bluuebunny/crossref_metadata_2025 huggingface dataset:
Protection of Animals during Transport: Analysis of the Infringements Reported from 2009 to 2013 during On-Road Inspections in Italy
Authors: Padalino Barbara , Barrasso Roberta , Tullio Daniele , Zappaterra Martina , Nanni Costa Leonardo , Bozzo Giancarlo
Published: February 2020

Council Regulation (EC) No 1/2005 requires that vehicles that are transporting animals be subjected to checks conducted by competent authorities. Yearly, each member state sends a report to the European government on the infringements that have been discovered during on-road inspections. The reports that were published by the Italian Ministry of Public Health from 2009 to 2013 were analyzed. Possible associations between the type of infringement (related to animal welfare (AW), vehicle (V) and accompanying documents (D)), year, season, transported species, place of inspection, and competent authorities were identified. A total of 985 infringements were analyzed, with some vehicles receiving more than one (mean: 1.58; max: 9). A score (from 1 to 3) that was related to the severity of the infringements was created. In 2009 and 2010, there was a 50% higher probability of encountering penalties of a lower severity (D or V) than in 2011 (p < 0.0001). Vehicles that were transporting pigs showed the highest probability of committing animal welfare-related infringements (odds ratio (OR) = 3.85, 95% confidence interval (95%CI) = 1.82–8.76, p < 0.0001). Vehicles were four times more likely to suffer animal welfare-related penalties when traffic police worked in synergy with veterinary services (OR = 4.12, 95%CI = 1.70–11.13, p = 0.0005). Vehicles that were transporting Equidae and “other species,” including pets, for commercial purposes were more likely to be fined for a lack or incompleteness of the veterinary documents than those transporting cattle (p = 0.002 and p = 0.004, respectively). This study gives statistical evidence of the implementation of EC 1/2005. The training of transporters and drivers on how to manage transport in an animal welfare-friendly manner and a standardized method on how to conduct road inspections among competent authorities are recommended.
Detection of rs665862918 (15-bp Indel) of the HIAT1 Gene and its Strong Genetic Effects on Growth Traits in Goats
Authors: Gao Jiayang , Song Xiaoyue , Wu Hui , Tang Qi , Wei Zhenyu , Wang Xinyu , Lan Xianyong , Zhang Bao
Published: February 2020

The hippocampus abundant transcript 1 (HIAT1) gene, which was detected by the genome-wide identification of selective sweeps among elite goat breeds and water buffalo, is proposed to play an important role in meat characteristics. Four indels of the HIAT1 gene selected from the NCBI and Ensembl databases were detected via a pooling and sequencing strategy. A 15 bp insertion (rs665862918) in the first intron of HIAT1 was selected and classified on an electrophoresis platform in the Shaanbei white cashmere goat (SBWC) population. The correlation analysis revealed that rs665862918 is significantly highly associated with chest width (p = 1.57 × 10−5), chest depth (p = 8.85 × 10−5), heart girth (p = 1.05 × 10−7), body length (p = 0.022), and height at hip cross (p = 0.023) in the SBWC population (n = 1013). Further analysis revealed that individuals with a genotype insertion/insertion (II) of the rs665862918 locus exhibited better growth trait performance than individuals with an insertion/deletion (ID) or deletion/deletion (DD). These findings verify that HIAT1 affects the body size of goats and that rs665862918 could be a potential molecular marker for growth traits in goat breeding.
Knockout Mouse Models for Peroxiredoxins
Authors: Lee Young Jae
Published: February 2020

Peroxiredoxins (PRDXs) are members of a highly conserved peroxidase family and maintain intracellular reactive oxygen species (ROS) homeostasis. The family members are expressed in most organisms and involved in various biological processes, such as cellular protection against ROS, inflammation, carcinogenesis, atherosclerosis, heart diseases, and metabolism. In mammals, six PRDX members have been identified and are subdivided into three subfamilies: typical 2-Cys (PRDX1, PRDX2, PRDX3, and PRDX4), atypical 2-Cys (PRDX5), and 1-Cys (PRDX6) subfamilies. Knockout mouse models of PRDXs have been developed to investigate their in vivo roles. This review presents an overview of the knockout mouse models of PRDXs with emphases on the biological and physiological changes of these model mice.
Academic Success Assessment through Version Control Systems
Authors: Guerrero-Higueras Ángel Manuel , Fernández Llamas Camino , Sánchez González Lidia , Gutierrez Fernández Alexis , Esteban Costales Gonzalo , Conde González Miguel Ángel
Published: February 2020

