bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Internalized Staphylococcus aureus Using Vancomycin-Loaded Nanoparticles to Treat Recurrent Bloodstream Infections
Authors: Nader Danielle , Yousef Fajer , Kavanagh Nicola , Ryan Benedict K. , Kerrigan Steven W.
Published: May 2021

The bacterial pathogen Staphylococcus aureus is a leading cause of bloodstream infections, where patients often suffer from relapse despite antibiotic therapy. Traditional anti-staphylococcal drugs display reduced effectivity against internalised bacteria, but nanoparticles conjugated with antibiotics can overcome these challenges. In the present study, we aimed to characterise the internalisation and re-emergence of S. aureus from human endothelial cells and construct a new formulation of nanoparticles that target intracellular bacteria. Using an in vitro infection model, we demonstrated that S. aureus invades and persists within endothelial cells, mediated through bacterial extracellular surface adhesion, Fibronectin-binding protein A/B. After internalising, S. aureus localises to vacuoles as determined by transmission electron microscopy. Viable S. aureus emerges from endothelial cells after 48 h, supporting the notion that intracellular persistence contributes to infection relapses during bloodstream infections. Poly lactic-co-glycolic acid nanoparticles were formulated using a water-in-oil double emulsion method, which loaded 10% vancomycin HCl with 82.85% ± 12 encapsulation efficiency. These non-toxic nanoparticles were successfully taken up by cells and demonstrated a biphasic controlled release of 91 ± 4% vancomycin. They significantly reduced S. aureus intracellular growth within infected endothelial cells, which suggests future potential applications for targeting internalised bacteria and reducing mortality associated with bacteraemia.
Novel N,N′-Disubstituted Selenoureas as Potential Antioxidant and Cytotoxic Agents
Authors: Calvo-Martín Gorka , Plano Daniel , Encío Ignacio , Sanmartín Carmen
Published: May 2021

A series of 30 novel N,N disubstituted selenoureas were synthesized, characterized, and their antioxidant ability was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. Additionally, their cytotoxic activity was tested in vitro in a panel of three different cancer (breast, lung and colon) and two normal cell lines. Each selenourea entity contains a para-substituted phenyl ring with different electron-withdrawing and electron-donating groups, and different aliphatic and aromatic nuclei. All of the synthesized selenoureas present antioxidant capacity at high concentrations in the DPPH assay, and three of them (2b, 2c and 2d) showed greater radical scavenging capacity than ascorbic acid at lower concentrations. These results were confirmed by the ABTS assay, where these novel selenoureas present even higher antioxidant capacity than the reference compound Trolox. On the other hand, 10 selenoureas present IC50 values below 10 µM in at least one cancer cell line, resulting in the adamantyl nucleus (6a–6e), the most interesting in terms of activity and selectivity. Outstanding results were found for selenourea 6c, tested in the NCI60 cell line panel and showing an average GI50 of 1.49 µM for the 60 cell lines, and LC50 values ranging from 9.33 µM to 4.27 µM against 10 of these cancer cell lines. To gain insight into its anticancer activity mechanism, we investigated the cell cycle progression of the promising compound 6c, as well as the type of programmed-cell death in a colon cancer cell line it provokes (HT-29). Compound 6c provoked S phase cell cycle arrest and the induction of cell death was independent of caspase activation, suggesting autophagy, though this assertion requires additional studies. Overall, we envision that this compound can be further developed for the potential treatment of colon cancer.
Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes
Authors: Kostyunina Daria S. , McLoughlin Paul
Published: May 2021

Pulmonary hypertension (PH) is a condition characterised by an abnormal elevation of pulmonary artery pressure caused by an increased pulmonary vascular resistance, frequently leading to right ventricular failure and reduced survival. Marked sexual dimorphism is observed in patients with pulmonary arterial hypertension, a form of pulmonary hypertension with a particularly severe clinical course. The incidence in females is 2–4 times greater than in males, although the disease is less severe in females. We review the contribution of the sex chromosomes to this sex dimorphism highlighting the impact of proteins, microRNAs and long non-coding RNAs encoded on the X and Y chromosomes. These genes are centrally involved in the cellular pathways that cause increased pulmonary vascular resistance including the production of reactive oxygen species, altered metabolism, apoptosis, inflammation, vasoconstriction and vascular remodelling. The interaction with genetic mutations on autosomal genes that cause heritable pulmonary arterial hypertension such as bone morphogenetic protein 2 (BMPR2) are examined. The mechanisms that can lead to differences in the expression of genes located on the X chromosomes between females and males are also reviewed. A better understanding of the mechanisms of sex dimorphism in this disease will contribute to the development of more effective therapies for both women and men.
Stabilization Methodology in Foundation Soils by ERT-3D Application in Estepona, South Spain
Authors: Gutiérrez-Martín Alfonso , Yenes José I. , Fernández-Hernández Marta , Castedo Ricardo
Published: May 2021

