bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacteriocins from Lactic Acid Bacteria. A Powerful Alternative as Antimicrobials, Probiotics, and Immunomodulators in Veterinary Medicine
Authors: Hernández-González Juan Carlos , Martínez-Tapia Abigail , Lazcano-Hernández Gebim , García-Pérez Blanca Estela , Castrejón-Jiménez Nayeli Shantal
Published: April 2021

In the search for an alternative treatment to reduce antimicrobial resistance, bacteriocins shine a light on reducing this problem in public and animal health. Bacteriocins are peptides synthesized by bacteria that can inhibit the growth of other bacteria and fungi, parasites, and viruses. Lactic acid bacteria (LAB) are a group of bacteria that produce bacteriocins; their mechanism of action can replace antibiotics and prevent bacterial resistance. In veterinary medicine, LAB and bacteriocins have been used as antimicrobials and probiotics. However, another critical role of bacteriocins is their immunomodulatory effect. This review shows the advances in applying bacteriocins in animal production and veterinary medicine, highlighting their biological roles.
Diseases Caused by Amoebae in Fish: An Overview
Authors: Padrós Francesc , Constenla Maria
Published: April 2021

Parasitic and amphizoic amoebae are ubiquitous and can affect a huge variety of hosts, from invertebrates to humans, and fish are not an exception. Most of the relationships between amoebae and fish are based on four different types: ectocommensals, ectoparasites, endocommensals and endoparasites, although the lines between them are not always clear. As ectocommensals, they are located specially on the gills and particularly the amphizoic Neoparamoeba perurans is the most relevant species, being a real pathogenic parasite in farmed salmon. It causes amoebic gill disease, which causes a progressive hyperplasia of epithelial cells in the gill filaments and lamellae. Nodular gill disease is its analogue in freshwater fish but the causative agent is still not clear, although several amoebae have been identified associated to the lesions. Other species have been described in different fish species, affecting not only gills but also other organs, even internal ones. In some cases, species of the genera Naegleria or Acanthamoeba, which also contain pathogenic species affecting humans, are usually described affecting freshwater fish species. As endocommensals, Entamoebae species have been described in the digestive tract of freshwater and marine fish species, but Endolimax nana can reach other organs and cause systemic infections in farmed Solea senegalensis. Other systemic infections caused by amoebae are usually described in wild fish, although in most cases these are isolated cases without clinical signs or significance.
Complexity of the Nano-Bio Interface and the Tortuous Path of Metal Oxides in Biological Systems
Authors: Erlichman Joseph S. , Leiter James C.
Published: April 2021

Metal oxide nanoparticles (NPs) have received a great deal of attention as potential theranostic agents. Despite extensive work on a wide variety of metal oxide NPs, few chemically active metal oxide NPs have received Food and Drug Administration (FDA) clearance. The clinical translation of metal oxide NP activity, which often looks so promising in preclinical studies, has not progressed as rapidly as one might expect. The lack of FDA approval for metal oxide NPs appears to be a consequence of the complex transformation of NP chemistry as any given NP passes through multiple extra- and intracellular environments and interacts with a variety of proteins and transport processes that may degrade or transform the chemical properties of the metal oxide NP. Moreover, the translational models frequently used to study these materials do not represent the final therapeutic environment well, and studies in reduced preparations have, all too frequently, predicted fundamentally different physico-chemical properties from the biological activity observed in intact organisms. Understanding the evolving pharmacology of metal oxide NPs as they interact with biological systems is critical to establish translational test systems that effectively predict future theranostic activity.
The Effect of Biogas Origin on the Electricity Production by Solid Oxide Fuel Cells
Authors: Prodromidis George N. , Coutelieris Frank A.
Published: April 2021

This work simulates electricity production in a Solid Oxide Fuel Cell (SOFC)-based power plant, fed by biogas of various compositions. Steam reforming of the gas feed stream is used to produce the required supply for the SOFC. Given the constraints of the feed stream compositions, resulting from the origin of biogas, i.e., by the biomass from which the biogas has been produced as well as by the operating conditions selected for its production, the overall plant performance is modelled in terms of energy and exergy. The model provides results on the efficiency, power output and thermal behavior of the system, thus presenting the potential to offer great advantages in generating electricity from biogas and reducing the environmental impact. This research study presents the efficiency of such a system in terms of energy and exergy, by considering several values of the operational parameters (extensions of reactions that take place in the apparatus, temperatures, feed stream compositions, etc.). It is found that moving towards a methane richer fuel, the energy and exergy efficiency can remain almost constant at high levels (around 70%), while in absolute value the electric energy can increase up to 35% according to the system’s needs. Therefore, under this prospect, the present research study reveals the usefulness of low content methane fuels, which through the optimization process can succeed identical energy management compared to high content methane fuels.
SIoTFuzzer: Fuzzing Web Interface in IoT Firmware via Stateful Message Generation
Authors: Zhang Hangwei , Lu Kai , Zhou Xu , Yin Qidi , Wang Pengfei , Yue Tai
Published: April 2021

