benjamin
Published: June 2021

Background: Parametrial tumor involvement is an important prognostic factor in cervical cancer and is used to guide management. Here, we investigate the diagnostic value of clinical examination under general anesthesia (EUA) and magnetic resonance imaging (MRI) in determining parametrial tumor spread. Methods: Post-operative pathological findings of 400 patients with primary cervical cancer were compared to the respective MRI data and the results from EUA. The gynecological oncologist had access to the MR images during clinical assessment (augmented EUA, aEUA). Results: Pathologically proven parametrial tumor invasion was present in 165 (41%) patients. aEUA exhibited a higher accuracy than MRI alone (83% vs. 76%; McNemar’s odds ratio [OR] = 2.0, 95%CI 1.25–3.27, p = 0.003). Although accuracy was not affected by tumor size in aEUA, MRI was associated with a lower accuracy in tumors ≥2.5 cm (OR for a correct diagnosis compared to smaller tumors 0.22, p < 0.001). There was also a decrease in specificity when evaluating parametrial invasion by MRI in tumors ≥2.5 cm in diameter (p < 0.0001) compared to smaller tumors (< 2.5 cm). Body mass index had no influence on performance of either method. Conclusions: aEUA has the potential to increase the diagnostic accuracy of MRI in determining parametrial tumor involvement in cervical cancer patients.
Realization of Osteolysis, Angiogenesis, Immunosuppression, and Drug Resistance by Extracellular Vesicles: Roles of RNAs and Proteins in Their Cargoes and of Ectonucleotidases of the Immunosuppressive Adenosinergic Noncanonical Pathway in the Bone Marrow Niche of Multiple Myeloma
Authors: Watanabe Takashi
Published: June 2021

Angiogenesis and immunosuppression promote multiple myeloma (MM) development, and osteolysis is a primary feature of MM. Although immunomodulatory drugs and proteasome inhibitors (PIs) markedly improve the survival of patients with MM, this disease remains incurable. In the bone marrow niche, a chain of ectoenzymes, including CD38, produce immunosuppressive adenosine, inhibiting T cell proliferation as well as immunosuppressive cells. Therefore, anti-CD38 antibodies targeting myeloma cells have the potential to restore T cell responses to myeloma cells. Meanwhile extracellular vesicles (EVs) containing microRNAs, proteins such as cytokines and chemokines, long noncoding RNAs, and PIWI-interacting RNAs have been shown to act as communication tools in myeloma cell/microenvironment interactions. Via EVs, mesenchymal stem cells allow myeloma cell dissemination and confer PI resistance, whereas myeloma cells promote angiogenesis, myeloid-derived suppressor cell proliferation, and osteoclast differentiation and inhibit osteoblast differentiation. In this review, to understand key processes of MM development involving communication between myeloma cells and other cells in the tumor microenvironment, EV cargo and the non-canonical adenosinergic pathway are introduced, and ectoenzymes and EVs are discussed as potential druggable targets for the treatment of MM patients.
The Efficacy and Adverse Events in Patients with Head and Neck Cancer Following Radiotherapy Combined with S-1 Therapy: A Meta-Analysis
Authors: Shih Hung-Sheng , Jhou Hong-Jie , Ou Yang-Hao , Liu Yen-Tze , Kor Chew-Teng , Chen Andy Wei-Ge , Chen Mu-Kuan
Published: June 2021

This meta-analysis was conducted to assess the efficacy and adverse events associated with S-1 chemotherapy combined with radiotherapy for patients with head and neck cancer. The PubMed, Embase, and Cochrane Library databases were searched up to 10 February 2021. Eligible studies included clinical trials using S-1 chemotherapy combined with radiotherapy for head and neck cancer patients that measured tumor response, local control rate, overall survival, and grade 3/4 adverse events. A meta-analysis was performed using a random effects model. Twelve trials involving 378 patients met the selection criteria. The objective response and clinical benefit rate (complete/partial response and stable disease) of S-1 chemotherapy with radiotherapy were 86.3% (95% confidence interval (CI), 60.3–96.3) and 88.3% (95% CI, 70.1–96.1), respectively. The median 3-year local control rate, 3-year overall survival rate, and grade 3/4 adverse event rate were 84.0% (95% CI, 71.4–91.7), 69.6% (95% CI, 54.9–81.1), and 42.0% (95% CI, 36.2–48.0), respectively. S-1 combined with radiotherapy for patients with head and neck squamous cell carcinoma results in a good tumor response, favorable survival rate, and low toxicity. A prospective randomized, double-blind trial is required to assess the efficacy and safety of S-1 combined with radiotherapy to treat HNSCC.
A Novel Protein–Protein Interaction between RSK3 and IκBα and a New Binding Inhibitor That Suppresses Breast Cancer Tumorigenesis
Authors: Yoon Hee-Sub , Choi Sung Hoon , Park Jung-Hyun , Min Jin-Young , Hyon Ju-Yong , Yang Yeji , Jung Sejin , Kim Jae-Young , Kim Nam Doo , Lee Ji Hoon , Han Eun Hee , Chi Sung-Gil , Chung Young-Ho
Published: June 2021