The paper proposes a novel methodology for the stabilization of shallow foundations, with a simplified model combined with 3D electrical resistivity tomography (ERT-3D and consolidation injections. To determine its usefulness, the method has been applied in a case located in Estepona (southern Spain). The chosen tomography model is the dipole–dipole configuration, with an optimized distance between electrodes of 0.80 m for a better visualization of the foundation subsoil; with this parameterization, a total of 72 electrodes were installed in the analyzed case. In this work, the depth of the anomaly in the building’s supporting subsoil was detected ranging from 2.00 m to 3.90 m deep. The study also delineates areas of high resistivity variations (50–1000 Ω m) in the middle and eastern end of the field. These data have been validated and corroborated with a field campaign. The results of the ERT-3D monitoring are presented, once the investment data has been processed with the RES3DINV software, from the beginning to the end of the stabilization intervention. The novelty occurs with the interaction between the tomography and the foundation consolidation injections, until the final stabilization. This is a very useful methodology in case of emergency consolidation, where there is a need to minimize damage to the building. Thus, people using this combined system will be able to practically solve the initial anomalies of the subsoil that caused the damages, in a non-invasive way, considerably lowering the value of the resistivities.
Determination of the Waterway Parameters as a Component of Safety Management System
Authors: Bąk Andrzej , Zalewski Paweł
Published: May 2021

This article presents the use of a computer application codenamed “NEPTUN” to ascertain the waterway parameters of the modernised Świnoujście–Szczecin waterway. The designed program calculates the individual risks in selected sections of the fairway depending on the input data, including the parameters of the ship, available water area, and positioning methods. The collected data used for analyses in individual modules are stored in a SQL server of shared access. Vector electronic navigation charts of S-57 standard specification are used as the cartographic background. The width of the waterway is calculated by means of the method developed on the basis of the modified PIANC guidelines. The main goal of the research is to prove and demonstrate that the designed software would directly increase the navigation safety level of the Świnoujście–Szczecin fairway and indicate the optimal positioning methods in various navigation circumstances.
Microstructural and Corrosion Properties of Burnished 6060 Aluminum Alloy
Authors: Logori Debora , Pezzato Luca , Settimi Alessio Giorgio , Hanoz Denise , Dabalà Manuele
Published: May 2021

A process for producing a black oxide coating on aluminum alloy was investigated in the present work. The blackening process is widely used in industrial applications, but it was not deeply studied for aluminum alloys. The aim of this work is to study the black coating obtained on AA6060 surfaces employing two different solutions, both containing potassium permanganate, copper nitrate and nitric acid. The first solution carried out the coloring treatment at 50 °C, whereas the second one was done at room temperature. Different immersion times were investigated. The morphology of the coating was investigated by means of optical and electron microscopy to evaluate the color of the layer and the presence of defects, porosities, and cracks. X-ray diffraction analysis was performed to evaluate the protective layer composition. The corrosion properties were studied with potentiodynamic polarization tests and electrochemical impedance spectroscopy tests. The results showed that the blackening process performed at room temperature, besides the clear advantages in term of costs and safety, obtained more uniform coatings with increased corrosion performance in comparison with the ones obtained at higher temperatures.
Evaluating the Impact of the COVID-19 Pandemic on Residential Energy Use in Los Angeles
Authors: Klopfer Michael J. , Pixley Joy E. , Saiyan Armen , Tabakh Amir , Jacot David , Li Guann-Pyng
Published: May 2021

The 2020 COVID-19 pandemic provided an opportunity to assess energy use during times of emergency that disrupt daily and seasonal patterns. The authors present findings from a regional evaluation in the city of Los Angeles (California, USA) with broad application to other areas and demonstrate an approach for isolating and analyzing residential loads from community-level electric utility feeder data. The study addresses effects on residential energy use and the implications for future energy use models, energy planning, and device energy standards and utility program development. In this study we review changes in residential energy use during the progression of the COVID-19 pandemic from four residential communities across Los Angeles covering approximately 6603 households within two microclimate sub regional areas (Los Angeles Basin and San Fernando Valley). Analyses address both absolute and seasonal temperature-corrected energy use changes while assessing estimated changes on energy usage from both temperature-sensitive loads (e.g., air conditioning and electric heating) and non-temperature-sensitive loads (e.g., consumer electronics and major appliance use). An average 5.1% increase in total residential energy use was observed for non-temperature sensitive loads during the pandemic period compared to a 2018–2019 baseline. During mid-spring when shelter in place activity was highest a peak monthly energy use of 20.9% increase was seen compared to a 2018–2019 composite baseline. Considering an average of the top five warmest summer days, a 9.5% increase in energy use was observed for events during summer 2020 compared to summer 2018 (a year with similar magnitude summer high heat events). Based on these results, a potential trend is identified for increased residential load during pandemics and other shelter-in-place disruptions, net of any temperature-sensitive load shifts with greater impacts expected for lower-income communities.
Phytochemical Analysis of Symphytum officinale Root Culture Extract
Authors: Le Violeta , Dolganyuk Vyacheslav , Sukhikh Andrey , Babich Olga , Ivanova Svetlana , Prosekov Alexander , Dyshlyuk Lyubov
Published: May 2021