Cyber attacks against the web management interface of Internet of Things (IoT) devices often have serious consequences. Current research uses fuzzing technologies to test the web interfaces of IoT devices. These IoT fuzzers generate messages (a test case sent from the client to the server to test its functionality) without considering their dependency, which is unlikely to bypass the early check of the server. These invalid test cases significantly reduce the efficiency of fuzzing. To overcome this problem, we propose a stateful message generation (SMG) mechanism for IoT web fuzzing. SMG addresses two problems in IoT fuzzing. First, we retrieve the message dependency by using web front-end analysis and status analysis. These dependent messages, which can easily bypass the server check, are used as a valid seed. Second, we adopt a multi-message seed format to preserve the dependency of the messages when mutating the seed to get a valid test case, so that the test case can bypass the state check of the server to make a valid test. Message dependency preservation is implemented by our proposed parameter mutation and structural mutation methods. We implement SMG in our IoT fuzzer, SIoTFuzzer, which applies IoT firmware on the latest Linux-based simulation tool, FirmAE. We test nine IoT devices including a router and an IP camera and adopt a vulnerability detection mechanism. Our evaluation results show that (1) SIoTFuzzer is capable of finding real-world vulnerabilities in IoT devices; (2) our SMG is effective as it enables Boofuzz (a popular protocol fuzzer) to find command injection and cross-site scripting (XSS) vulnerabilities; and (3) compared to FirmFuzz, SIoTFuzzer found all the vulnerabilities in our benchmarks, while FirmFuzz found only four—the efficiency of our tool increased by 20.57% on average.
A Hybrid Hidden Markov Model for Pipeline Leakage Detection
Authors: Zhang Mingchi , Chen Xuemin , Li Wei
Published: April 2021

In this paper, a deep neural network hidden Markov model (DNN-HMM) is proposed to detect pipeline leakage location. A long pipeline is divided into several sections and the leakage occurs in different section that is defined as different state of hidden Markov model (HMM). The hybrid HMM, i.e., DNN-HMM, consists of a deep neural network (DNN) with multiple layers to exploit the non-linear data. The DNN is initialized by using a deep belief network (DBN). The DBN is a pre-trained model built by stacking top-down restricted Boltzmann machines (RBM) that compute the emission probabilities for the HMM instead of Gaussian mixture model (GMM). Two comparative studies based on different numbers of states using Gaussian mixture model-hidden Markov model (GMM-HMM) and DNN-HMM are performed. The accuracy of the testing performance between detected state sequence and actual state sequence is measured by micro F1 score. The micro F1 score approaches 0.94 for GMM-HMM method and it is close to 0.95 for DNN-HMM method when the pipeline is divided into three sections. In the experiment that divides the pipeline as five sections, the micro F1 score for GMM-HMM is 0.69, while it approaches 0.96 with DNN-HMM method. The results demonstrate that the DNN-HMM can learn a better model of non-linear data and achieve better performance compared to GMM-HMM method.
The Influence of Viburnum opulus Fruits Addition on Some Quality Properties of Homogenized Meat Products
Authors: Mazur Monika , Salejda Anna Marietta , Pilarska Kinga Maria , Krasnowska Grażyna , Nawirska-Olszańska Agnieszka , Kolniak-Ostek Joanna , Bąbelewski Przemysław
Published: April 2021

This review describes the effect of added freeze-dried guelder rose fruit powder (GRFP) on the quality parameter of homogenized meat products (HMP). In this study, the pH, cooking loss, instrumental color (L*, a* and b*), texture profile, TBARS (Thiobarbituric acid reactive substances), antimicrobial assay, polyphenol content and sensory evaluation of HMP were evaluated. Due to the antioxidant activity of guelder rose fruit (the chlorogenic acid dominated among the identified compounds of the fruit), it was observed that, in the samples with the highest amount of the extract, the amount of microorganisms responsible for food spoilage decreased after storage time (14 days, 4 °C). The addition of lyophilized fruits with a low pH value resulted in the highest cooking loss. The results of sensory evaluation show that, along with the increase of GRFP addition, the taste and smell of meat products become less acceptable. The bitter taste of guelder rose fruit can affect the sensory assessment of meat products. This study is of a pilot nature; further research attempts will be made to offset the problems and design certain solutions, e.g., the use of freeze-dried encapsulation and its addition to meat products.
Uncertainty of the 2D Resistivity Survey on the Subsurface Cavities
Authors: Doyoro Yonatan Garkebo , Chang Ping-Yu , Puntu Jordi Mahardika
Published: April 2021

We examined the uncertainty of the two-dimensional (2D) resistivity method using conceptual cavity models. The experimental cavity study was conducted to validate numerical model results. Spatial resolution and sensitivity to resistivity perturbations were also assessed using checkerboard tests. Conceptual models were simulated to generate synthetic resistivity data for dipole-dipole (DD), pole-dipole (PD), Wenner–Schlumberger (WS), and pole-pole (PP) arrays. The synthetically measured resistivity data were inverted to obtain the geoelectric models. The highest anomaly effect (1.46) and variance (24,400 Ω·m) in resistivity data were recovered by the DD array, whereas the PP array obtained the lowest anomaly effect (0.60) and variance (2401 Ω·m) for the shallowest target cavity set at 2.2 m depth. The anomaly effect and variance showed direct dependency on the quality of the inverted models. The DD array provided the highest model resolution that shows relatively distinct anomaly geometries. In contrast, the PD and WS arrays recovered good resolutions, but it is challenging to determine the correct anomaly geometries with them. The PP array reproduced the lowest resolution with less precise anomaly geometries. Moreover, all the tested arrays showed high sensitivity to the resistivity contrasts at shallow depth. The DD and WS arrays displayed the higher sensitivity to the resistivity perturbations compared to the PD and PP arrays. The inverted models showed a reduction in sensitivity, model resolution, and accuracy at deeper depths, creating ambiguity in resistivity model interpretations. Despite these uncertainties, our modeling specified that two-dimensional resistivity imaging is a potential technique to study subsurface cavities. We inferred that the DD array is the most appropriate for cavity surveys. The PD and WS arrays are adequate, while the PP array is the least suitable for cavity studies.
Aerodynamics Analysis of Speed Skating Helmets: Investigation by CFD Simulations
Authors: Puelles Magán Guillermo , Terra Wouter , Sciacchitano Andrea
Published: April 2021