Multiple cancer-related biological processes are mediated by protein-protein interactions (PPIs). Through interactions with a variety of factors, members of the ribosomal S6 kinase (RSK) family play roles in cell cycle progression and cell proliferation. In particular, RSK3 contributes to cancer viability, but the underlying mechanisms remain unknown. We performed a kinase library screen to find IκBα PPI binding partners and identified RSK3 as a novel IκBα binding partner using a cell-based distribution assay. In addition, we discovered a new PPI inhibitor using mammalian two-hybrid (MTH) analysis. We assessed the antitumor effects of the new inhibitor using cell proliferation and colony formation assays and monitored the rate of cell death by FACS apoptosis assay. IκBα is phosphorylated by the active form of the RSK3 kinase. A small-molecule inhibitor that targets the RSK3/IκBα complex exhibited antitumor activity in breast cancer cells and increased their rate of apoptosis. RSK3 phosphorylation and RSK3/IκBα complex formation might be functionally important in breast tumorigenesis. The RSK3/IκBα-specific binding inhibitor identified in this study represents a lead compound for the development of new anticancer drugs.
Pathogenesis and Potential Therapeutic Targets for Triple-Negative Breast Cancer
Authors: Li Chia-Jung , Tzeng Yen-Dun Tony , Chiu Yi-Han , Lin Hung-Yu , Hou Ming-Feng , Chu Pei-Yi
Published: June 2021

Triple negative breast cancer (TNBC) is a heterogeneous tumor characterized by early recurrence, high invasion, and poor prognosis. Currently, its treatment includes chemotherapy, which shows a suboptimal efficacy. However, with the increasing studies on TNBC subtypes and tumor molecular biology, great progress has been made in targeted therapy for TNBC. The new developments in the treatment of breast cancer include targeted therapy, which has the advantages of accurate positioning, high efficiency, and low toxicity, as compared to surgery, radiotherapy, and chemotherapy. Given its importance as cancer treatment, we review the latest research on the subtypes of TNBC and relevant targeted therapies.
The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway
Authors: Shibel Rand , Sarfstein Rive , Nagaraj Karthik , Lapkina-Gendler Lena , Laron Zvi , Dixit Manisha , Yakar Shoshana , Werner Haim
Published: June 2021

Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial cancer biology and emerged as a promising therapeutic target in oncology. However, there is an urgent need to identify biomarkers that may help in patient stratification and prognosis. Laron syndrome (LS) is a type of dwarfism that results from the mutation of the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. While high circulating IGF1 is regarded as a risk factor in cancer, epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide profilings conducted on LS-derived lymphoblastoid cells led to the identification of a series of genes whose over- or under-representation in this condition might be mechanistically linked to cancer protection. The olfactory receptor 5 subfamily H member 2 (OR5H2) was the top downregulated gene in LS, its expression level being 5.8-fold lower than in the control cells. In addition to their typical role in the olfactory epithelium, olfactory receptors (ORs) are expressed in multiple tissues and play non-classical roles in various pathologies, including cancer. The aim of our study was to investigate the regulation of OR5H2 gene expression by IGF1 in endometrial cancer. Data showed that IGF1 and insulin stimulate OR5H2 mRNA and the protein levels in uterine cancer cell lines expressing either a wild-type or a mutant p53. OR5H2 silencing led to IGF1R downregulation, with ensuing reductions in the downstream cytoplasmic mediators. In addition, OR5H2 knockdown reduced the proliferation rate and cell cycle progression. Analyses of olfr196 (the mouse orthologue of OR5H2) mRNA expression in animal models of GHR deficiency or GH overexpression corroborated the human data. In summary, OR5H2 emerged as a novel target for positive regulation by IGF1, with potential relevance in endometrial cancer.