Comfrey (Symphytum officinale) root preparations are known for their analgesic and anti-inflammatory properties. In this study, the phenolic profile of extract samples of Symphytum officinale callus root cultures (up to 70% of ethanol) was determined using various approaches. For the first time, a unique polymer of two types was isolated from samples of comfrey root cultures (the caffeic acid derivative is a new class of natural polyether with 3-(3,4-dihydroxyphenyl) glyceric acid as a repeating unit). M-methoxybenzoic acid (30.05 μg/mL extract) or rosmarinic acid (45.70 μL/mL extract) were identified as the main phenolic component. Rosmarinic, chlorogenic, and caffeic acids have anti-inflammatory, anti-apoptotic, antitumor, neuroprotective, antioxidant, and other properties, which also determine the characteristics of comfrey and preparations made from it. The studied phenolic profile and the analysis of published data showed that the extract samples of comfrey callus cultures had similar characteristics, which makes them an important source of phenolic compounds with pronounced antioxidant activity.
Combining a Universal OBD-II Module with Deep Learning to Develop an Eco-Driving Analysis System
Authors: Yen Meng-Hua , Tian Shang-Lin , Lin Yan-Ting , Yang Cheng-Wei , Chen Chi-Chun
Published: May 2021

Vehicle technology development drives economic development but also causes severe mobile pollution sources. Eco-driving is an effective driving strategy for solving air pollution and achieving driving safety. The on-board diagnostics II (OBD-II) module is a common monitoring tool used to acquire sensing data from in-vehicle electronic control units. However, different vehicle models use different controller area network (CAN) standards, resulting in communication difficulties; however, relevant literature has not discussed compatibility problems. The present study researched and developed the universal OBD-II module, adopted deep learning methods to evaluate fuel consumption, and proposed an intuitive driving graphic user interface design. In addition to using the universal module to obtain data on different CAN standards, this study used deep learning methods to analyze the fuel consumption of three vehicles of different brands on various road conditions. The accuracy was over 96%, thus validating the practicability of the developed system. This system will greatly benefit future applications that employ OBD-II to collect various types of driving data from different car models. For example, it can be implemented for achieving eco-driving in bus driver training. The developed system outperforms those proposed by previous research regarding its completeness and universality.
Distortion of Thomson Parabolic-Like Proton Patterns Due to Electromagnetic Interference
Authors: Grepl Filip , Krása Josef , Velyhan Andriy , De Marco Massimo , Dostál Jan , Pfeifer Miroslav , Margarone Daniele
Published: May 2021

Intense electromagnetic pulses (EMPs) accompany the production of plasma when a high-intensity laser irradiates a solid target. The EMP occurs both during and long after the end of the laser pulse (up to hundreds of nanoseconds) within and outside the interaction chamber, and interferes with nearby electronics, which may lead to the disruption or malfunction of plasma diagnostic devices. This contribution reports a correlation between the frequency spectrum of the EMP and the distortion of Thomson parabola tracks of protons observed at the kJ-class PALS laser facility in Prague. EMP emission was recorded using a simple flat antenna. Ions accelerated from the front side of the target were simultaneously detected by a Thomson parabola ion spectrometer. The comparison of the two signals suggests that the EMP may be considered to be the source of parabolic track distortion.
Objective Assessment of Porcine Voice Acoustics for Laryngeal Surgical Modeling
Authors: Schlegel Patrick , Wong Kirsten , Aker Mamdouh , Alhiyari Yazeed , Long Jennifer
Published: May 2021

Pigs have become important animal models in voice research. Several objective parameters exist to characterize the pig voice, but it is not clear which of them are sensitive to the impaired voice quality after laryngeal injury or surgery. In order to conduct meaningful voice research in pigs, it is critical to have standard functional voice outcome measures that can distinguish between normal and impaired voices. For this reason, we investigated 17 acoustic parameters before and early after surgery in three Yucatan mini pigs. Four parameters showed consistent changes between pre- and post-surgery recordings, mostly related to decreased spectral energy in higher frequencies after surgery. We recommend two of these, 50% spectral energy quartile (Q50) and Flux, for objective functional voice assessment of pigs undergoing laryngeal surgery. The long-term goal of this process is to enable quantitative voice outcome tracking of laryngeal surgical interventions in porcine models.
Estimation of Grey-Box Dynamic Model of 2-DOF Pneumatic Actuator Robotic Arm Using Gravity Tests
Authors: Trojanová Monika , Čakurda Tomáš , Hošovský Alexander , Krenický Tibor
Published: May 2021

This article describes the dynamics of a manipulator with two degrees of freedom, while the dynamic model of the manipulator’s arm is derived using Lagrangian formalism, which considers the difference between the kinetic and potential energy of the system. The compiled dynamic model was implemented in Matlab, taking into account the physical parameters of the manipulator and friction term. Physical parameters were exported from the 3D CAD model. A scheme (model) was compiled in the Simulink, which was used for the subsequent validation process. The outputs of the validations were compared with measured data of joint angles from the system (expected condition) obtained by using gravity tests. For obtaining better results were parameters of the model optimizing by using the Trust Region Algorithm for Nonlinear Least Squares optimization method. Therefore, the aim of the research described in the article is the comparison of the model with the parameters that come from CAD and its improvement by estimating the parameters based on gravitational measurements. The model with estimated parameters achieved an improvement in the results of the Normal Root Mean Square Error compared to the model with CAD parameters. For link 1 was an improvement from 28.49% to 67.93% depending on the initial joint angle, and for link 2, from 63.84% to 66.46%.
Designing Hydrogel-Based Bone-On-Chips for Personalized Medicine
Authors: Nasello Gabriele , Cóndor Mar , Vaughan Ted , Schiavi Jessica
Published: May 2021