In this work, we investigate the flow field around speed skating helmets and their associated aerodynamic drag by means of computational fluid dynamics (CFD) simulations. An existing helmet frequently used in competition was taken as a baseline. Six additional helmet designs, as well as the bare-head configuration, were analysed. All the numerical simulations were performed via 3D RANS simulations using the SST k-ω turbulence model. The results show that the use of a helmet always reduces the aerodynamic drag with respect to the bare head configuration. Besides, an optimised helmet design enables a reduction of the skaters aerodynamic drag by 5.9%, with respect to the bare-head configuration, and by 1.6% with respect to the use of the baseline Omega helmet.
Vision-Based Pavement Marking Detection and Condition Assessment—A Case Study
Authors: Xu Shuyuan , Wang Jun , Wu Peng , Shou Wenchi , Wang Xiangyu , Chen Mengcheng
Published: April 2021

Pavement markings constitute an effective way of conveying regulations and guidance to drivers. They constitute the most fundamental way to communicate with road users, thus, greatly contributing to ensuring safety and order on roads. However, due to the increasingly extensive traffic demand, pavement markings are subject to a series of deterioration issues (e.g., wear and tear). Markings in poor condition typically manifest as being blurred or even missing in certain places. The need for proper maintenance strategies on roadway markings, such as repainting, can only be determined based on a comprehensive understanding of their as-is worn condition. Given the fact that an efficient, automated and accurate approach to collect such condition information is lacking in practice, this study proposes a vision-based framework for pavement marking detection and condition assessment. A hybrid feature detector and a threshold-based method were used for line marking identification and classification. For each identified line marking, its worn/blurred severity level was then quantified in terms of worn percentage at a pixel level. The damage estimation results were compared to manual measurements for evaluation, indicating that the proposed method is capable of providing indicative knowledge about the as-is condition of pavement markings. This paper demonstrates the promising potential of computer vision in the infrastructure sector, in terms of implementing a wider range of managerial operations for roadway management.
VAGADRONE: Intelligent and Fully Automatic Drone Based on Raspberry Pi and Android
Authors: Benhadhria Saifeddine , Mansouri Mohamed , Benkhlifa Ameni , Gharbi Imed , Jlili Nadhem
Published: April 2021

Multirotor drones are widely used currently in several areas of life. Their suitable size and the tasks that they can perform are their main advantages. However, to the best of our knowledge, they must be controlled via remote control to fly from one point to another, and they can only be used for a specific mission (tracking, searching, computing, and so on). In this paper, we intend to present an autonomous UAV based on Raspberry Pi and Android. Android offers a wide range of applications for direct use by the UAV depending on the context of the assigned mission. The applications cover a large number of areas such as object identification, facial recognition, and counting objects such as panels, people, and so on. In addition, the proposed UAV calculates optimal trajectories, provides autonomous navigation without external control, detects obstacles, and ensures live streaming during the mission. Experiments are carried out to test the above-mentioned criteria.
Cervical Vertebral Maturation Method: Reproducibility and Efficiency of Chronological Age Estimation
Authors: Schoretsaniti Lydia , Mitsea Anastasia , Karayianni Kety , Sifakakis Iosif
Published: April 2021

The aim of this study was to investigate the reproducibility of the Cervical Vertebral Maturation (CVM) method and the potential for chronological age estimation using this method. The sample consisted of 474 lateral cephalometric radiographs, from orthodontic patients aged 6.4–22.4 years. Six raters were trained to the CVM method (Baccetti). All images were assessed twice. Intra- and inter-rater agreements were assessed by Cohen’s weighted kappa and intraclass correlation coefficient, respectively. Analysis of variance was performed to investigate the correlation between cervical maturation stages and chronological age. The age prediction potential of the method was tested by general linear model regression analysis. Intra-rater reliability ranged from 0.857 to 0.931. Intra-rater absolute agreement ranged from 77% to 87% however inter-rater absolute agreement was lower than 50%. Inter-rater reliability was higher than 0.9. The 3rd Cervical Maturation Stage (CS3) showed the lowest reproducibility. The mean age differences among the 6 CS stages were statistically significant and increased as the CS increased. CS and gender could roughly explain the 60% (adjusted R2 = 0.61) of the age variance of the sample. This CVM method proved able to show high reliability; however, it cannot predict accurately the pubertal growth spurt. A direct correlation was found between cervical stages and chronological age. This method provides a broad estimation of chronological age.
The Neural Network Assisted Land Use Regression
Authors: Bitta Jan , Svozilík Vladislav , Svozilíková Krakovská Aneta
Published: April 2021

Land Use Regression (LUR) is one of the air quality assessment modelling techniques. Its advantages lie mainly in a much simpler mathematical apparatus, quicker and simpler calculations, and a possibility to incorporate more factors affecting pollutant concentration than standard dispersion models. The goal of the study was to perform the LUR model in the Polish-Czech-Slovakian Tritia region, to test two sets of pollution data input factors, i.e., factors based on emission data and pollution dispersion model results, to test regression via neural networks and compare it with standard linear regression. Both input datasets, emission data and pollution dispersion model results, provided a similar quality of results in the case when standard linear regression was used, the R2 of the models was 0.639 and 0.652. Neural network regression provided a significantly higher quality of the models, their R2 was 0.937 and 0.938 for the factors based on emission data and pollution dispersion model results respectively.
Diameter Estimation of Fallopian Tubes Using Visual Sensing
Authors: Hajiyavand Amir M. , Graham Matthew J. , Dearn Karl D.
Published: April 2021

Calculating an accurate diameter of arbitrary vessel-like shapes from 2D images is of great use in various applications within medical and biomedical fields. Understanding the changes in morphological dimensioning of the biological vessels provides a better understanding of their properties and functionality. Estimating the diameter of the tubes is very challenging as the dimensions change continuously along its length. This paper describes a novel algorithm that estimates the diameter of biological tubes with a continuously changing cross-section. The algorithm, evaluated using various controlled images, provides an automated diameter estimation with higher and better accuracy than manual measurements and provides precise information about the diametrical changes along the tube. It is demonstrated that the automated algorithm provides more accurate results in a much shorter time. This methodology has the potential to speed up diagnostic procedures in a wide range of medical fields.
Overview on the Nonlinear Static Procedures and Performance-Based Approach on Modern Unreinforced Masonry Buildings with Structural Irregularity
Authors: Aşıkoğlu Abide , Vasconcelos Graça , Lourenço Paulo B.
Published: April 2021

Performance-based design plays a significant role in the structural and earthquake engineering community to ensure both safety and economic feasibility. Its application to masonry building design/assessment is limited and requires straightforward rules considering the characteristics of masonry behavior. Nonlinear static procedures mainly cover regular frame system structures, and their application to both regular and irregular masonry buildings require further investigation. The present paper addresses two major issues: (i) the definition of irregularity in masonry buildings, and (ii) the applicability of classical nonlinear static procedures to irregular masonry buildings. It is observed that the irregularity definition is not comprehensive and has different descriptions among the seismic codes as well as among researchers, particularly in the case of masonry buildings. The lack of global language may result in the misuse of the procedures, while adjustments may be essential due to irregularity effects. Therefore, irregularity indices given by different codes and research studies are discussed. Furthermore, an overview of nonlinear static procedures implemented within the framework of the performance-based approach and improvements proposed for its application in masonry buildings is presented.
Site-Specific Metastasis and Survival in Papillary Thyroid Cancer: The Importance of Brain and Multi-Organ Disease
Authors: Toraih Eman A. , Hussein Mohammad H. , Zerfaoui Mourad , Attia Abdallah S. , Marzouk Ellythy Assem , Mostafa Arwa , Ruiz Emmanuelle M. L. , Shama Mohamed Ahmed , Russell Jonathon O. , Randolph Gregory W. , Kandil Emad
Published: April 2021

Introduction—heterogeneity in clinical outcomes and survival was observed in patients with papillary thyroid cancer (PTC) and distant metastases. Here, we investigated the effect of distant metastases sites on survival in PTC patients. Methods—patients with a diagnosis of PTC and known metastases were identified using the Surveillance, Epidemiology, and End Results database (1975–2016). Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on thyroid cancer-specific survival (TCSS) and overall survival (OS). Results—from 89,694 PTC patients, 1819 (2%) developed distant metastasis at the initial diagnosis, of whom 26.3% presented with the multiple-organ disease. The most common metastatic sites were lung (53.4%), followed by bone (28.1%), liver (8.3%), and brain (4.7%). In metastatic patients, thyroid cancer-specific death accounted for 73.2%. Kaplan–Meier curves showed decreased OS in patients with metastases to the brain (median OS = 5 months) and liver (median OS = 6 months) compared to lung (median OS = 10 months) and bone (median OS = 23 months). Moreover, multiple organ metastasis had a higher mortality rate (67.4%) compared to single organ metastasis (51.2%, p < 0.001). Using multivariate analysis, risk factors that significantly influence TCSS and OS were male gender (HR = 1.86, 95% CI = 1.17–2.94, p < 0.001, and HR = 1.90, 95% CI = 1.40–2.57, p = 0.009), higher tumor grade (HR = 7.31, 95% CI = 2.13–25.0, p < 0.001 and HR = 4.76, 95% CI = 3.93–5.76, p < 0.001), multiple organ involvement (HR = 6.52, 95% CI = 1.50–28.39, p = 0.026 and HR = 5.08, 95% CI = 1.21–21.30, p = 0.013), and brain metastasis (HR = 1.82, 95% CI = 1.15–2.89, p < 0.001 and HR = 4.21, 95% CI = 2.20–8.07, p = 0.010). Conclusion—the pattern of distant metastatic organ involvement was associated with variability in OS in PTC. Multi-organ metastasis and brain involvement are associated with lower survival rates in PTC. Knowledge of the patterns of distant metastasis is crucial to personalize the treatment and follow-up strategies.
Non-Canonical Kinases and Substrates in Cancer Progression
Authors: Vega Francisco M.
Published: April 2021