The recent development of bone-on-chips (BOCs) holds the main advantage of requiring a low quantity of cells and material, compared to traditional In Vitro models. By incorporating hydrogels within BOCs, the culture system moved to a three dimensional culture environment for cells which is more representative of bone tissue matrix and function. The fundamental components of hydrogel-based BOCs, namely the cellular sources, the hydrogel and the culture chamber, have been tuned to mimic the hematopoietic niche in the bone aspirate marrow, cancer bone metastasis and osteo/chondrogenic differentiation. In this review, we examine the entire process of developing hydrogel-based BOCs to model In Vitro a patient specific situation. First, we provide bone biological understanding for BOCs design and then how hydrogel structural and mechanical properties can be tuned to meet those requirements. This is followed by a review on hydrogel-based BOCs, developed in the last 10 years, in terms of culture chamber design, hydrogel and cell source used. Finally, we provide guidelines for the definition of personalized pathological and physiological bone microenvironments. This review covers the information on bone, hydrogel and BOC that are required to develop personalized therapies for bone disease, by recreating clinically relevant scenarii in miniaturized devices.
Use of Machine Learning and Deep Learning to Predict the Outcomes of Major League Baseball Matches
Authors: Huang Mei-Ling , Li Yun-Zhi
Published: May 2021

Major League Baseball (MLB) is the highest level of professional baseball in the world and accounts for some of the most popular international sporting events. Many scholars have conducted research on predicting the outcome of MLB matches. The accuracy in predicting the results of baseball games is low. Therefore, deep learning and machine learning methods were used to build models for predicting the outcomes (win/loss) of MLB matches and investigate the differences between the models in terms of their performance. The match data of 30 teams during the 2019 MLB season with only the starting pitcher or with all pitchers in the pitcher category were collected to compare the prediction accuracy. A one-dimensional convolutional neural network (1DCNN), a traditional machine learning artificial neural network (ANN), and a support vector machine (SVM) were used to predict match outcomes with fivefold cross-validation to evaluate model performance. The highest prediction accuracies were 93.4%, 93.91%, and 93.90% with the 1DCNN, ANN, SVM models, respectively, before feature selection; after feature selection, the highest accuracies obtained were 94.18% and 94.16% with the ANN and SVM models, respectively. The prediction results obtained with the three models were similar, and the prediction accuracies were much higher than those obtained in related studies. Moreover, a 1DCNN was used for the first time for predicting the outcome of MLB matches, and it achieved a prediction accuracy similar to that achieved by machine learning methods.
Innovative Line for Door Production TechnoPORTA—Technological and Economic Aspects of Application of Wood-Based Materials
Authors: Kwidziński Zdzisław , Bednarz Joanna , Pędzik Marta , Sankiewicz Łukasz , Szarowski Piotr , Knitowski Bartłomiej , Rogoziński Tomasz
Published: May 2021

Material losses are caused by the machining process and the manufacturing process, as well as the use of excessive dimensional allowances applied to the machined materials. An adequate reduction of the planned machining allowances for wood-based panel components is possible when the machining line is properly designed and equipped with high-precision machines and devices. The aim of the study was to determine the size of material savings in relation to the most important construction materials when implementing an innovative technological line for processing industrial doors made of wood materials. The achieved savings improve the competitiveness of the door manufacturer on the market. In order to calculate the material savings obtained in the production of the most important models of door leaves that can be obtained in machining on the TechnoPORTA line, numerical data were compiled specifying the dimensions of semi-finished products, taking into account machining allowances applied before and after reduction. The implementation of the TechnoPORTA line makes it possible to reduce the negative impact on the environment by reducing the consumption of wood. It reduces the consumption of materials and the operating costs associated with the reduction of labor intensity, the load on machines and devices, and inventory levels.
Unconstrained Estimation of Multitype Car Rental Demand
Authors: Yang Yazao , Ceder Avishai (Avi) , Zhang Weiyong , Tang Haodong
Published: May 2021

The unconstrained demand forecast for car rentals has become a difficult problem for revenue management due to the need to cope with a variety of rental vehicles, the strong subjective desires and requests of customers, and the high probability of upgrading and downgrading circumstances. The unconstrained demand forecast mainly includes repairing of constrained historical demand and forecasting of future demand. In this work, a new methodology is developed based on multiple discrete choice models to obtain customer choice preference probabilities and improve a known spill model, including a repair process of the unconstrained demand. In addition, the linear Holt–Winters model and the nonlinear backpropagation neural network are combined to predict future demand and avoid excessive errors caused by a single method. In a case study, we take advantage of a stated preference and a revealed preference survey and use the variable precision rough set to obtain factors and weights that affect customer choices. In this case study and based on a numerical example, three forecasting methods are compared to determine the car rental demand of the next time cycle. The comparison with real demand verifies the feasibility and effectiveness of the hybrid forecasting model with a resulting average error of only 3.06%.
Living in a Puddle of Mud: Isolation and Characterization of Two Novel Caulobacteraceae Strains Brevundimonas pondensis sp. nov. and Brevundimonas goettingensis sp. nov.
Authors: Friedrich Ines , Klassen Anna , Neubauer Hannes , Schneider Dominik , Hertel Robert , Daniel Rolf
Published: May 2021