Cellular protein kinases remain the target of choice when the intention is to intervene in a particular signaling pathway leading to cancer progression [...]
Artificial Tumor Microenvironments in Neuroblastoma
Authors: Quinn Colin H. , Beierle Andee M. , Beierle Elizabeth A.
Published: April 2021

In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix proteins to tumor associated macrophages, the TME is a robust and diverse network functioning in symbiosis with the solid tumor. Herein, we review the major components of the TME including the extracellular matrix, cytokines, immune cells, and vasculature that support a more aggressive neuroblastoma phenotype and encumber current therapeutic interventions. Contemporary treatments for neuroblastoma are the result of traditional two-dimensional culture studies and in vivo models that have been translated to clinical trials. These pre-clinical studies are costly, time consuming, and neglect the study of cofounding factors such as the contributions of the TME. Three-dimensional (3D) bioprinting has become a novel approach to studying adult cancers and is just now incorporating portions of the TME and advancing to study pediatric solid. We review the methods of 3D bioprinting, how researchers have included TME pieces into the prints, and highlight present studies using neuroblastoma. Ultimately, incorporating the elements of the TME that affect neuroblastoma responses to therapy will improve the development of innovative and novel treatments. The use of 3D bioprinting to achieve this aim will prove useful in developing optimal therapies for children with neuroblastoma.
Increased Hospitalization and Mortality from COVID-19 in Prostate Cancer Patients
Authors: Chakravarty Dimple , Ratnani Parita , Sobotka Stanislaw , Lundon Dara , Wiklund Peter , Nair Sujit S. , Tewari Ashutosh K.
Published: April 2021

Background: Cancer patients with COVID-19 have a poor disease course. Among tumor types, prostate cancer and COVID-19 share several risk factors, and the interaction of prostate cancer and COVID-19 is purported to have an adverse outcome. Methods: This was a single-institution retrospective study on 286,609 patients who underwent the COVID-19 test at Mount Sinai Hospital system from March 2020 to December 2020. Chi-square/Fisher’s exact tests were used to summarize baseline characteristics of categorical data, and Mann–Whitney U test was used for continuous variables. Univariable logistic regression analysis to compare the hospitalization and mortality rates and the strength of association was obtained by the odds ratio and confidence interval. Results: This study aimed to compare hospitalization and mortality rates between men with COVID-19 and prostate cancer and those who were COVID-19-positive with non-prostate genitourinary malignancy or any solid cancer, and with breast cancer patients. We also compared our studies to others that reported the incidence and severity of COVID-19 in prostate cancer patients. Our studies highlight that patients with prostate cancer had higher susceptibility to COVID-19-related pathogenesis, resulting in higher mortality and hospitalization rates. Hospitalization and mortality rates were higher in prostate cancer patients with COVID-19 when compared with COVID-19 patients with non-prostate genitourinary (GU) malignancies.
Multiple Myeloma Patients Undergoing Carfilzomib: Development and Validation of a Risk Score for Cardiovascular Adverse Events Prediction
Authors: Astarita Anna , Mingrone Giulia , Airale Lorenzo , Vallelonga Fabrizio , Covella Michele , Catarinella Cinzia , Cesareo Marco , Bruno Giulia , Leone Dario , Giordana Carlo , Cetani Giusy , Salvini Marco , Gay Francesca , Bringhen Sara , Rabbia Franco , Veglio Franco , Milan Alberto
Published: April 2021

Cardiovascular adverse events (CVAEs) are linked to Carfilzomib (CFZ) therapy in multiple myeloma (MM); however, no validated protocols on cardiovascular risk assessment are available. In this prospective study, the effectiveness of the European Myeloma Network protocol (EMN) in cardiovascular risk assessment was investigated, identifying major predictors of CVAEs. From January 2015 to March 2020, 116 MM patients who had indication for CFZ therapy underwent a baseline evaluation (including blood pressure measurements, echocardiography and arterial stiffness estimation) and were prospectively followed. The median age was 64.53 ± 8.42 years old, 56% male. Five baseline independent predictors of CVAEs were identified: office systolic blood pressure, 24-h blood pressure variability, left ventricular hypertrophy, pulse wave velocity value and global longitudinal strain. The resulting ‘CVAEs risk score’ distinguished a low- and a high-risk group, obtaining a negative predicting value for the high-risk group of 90%. 52 patients (44.9%) experienced one or more CVAEs: 17 (14.7%) had major and 45 (38.7%) had hypertension-related events. In conclusion, CVAEs are frequent and a specific management protocol is crucial. The EMN protocol and the risk score proved to be useful to estimate the baseline risk for CVAEs during CFZ therapy, allowing the identification of higher-risk patients.
An Fc-Optimized CD133 Antibody for Induction of NK Cell Reactivity against B Cell Acute Lymphoblastic Leukemia
Authors: Riegg Fabian , Lutz Martina S. , Schmied Bastian J. , Heitmann Jonas S. , Queudeville Manon , Lang Peter , Jung Gundram , Salih Helmut R. , Märklin Melanie
Published: April 2021

In recent decades, antibody-dependent cellular cytotoxicity (ADCC)-inducing monoclonal antibodies (mAbs) have revolutionized cancer immunotherapy, and Fc engineering strategies have been utilized to further improve efficacy. A promising option is to enhance the affinity of an antibody’s Fc-part to the Fc-receptor CD16 by altering the amino acid sequence. Herein, we characterized an S239D/I332E-modified CD133 mAb termed 293C3-SDIE for treatment of B cell acute lymphoblastic leukemia (B-ALL). Flow cytometric analysis revealed CD133 expression on B-ALL cell lines and leukemic cells of 50% (14 of 28) B-ALL patients. 293C3-SDIE potently induced NK cell reactivity against the B-ALL cell lines SEM and RS4;11, as well as leukemic cells of B-ALL patients in a target antigen-dependent manner, as revealed by analysis of NK cell activation, degranulation, and cytotoxicity. Of note, CD133 expression did not correlate with BCR-ABL, CD19, CD20, or CD22, which are presently used as therapeutic targets in B-ALL, which revealed CD133 as an independent target for B-ALL treatment. Increased CD133 expression was also observed in MLL-AF4-rearranged B-ALL, indicating that 293C3-SDIE may constitute a particularly suitable treatment option in this hard-to-treat subpopulation. Taken together, our results identify 293C3-SDIE as a promising therapeutic agent for the treatment of B-ALL.
Change in Physical Performance Correlates with Decline in Quality of Life and Frailty Status in Head and Neck Cancer Patients Undergoing Radiation with and without Chemotherapy
Authors: Farrugia Mark , Erickson Kayleigh , Wendel Elizabeth , Platek Mary E. , Ji Wenyan , Attwood Kristopher , Ma Sung Jun , Gu Fangyi , Singh Anurag K. , Ray Andrew D.
Published: April 2021

Patient-reported quality of life (QoL) metrics, frailty status, and physical functioning are emerging concepts in head and neck cancer (HNC) with implications on both treatment decision-making and prognosis. The impact of treatment-related functional decline on QoL and frailty has not been well-characterized in HNC and was the focus of this investigation. Methods: Patients who underwent radiation therapy for HNC from 2018 to 2020 were evaluated as a prospective observational cohort. Functional decline, QoL, and the frailty phenotype were measured via the Short Physical Performance Battery (SPPB), European Organization for Research and Treatment of Cancer (EORTC) qlq-C30, and Fried Frailty index, respectively. Results: A total of 106 HNC patients were included, 75 of which received concurrent chemoradiation therapy (CCRT) and 31 received radiation alone, both with and without surgery. There was a decrease in SPPB overall (p < 0.001) from the beginning to the end of treatment in the CCRT group but not the radiation group (p = 0.43). Change in overall SPPB points following treatment correlated with the decline in physical QoL for both groups (p < 0.05) as well as transition frail status in the CCRT group (p < 0.001) with a trend in the radiation group (p = 0.08). Conclusions: Change in SPPB correlates with QoL and transition to frailty status in patients undergoing definitive CCRT for HNC with similar trends in those receiving radiation alone. Decline in SPPB could potentially be useful in identification of those who may benefit from rehabilitation in future studies.
Targeting the Metabolic Adaptation of Metastatic Cancer
Authors: Tarragó-Celada Josep , Cascante Marta
Published: April 2021

Metabolic adaptation is emerging as an important hallmark of cancer and metastasis. In the last decade, increasing evidence has shown the importance of metabolic alterations underlying the metastatic process, especially in breast cancer metastasis but also in colorectal cancer metastasis. Being the main cause of cancer-related deaths, it is of great importance to developing new therapeutic strategies that specifically target metastatic cells. In this regard, targeting metabolic pathways of metastatic cells is one of the more promising windows for new therapies of metastatic colorectal cancer, where still there are no approved inhibitors against metabolic targets. In this study, we review the recent advances in the field of metabolic adaptation of cancer metastasis, focusing our attention on colorectal cancer. In addition, we also review the current status of metabolic inhibitors for cancer treatment.
Targeting p53 for Melanoma Treatment: Counteracting Tumour Proliferation, Dissemination and Therapeutic Resistance
Authors: Loureiro Joana B. , Raimundo Liliana , Calheiros Juliana , Carvalho Carla , Barcherini Valentina , Lima Nuno R. , Gomes Célia , Almeida Maria Inês , Alves Marco G. , Costa José Luís , Santos Maria M. M. , Saraiva Lucília
Published: April 2021

Melanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outcomes for p53 activators in melanoma therapy. Herein, we aimed to investigate the antitumor potential of the p53-activating agent SLMP53-2 against melanoma. Two- and three-dimensional cell cultures and xenograft mouse models were used to unveil the antitumor activity and the underlying molecular mechanism of SLMP53-2 in melanoma. SLMP53-2 inhibited the growth of human melanoma cells in a p53-dependent manner through induction of cell cycle arrest and apoptosis. Notably, SLMP53-2 induced p53 stabilization by disrupting the p53–MDM2 interaction, enhancing p53 transcriptional activity. It also promoted the expression of p53-regulated microRNAs (miRNAs), including miR-145 and miR-23a. Moreover, it displayed anti-invasive and antimigratory properties in melanoma cells by inhibiting the epithelial-to-mesenchymal transition (EMT), angiogenesis and extracellular lactate production. Importantly, SLMP53-2 did not induce resistance in melanoma cells. Additionally, it synergized with vemurafenib, dacarbazine and cisplatin, and resensitized vemurafenib-resistant cells. SLMP53-2 also exhibited antitumor activity in human melanoma xenograft mouse models by repressing cell proliferation and EMT while stimulating apoptosis. This work discloses the p53-activating agent SLMP53-2 which has promising therapeutic potential in advanced melanoma, either as a single agent or in combination therapy. By targeting p53, SLMP53-2 may counteract major features of melanoma aggressiveness.
Clinical Implications of Geometric and Dosimetric Uncertainties of Inter- and Intra-Fractional Movement during Volumetric Modulated Arc Therapy for Breast Cancer Patients
Authors: Lee Jason Joon Bock , Lee Ik Jae , Choi Yeonho , Jeon Mi Jin , Jung Il Hun , Lee Ho
Published: April 2021