Brevundimonas is a genus of freshwater bacteria belonging to the family Caulobacteraceae. The present study describes two novel species of the genus Brevundimonas (LVF1T and LVF2T). Both were genomically, morphologically, and physiologically characterized. Average nucleotide identity analysis revealed both are unique among known Brevundimonas strains. In silico and additional ProphageSeq analyses resulted in two prophages in the LVF1T genome and a remnant prophage in the LVF2T genome. Bacterial LVF1T cells form an elliptical morphotype, in average 1 µm in length and 0.46 µm in width, with a single flagellum. LVF2T revealed motile cells approximately 1.6 µm in length and 0.6 µm in width with a single flagellum, and sessile cell types 1.3 µm in length and 0.6 µm in width. Both are Gram-negative, aerobic, have optimal growth at 30 °C (up to 0.5 to 1% NaCl). Both are resistant towards erythromycin, meropenem, streptomycin, tetracycline and vancomycin. Anaerobic growth was observed after 14 days for LVF1T only. For LVF1T the name Brevundimonas pondensis sp. nov. and for LVF2T the name Brevundimonas goettingensis sp. nov. are proposed. Type strains are LVF1T (=DSM 112304T = CCUG 74982T = LMG 32096T) and LVF2T (=DSM 112305T = CCUG 74983T = LMG 32097T).
Antigenotoxic Effects and Possible Mechanism of Red Yeast (Sporidiobolus pararoseus) on Aflatoxin B1-Induced Mutagenesis
Authors: Kittichaiworakul Romteera , Taya Sirinya , Chariyakornkul Arpamas , Chaiyaso Thanongsak , Wongpoomchai Rawiwan
Published: May 2021

Red yeast (Sporidiobolus pararoseus), obtained from glycerol waste in the biodiesel process, has been used as a mycotoxin sorbent in some agricultural products. This study focused on the antigenotoxic effects of red yeast on aflatoxin B1 (AFB1)-induced mutagenesis, using a Salmonella mutation assay and a rat liver micronucleus test. Red yeast was sequentially extracted to obtain hexane, acetone, hot water, and residue fractions. Carbohydrates were mainly found in hot water extract (HWE), while proteins were observed in the residue fraction. The amount of lycopene in hexane extract (HE) was higher than the amount of β-carotene in HE. All red yeast extracts were not mutagenic in the Salmonella typhimurium strains TA98 and TA100 under the presence and absence of metabolic activation. Among the extracts obtained from red yeast, HE presented the strongest antimutagenicity against AFB1-induced mutagenesis in both strains, but HWE did not show any antimutagenicity. The oral administration of red yeast, HE, and HWE for 28 days was further investigated in rats. These extracts did not induce micronucleated hepatocytes. Furthermore, they modulated the activities of some detoxifying enzymes but did not alter the activities of various cytochrome P450 isozymes. Notably, they significantly decreased hepatic micronucleus formation in AFB1-initiated rats. HE altered the activity of hepatic glutathione-S-transferase but did not affect its protein expression. Taken together, the antigenotoxicity of red yeast against AFB1-induced mutagenesis might be partly due to the modulation of some detoxifying enzymes in AFB1 metabolism. β-Carotene and lycopene might be promising antigenotoxic compounds in red yeast.
From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies
Authors: Adachi Hironori , Hengesbach Martin , Yu Yi-Tao , Morais Pedro
Published: May 2021

Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.
Predictive Relevance of Baseline Lactate and Glucose Levels in Patients with Spontaneous Deep-Seated Intracerebral Hemorrhage
Authors: Lehmann Felix , Schenk Lorena M. , Schneider Matthias , Bernstock Joshua D. , Bode Christian , Borger Valeri , Gessler Florian , Güresir Erdem , Hadjiathanasiou Alexis , Hamed Motaz , Müller Marcus , Putensen Christian , Zimmermann Julian , Vatter Hartmut , Schuss Patrick
Published: May 2021

(1) Background: As elements of the standard admission blood panel, lactate and glucose represent potential biomarkers for outcome prediction. In patients with intracranial hemorrhage (ICH), data on the predictive value of these blood values is exceedingly sparse. (2) Methods: Between 2014 and August 2020, all patients with deep-seated ICH referred to the neurovascular center at the authors’ institution were included in the subsequent study. Serum levels of lactate and glucose at the time of admission were compared with mortality at 90 days. In addition, a multivariate analysis was performed in order to identify independent admission predictors for 90-day mortality. (3) Results: Among the 102 patients with deep-seated ICH, elevated lactate and glucose levels on admission were significantly associated with increased mortality at 90 days. Multivariate logistic regression analysis identified “ICH score ≥3” (p = 0.004) along with “admission hyperlactatemia” (p = 0.025) and “admission hyperglycemia” (p = 0.029) as independent and significant predictors of 90-day mortality in patients with deep-seated ICH. (4) Conclusions: Initially elevated lactate and glucose levels after spontaneous intracerebral hemorrhage are associated with poor outcome, suggesting a potential application for future prognostic models when considered in conjunction with other parameters.
Inhibitory Dimensions and Delay of Gratification: A Comparative Study on Individuals with Down Syndrome and Typically Developing Children
Authors: Fontana Martina , Usai Maria Carmen , Pellizzoni Sandra , Passolunghi Maria Chiara
Published: May 2021