With the introduction of modern sophisticated radiotherapy (RT) techniques, the significance of accuracy has increased considerably. This study evaluated the necessity of pre-treatment and intra-fractional cone-beam computed tomography (CBCT) by analyzing inter- and intra-fractional CBCT images of breast cancer patients receiving RT. From 57 patients, 1206 pre-treatment CBCT and 1067 intra-fractional CBCT images were collected. Geometric movements of patients were measured quantitively in both inter- and intra-fractional CBCT, and changes in dosimetric parameters were evaluated in selected patients with extreme intra-fractional movement. For right-sided breast cancer patients, left-sided breast cancer patients treated using deep-inspiration breath hold (DIBH), and left-sided breast cancer patients treated using continuous positive airway pressure (CPAP), median inter-fractional deviations were 0.53 (range 0.06–2.98) cm, 0.66 (range 0.08–4.41) cm, and 0.69 (range 0.04–3.80) cm, and median intra-fractional deviations were 0.14 (range 0.00–0.62) cm, 0.23 (range 0.02–0.96) cm, and 0.24 (0.00–1.15) cm, respectively. Modified plans reflecting large changes in intra-fractional position in 10 selected cases revealed insufficient target coverage in seven cases and more than 20-fold increase in the volume of heart receiving at least 25 Gy in two cases. Intra-fractional verification, as well as pre-treatment verification, might be considered in patients using DIBH or CPAP.
Histological Features of Sporadic and Familial Testicular Germ Cell Tumors Compared and Analysis of Age-Related Changes of Histology
Authors: Stang Andreas , McMaster Mary L. , Sesterhenn Isabell A. , Rapley Elizabeth , Huddart Robert , Heimdal Ketil , McGlynn Katherine A. , Oosterhuis Jan Wolter , Greene Mark H.
Published: April 2021

This study aimed to compare histological features of familial and sporadic testicular germ cell tumors (TGCTs) and surrounding parenchyma, since discriminating features might be etiologically relevant and clinically useful. The study of parenchyma was prompted by reports claiming a higher prevalence of testicular microlithiasis in familial cases. Histological features of TGCTs and surrounding parenchyma of 296 sporadic and 305 familial cases were compared. For each case, one representative hematoxylin and eosin-stained slide was available. Slides were independently scored by two expert pathologists using a semi-quantitative data abstract. Discrepancies were resolved by consensus. A logistic regression model was used to assess the ability to discriminate between sporadic and familial GCT. The histological composition of a tumor, amount of lymphocytic infiltration, amount of germ cell neoplasia in situ (GCNIS), and presence of testicular microlithiasis (TM) did not discriminate between sporadic and familial GCT (area under the curve 0.56, 95%CI 0.51–0.61). Novel observations included increasing lymphocytic infiltration and decreasing GCNIS and TM with increasing age at diagnosis. The presence of tubules with infiltrating lymphocytes was mainly associated with pure seminomas and nonseminomas with a seminoma component. Among seminomas, tubules with infiltrating lymphocytes decreased with increasing age. No discernable differences between sporadic and familial TGCTs were found. The age-related changes in the tumors and surrounding parenchyma in these groups combined are consistent with a host response building up over time predominantly affecting seminomas, the seminoma-component of nonseminomas and GCNIS. TM may gradually dissolve with age. Our hypothesis that histological differences between sporadic and familial TGCT might identify genetically distinct disease subsets was not supported.
Perceptions of Chinese Patients Treated for Gynaecological Cancer about Sexual Health and Sexual Information Provided by Healthcare Professionals: A Qualitative Study
Authors: Chow Ka Ming , Chan Carmen W. H. , Law Bernard M. H.
Published: April 2021

Patients treated for gynaecological cancer (GC) generally experience impaired sexual function. Research on their sexual life experiences and perceptions on the sexuality care they receive is warranted. This study aimed to examine the perceptions of Chinese patients treated for GC regarding the effects of cancer treatment on their sexual function and femininity, their relationships with their partners, and the adequacy of the sexual information received from healthcare professionals during treatment. Individual, semi-structured interviews were conducted with 21 Chinese patients treated for GC, collecting data on their perceptions regarding the effects of cancer treatment on their sexual lives, femininity, and relationships with partners; and their views about the quality of sexuality care received. Data were analysed using content analysis. Participants experienced impaired sexual function, reduced sex drive, and expressed dissatisfaction with their sex lives. They perceived a loss of femininity and poor body image. They desired more information about how to address sexual problems and opted to receive this information from female healthcare professionals in individual counselling sessions during which the professionals could initiate such discussions. Overall, Chinese patients treated for GC have concerns about multiple sexual issues and a strong desire for information about strategies to address these issues. Nurse-led interventions should be implemented via a shared care approach to enhance patients’ awareness about managing their sexual and psychological symptoms.
Clinical Activity of an hTERT-Specific Cancer Vaccine (Vx-001) in “Immune Desert” NSCLC
Authors: Pateras Ioannis S. , Kotsakis Athanasios , Avgeris Margaritis , Baliou Evangelia , Kouroupakis Panagiotis , Patsea Eleni , Georgoulias Vassilis , Menez-Jamet Jeanne , Kinet Jean-Pierre , Kosmatopoulos Kostas
Published: April 2021

Background: Tumors can be separated into immunogenic/hot and non-immunogenic/cold on the basis of the presence of tumor-infiltrating lymphocytes (TILs), the expression of PD-L1 and the tumor mutation burden (TMB). In immunogenic tumors, TILs become unable to control tumor growth because their activity is suppressed by different inhibitory pathways, including PD-1/PD-L1. We hypothesized that tumor vaccines may not be active in the immunosuppressive microenvironment of immunogenic/hot tumors while they could be efficient in the immune naïve microenvironment of non-immunogenic/cold tumors. Methods: The randomized phase II Vx-001-201 study investigated the effect of the Vx-001 vaccine as maintenance treatment in metastatic non-small cell lung cancer (NSCLC) patients. Biopsies from 131 (68 placebo and 63 Vx-001) patients were retrospectively analyzed for PD-L1 expression and TIL infiltration. TILs were measured as tumor-associated immune cells (TAICs), CD3-TILs, CD8-TILs and granzyme B-producing TILs (GZMB-TILs). Patients were distinguished into PD-L1(+) and PD-L1(-) and into TIL high and TIL low. Findings: There was no correlation between PD-L1 expression and Vx-001 clinical activity. In contrast, Vx-001 showed a significant improvement of overall survival (OS) vs. placebo in TAIC low (21 vs. 8.1 months, p = 0.003, HR = 0.404, 95% CI 0.219–0.745), CD3-TIL low (21.6 vs. 6.6 months, p < 0.001, HR = 0.279, 95% CI 0.131–0.595), CD8-TIL low (21 vs. 6.6 months, p < 0.001; HR = 0.240, 95% CI 0.11–0.522) and GZMB-TIL low (20.7 vs. 11.1 months, p = 0.011, HR = 0.490, 95% CI 0.278–0.863). Vx-001 did not offer any clinical benefit in patients with TAIC high, CD3-TIL high, CD8-TIL high or GZMB-TIL high tumors. CD3-TIL, CD8-TIL and GZMB-TIL were independent predictive factors of Vx-001 efficacy. Conclusions: These results support the hypothesis that Vx-001 may be efficient in patients with non-immunogenic/cold but not with immunogenic/hot tumors.
ImmunoAIzer: A Deep Learning-Based Computational Framework to Characterize Cell Distribution and Gene Mutation in Tumor Microenvironment
Authors: Bian Chang , Wang Yu , Lu Zhihao , An Yu , Wang Hanfan , Kong Lingxin , Du Yang , Tian Jie
Published: April 2021

Spatial distribution of tumor infiltrating lymphocytes (TILs) and cancer cells in the tumor microenvironment (TME) along with tumor gene mutation status are of vital importance to the guidance of cancer immunotherapy and prognoses. In this work, we developed a deep learning-based computational framework, termed ImmunoAIzer, which involves: (1) the implementation of a semi-supervised strategy to train a cellular biomarker distribution prediction network (CBDPN) to make predictions of spatial distributions of CD3, CD20, PanCK, and DAPI biomarkers in the tumor microenvironment with an accuracy of 90.4%; (2) using CBDPN to select tumor areas on hematoxylin and eosin (H&E) staining tissue slides and training a multilabel tumor gene mutation detection network (TGMDN), which can detect APC, KRAS, and TP53 mutations with area-under-the-curve (AUC) values of 0.76, 0.77, and 0.79. These findings suggest that ImmunoAIzer could provide comprehensive information of cell distribution and tumor gene mutation status of colon cancer patients efficiently and less costly; hence, it could serve as an effective auxiliary tool for the guidance of immunotherapy and prognoses. The method is also generalizable and has the potential to be extended for application to other types of cancers other than colon cancer.
O-GlcNAcylation and O-GlcNAc Cycling Regulate Gene Transcription: Emerging Roles in Cancer
Authors: Parker Matthew P. , Peterson Kenneth R. , Slawson Chad
Published: April 2021

O-linked β-N-acetylglucosamine (O-GlcNAc) is a single sugar post-translational modification (PTM) of intracellular proteins linking nutrient flux through the Hexosamine Biosynthetic Pathway (HBP) to the control of cis-regulatory elements in the genome. Aberrant O-GlcNAcylation is associated with the development, progression, and alterations in gene expression in cancer. O-GlcNAc cycling is defined as the addition and subsequent removal of the modification by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) provides a novel method for cells to regulate various aspects of gene expression, including RNA polymerase function, epigenetic dynamics, and transcription factor activity. We will focus on the complex relationship between phosphorylation and O-GlcNAcylation in the regulation of the RNA Polymerase II (RNAP II) pre-initiation complex and the regulation of the carboxyl-terminal domain of RNAP II via the synchronous actions of OGT, OGA, and kinases. Additionally, we discuss how O-GlcNAcylation of TATA-box binding protein (TBP) alters cellular metabolism. Next, in a non-exhaustive manner, we will discuss the current literature on how O-GlcNAcylation drives gene transcription in cancer through changes in transcription factor or chromatin remodeling complex functions. We conclude with a discussion of the challenges associated with studying O-GlcNAcylation and present several new approaches for studying O-GlcNAc regulated transcription that will advance our understanding of the role of O-GlcNAc in cancer.