While previous research on inhibition in people with Down syndrome (DS) reported contradictory results, with no explicit theoretical model, on the other hand, a more homogeneous impaired profile on the delay of gratification skills emerged. The main goal of the present study was to investigate response inhibition, interference suppression, and delay of gratification in 51 individuals with DS matched for a measure of mental age (MA) with 71 typically developing (TD) children. Moreover, we cross-sectionally explored the strengths and weaknesses of these components in children and adolescents vs. adults with DS with the same MA. A battery of laboratory tasks tapping on inhibitory sub-components and delay of gratification was administrated. Results indicated that individuals with DS showed an overall worse performance compared to TD children on response inhibition and delay of gratification, while no differences emerged between the two samples on the interference suppression. Additionally, our results suggested that older individuals with DS outperformed the younger ones both in response inhibition and in the delay of gratification, whereas the interference suppression still remains impaired in adulthood. This study highlights the importance of evaluating inhibitory sub-components considering both MA and chronological age in order to promote more effective and evidence-based training for this population.
Studying Behaviour Change Mechanisms under Complexity
Authors: Heino Matti T. J. , Knittle Keegan , Noone Chris , Hasselman Fred , Hankonen Nelli
Published: May 2021

Understanding the mechanisms underlying the effects of behaviour change interventions is vital for accumulating valid scientific evidence, and useful to informing practice and policy-making across multiple domains. Traditional approaches to such evaluations have applied study designs and statistical models, which implicitly assume that change is linear, constant and caused by independent influences on behaviour (such as behaviour change techniques). This article illustrates limitations of these standard tools, and considers the benefits of adopting a complex adaptive systems approach to behaviour change research. It (1) outlines the complexity of behaviours and behaviour change interventions; (2) introduces readers to some key features of complex systems and how these relate to human behaviour change; and (3) provides suggestions for how researchers can better account for implications of complexity in analysing change mechanisms. We focus on three common features of complex systems (i.e., interconnectedness, non-ergodicity and non-linearity), and introduce Recurrence Analysis, a method for non-linear time series analysis which is able to quantify complex dynamics. The supplemental website provides exemplifying code and data for practical analysis applications. The complex adaptive systems approach can complement traditional investigations by opening up novel avenues for understanding and theorising about the dynamics of behaviour change.
Lower-Limb Lymphedema after Sentinel Lymph Node Biopsy in Cervical Cancer Patients
Authors: Cibula David , Borčinová Martina , Marnitz Simone , Jarkovský Jiří , Klát Jaroslav , Pilka Radovan , Torné Aureli , Zapardiel Ignacio , Petiz Almerinda , Lay Laura , Sehnal Borek , Ponce Jordi , Felsinger Michal , Arencibia-Sánchez Octavio , Kaščák Peter , Zalewski Kamil , Presl Jiri , Palop-Moscardó Alicia , Tingulstad Solveig , Vergote Ignace , Redecha Mikuláš , Frühauf Filip , Köhler Christhardt , Kocián Roman
Published: May 2021

Background: To prospectively assess LLL incidence among cervical cancer patients treated by uterine surgery complemented by SLN biopsy, without PLND. Methods: A prospective study in 150 patients with stage IA1–IB2 cervical cancer treated by uterine surgery with bilateral SLN biopsy. Objective LLL assessments, based on limb volume increase (LVI) between pre- and postoperative measurements, and subjective patient-perceived swelling were conducted in six-month periods over 24-months post-surgery. Results: The cumulative incidence of LLL at 24 months was 17.3% for mild LLL (LVI 10–19%), 9.2% for moderate LLL (LVI 20–39%), while only one patient (0.7%) developed severe LLL (LVI > 40%). The median interval to LLL onset was nine months. Transient edema resolving without intervention within six months was reported in an additional 22% of patients. Subjective LLL was reported by 10.7% of patients, though only a weak and partial correlation between subjective-report and objective-LVI was found. No risk factor directly related to LLL development was identified. Conclusions: The replacement of standard PLND by bilateral SLN biopsy in the surgical treatment of cervical cancer does not eliminate the risk of mild to moderate LLL, which develops irrespective of the number of SLN removed.
Are Volatile Organic Compounds Accurate Markers in the Assessment of Colorectal Cancer and Inflammatory Bowel Diseases? A Review
Authors: Vernia Filippo , Valvano Marco , Fabiani Stefano , Stefanelli Gianpiero , Longo Salvatore , Viscido Angelo , Latella Giovanni
Published: May 2021

Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the Western world. Early detection decreases incidence and mortality. Screening programs based on fecal occult blood testing help identify patients requiring endoscopic examination, but accuracy is far from optimal. Among the alternative strategies, volatile organic compounds (VOCs) represent novel potentially useful biomarkers of colorectal cancer. They also represent a promising tool for the screening of both intestinal inflammation and related CRC. The review is focused on the diagnostic potential of VOCs in sporadic CRC and in inflammatory bowel diseases (IBD), which increase the risk of CRC, analyzing future clinical applications. Despite limitations related to inadequate strength of evidence, differing analytical platforms identify different VOCs, and this unconventional approach for diagnosing colorectal cancer is promising. Some VOC profiles, besides identifying inflammation, seem disease-specific in inflammatory bowel diseases. Thus, breath, urine, and fecal VOCs provide a new and promising clinical approach to differential diagnosis, evaluation of the inflammatory status, and possibly the assessment of treatment efficacy in IBD. Conversely, specific VOC patterns correlating inflammatory bowel disease and cancer risk are still lacking, and studies focused on this issue are strongly encouraged. No prospective studies have assessed the risk of CRC development by using VOCs in samples collected before the onset of disease, both in the general population and in patients with IBD.
Copy Number Profiles of Prostate Cancer in Men of Middle Eastern Ancestry
Authors: Albawardi Alia , Livingstone Julie , Almarzooqi Saeeda , Palanisamy Nallasivam , Houlahan Kathleen E. , Awwad Aktham Adnan Ahmad , Abdelsalam Ramy A. , Boutros Paul C. , Bismar Tarek A.
Published: May 2021

Our knowledge of prostate cancer (PCa) genomics mainly reflects European (EUR) and Asian (ASN) populations. Our understanding of the influence of Middle Eastern (ME) and African (AFR) ancestry on the mutational profiles of prostate cancer is limited. To characterize genomic differences between ME, EUR, ASN, and AFR ancestry, fluorescent in situ hybridization (FISH) studies for NKX3-1 deletion and MYC amplification were carried out on 42 tumors arising in individuals of ME ancestry. These were supplemented by analysis of genome-wide copy number profiles of 401 tumors of all ancestries. FISH results of NKX3-1 and MYC were assessed in the ME cohort and compared to other ancestries. Gene level copy number aberrations (CNAs) for each sample were statistically compared between ancestry groups. NKX3-1 deletions by FISH were observed in 17/42 (17.5%) prostate tumors arising in men of ME ancestry, while MYC amplifications were only observed in 1/42 (2.3%). Using CNAs called from arrays, the incidence of NKX3-1 deletions was significantly lower in ME vs. other ancestries (20% vs. 52%; p = 2.3 × 10−3). Across the genome, tumors arising in men of ME ancestry had fewer CNAs than those in men of other ancestries (p = 0.014). Additionally, the somatic amplification of 21 specific genes was more frequent in tumors arising in men of ME vs. EUR ancestry (two-sided proportion test; Q < 0.05). Those included amplifications in the glutathione S-transferase family on chromosome 1 (GSTM1, GSTM2, GSTM5) and the IQ motif-containing family on chromosome 3 (IQCF1, IQCF2, IQCF13, IQCF4, IQCF5, IQCF6). Larger studies investigating ME populations are warranted to confirm these observations.
Radiooncological View on Therapy Outcome after Multidisciplinary Treatment of Sinonasal Tumors
Authors: Klymenko Olena , Buchberger Anna Maria Stefanie , Wollenberg Barbara , Wolff Klaus-Dietrich , Kehl Victoria , Combs Stephanie E. , Pickhard Anja , Pigorsch Steffi U.
Published: May 2021

Purpose: We report the outcome of a mono-institutional retrospective study of sinonasal carcinoma with the primary focus on GTV (gross tumor volume) and the effect of radiotherapy. Methods: 53 patients with sinonasal carcinoma and that of the nasal cavity, paranasal sinus or both except lymphoma were included. All patients were treated between 1999 and 2017. For tumor volume delineation, all pre-therapeutic images were fused to the planning CT (computed tomography). Results: The median follow-up was 17 months [0.3–60], the median age 60 years, 35 males and 18 females were included. Squamous cell carcinoma (SCC) (60.4%) was the predominant histology, followed by adenocarcinoma (15.1%). The mean composite OS (overall survival) time was 33.3 ± 3.5 months. There was no significant difference in the 5 y composite OS between tumor localization or radiotherapy setting. The simultaneous integrated boost concept showed a trend towards improving five-year composite OS compared to the sequential boost concept. The only factor with a significant impact on the 5 y composite OS rate was the pre-therapeutic GTV (cutoff 75 cm3; p = 0.033). The GTV ≥ 100 cm3 has no effect on the 5 y composite OS rate for SCC. Conclusions: The pre-therapeutic GTV is a prognostic factor for five-year composite OS for the entire group of patients with sinonasal tumors, influencing the outcome after completion of all treatment strategies. The GTV seems to not influence five-year composite OS in SCC. For this rare tumor entity, an intensive, multidisciplinary discussion is essential to finding the best treatment option for the patient.
Sequence Neighborhoods Enable Reliable Prediction of Pathogenic Mutations in Cancer Genomes
Authors: Banerjee Shayantan , Raman Karthik , Ravindran Balaraman
Published: May 2021

Identifying cancer-causing mutations from sequenced cancer genomes hold much promise for targeted therapy and precision medicine. “Driver” mutations are primarily responsible for cancer progression, while “passengers” are functionally neutral. Although several computational approaches have been developed for distinguishing between driver and passenger mutations, very few have concentrated on using the raw nucleotide sequences surrounding a particular mutation as potential features for building predictive models. Using experimentally validated cancer mutation data in this study, we explored various string-based feature representation techniques to incorporate information on the neighborhood bases immediately 5′ and 3′ from each mutated position. Density estimation methods showed significant distributional differences between the neighborhood bases surrounding driver and passenger mutations. Binary classification models derived using repeated cross-validation experiments provided comparable performances across all window sizes. Integrating sequence features derived from raw nucleotide sequences with other genomic, structural, and evolutionary features resulted in the development of a pan-cancer mutation effect prediction tool, NBDriver, which was highly efficient in identifying pathogenic variants from five independent validation datasets. An ensemble predictor obtained by combining the predictions from NBDriver with three other commonly used driver prediction tools (FATHMM (cancer), CONDEL, and MutationTaster) significantly outperformed existing pan-cancer models in prioritizing a literature-curated list of driver and passenger mutations. Using the list of true positive mutation predictions derived from NBDriver, we identified a list of 138 known driver genes with functional evidence from various sources. Overall, our study underscores the efficacy of using raw nucleotide sequences as features to distinguish between driver and passenger mutations from sequenced cancer genomes.
Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: A Big and Intriguing Challenge Which May Be Resolved by Integrated Treatments Combining Locoregional and Systemic Therapies
Authors: Ionna Franco , Bossi Paolo , Guida Agostino , Alberti Andrea , Muto Paolo , Salzano Giovanni , Ottaiano Alessandro , Maglitto Fabio , Leopardo Davide , De Felice Marco , Longo Francesco , Tafuto Salvatore , Della Vittoria Scarpati Giuseppina , Perri Francesco
Published: May 2021

Squamous cell carcinoma of the head and neck (SCCHN) is a complex group of malignancies, posing several challenges to treating physicians. Most patients are diagnosed with a locally advanced disease and treated with strategies integrating surgery, chemotherapy, and radiotherapy. About 50% of these patients will experience a recurrence of disease. Recurrent/metastatic SCCHN have poor prognosis with a median survival of about 12 months despite treatments. In the last years, the strategy to manage recurrent/metastatic SCCHN has profoundly evolved. Salvage treatments (surgery or re-irradiation) are commonly employed in patients suffering from locoregional recurrences and their role has gained more and more importance in the last years. Re-irradiation, using some particularly fractionating schedules, has the dual task of reducing the tumor mass and eliciting an immune response against cancer (abscopal effect). In this review, we will analyze the main systemic and/or locoregional strategies aimed at facing the recurrent/metastatic disease, underlining the enormous importance of the multidisciplinary approach in these types of patients.
Transferrin Modified GSH Sensitive Hyaluronic Acid Derivative Micelle to Deliver HSP90 Inhibitors to Enhance the Therapeutic Efficacy of Brain Cancers
Authors: Debele Tilahun Ayane , Wu Ping-Ching , Wei Yu-Feng , Chuang Jian-Ying , Chang Kwang-Yu , Tsai Jui-Hung , Su Wen-Pin
Published: May 2021

Herein, GSH-sensitive hyaluronic acid-poly(lactic-co-glycolic acid) (HA-SS-PLGA) was synthesized. Surface modification of PLGA with hyaluronic acid produced a highly stable micelle at physiological pH while a micelle was destabilized at a higher GSH level. Fluorescence microscopy results showed that rhodamine-encapsulated micelle was taken up by brain cancer cells, while competitive inhibition was observed in the presence of free HA and free transferrin. In vitro cytotoxicity results revealed that transferrin-targeted nanoformulated AUY922 (TF-NP-AUY922) shows higher cytotoxicity than either free AUY922 or non-targeted AUY922-loaded micelles (NP-AUY922). In comparison to the control groups, free AUY922, TF-NP-AUY922 or NP-AUY922 treatment revealed the upregulation of HSP70, while the expression of HSP90 client proteins was simultaneously depleted. In addition, the treatment group induced caspase-dependent PARP cleavage and the upregulation of p53 expression, which plays a key role in apoptosis of brain cancer cells. In vivo and ex vivo biodistribution studies showed that cypate-loaded micelle was taken up and accumulated in the tumor regions. Furthermore, in vivo therapeutic efficacy studies revealed that the AUY922-loaded micelle significantly suppressed tumor growth in comparison to the free AUY922, or control groups using tumor-bearing NOD-SCID mice. Moreover, biochemical index and histological analysis revealed synthesized micelle does not show any significant cytotoxicity to the selected major organs. Overall, a synthesized micelle is the best carrier for AUY922 to enhance the therapeutic efficiency of brain cancer.