Version control systems’ usage is a highly demanded skill in information and communication technology professionals. Thus, their usage should be encouraged by educational institutions. This work demonstrates that it is possible to assess if a student can pass a computer science-related subject by monitoring its interaction with a version control system. This paper proposes a methodology that compares the performance of several machine learning models so as to select the appropriate predicting model for the assessment of the students’ achievements. To fit predicting models, three subjects of the Degree in Computer Science at the University of León are considered to obtain the dataset: computer organization, computer programming, and operating systems extension. The common aspect of these subjects is their assignments, which are based on developing one or several programs with programming languages such as C or Java. To monitor the practical assignments and individual performance, a Git repository is employed allowing students to store source code, documentation, and supporting control versions. According to the presented experience, there is a huge correlation between the level of interaction for each student and the achieved grades.
Director Tools for Autonomous Media Production with a Team of Drones
Authors: Montes-Romero Ángel , Torres-González Arturo , Capitán Jesús , Montagnuolo Maurizio , Metta Sabino , Negro Fulvio , Messina Alberto , Ollero Aníbal
Published: February 2020

This paper proposes a set of director tools for autonomous media production with a team of drones. There is a clear trend toward using drones for media production, and the director is the person in charge of the whole system from a production perspective. Many applications, mainly outdoors, can benefit from the use of multiple drones to achieve multi-view or concurrent shots. However, there is a burden associated with managing all aspects in the system, such as ensuring safety, accounting for drone battery levels, navigating drones, etc. Even though there exist methods for autonomous mission planning with teams of drones, a media director is not necessarily familiar with them and their language. We contribute to close this gap between media crew and autonomous multi-drone systems, allowing the director to focus on the artistic part. In particular, we propose a novel language for cinematography mission description and a procedure to translate those missions into plans that can be executed by autonomous drones. We also present our director’s Dashboard, a graphical tool allowing the director to describe missions for media production easily. Our tools have been integrated into a real team of drones for media production and we show results of example missions.
A Simple Mono-Dimensional Approach for Lap Time Optimisation
Authors: Lenzo Basilio , Rossi Valerio
Published: February 2020

Lap time minimisation methods have great relevance in the analysis of race tracks, and in the design and optimisation of race vehicles. Several lap time minimisation approaches have been proposed in the literature, which are computationally demanding because they need to either solve differential equations or to implement a forward–backward integration based on an apex-finding method. This paper proposes an alternative method, based on a mono-dimensional quasi-steady-state numerical approach. The proposed approach uses a simplified vehicle model accounting for combined tyre–road interactions, aerodynamic effects, and power limitations. The method exploits the knowledge of the curvature of the trajectory, which is worked out through a rigorous approach that allows for the use trajectories defined with respect to ageneric curve parameter and not necessarily the arc length. An iterative routine is implemented that exploits the vehicle dynamics, without solving differential equations or performing forward–backward integrations from the trajectory apexes. Simulations are carried out on three different tracks and are shown to be computationally efficient. Despite being intentionally simple, the proposed method allows to grasp key aspects of the problem, such as the effect of the combined tyre–road interactions on the acceleration profiles, and the effect of aerodynamic drag and downforce on the position of the braking point on the track and on the speed profile.
Influence of Macrophyte and Gut Microbiota on Mercury Contamination in Fish: A Microcosms Study
Authors: Gentès Sophie , Monperrus Mathilde , Legeay Alexia , Gassie Claire , Maury-Brachet Régine , André Jean-Marc , Guyoneaud Rémy
Published: February 2020

The freshwater lakes of southwestern France are subject to the development of invasive macrophytes which are associated with mercury (Hg) contamination of the food web. The aim of this study was to determine the bioavailability of methylmercury (MeHg) produced by plant roots in aquatic ecosystems. A microcosm experiment was performed using isotopically enriched inorganic Hg at environmental concentrations (1 µg 199IHg·L−1). For all conditions, total Hg in fish as well as Hg species associated with different compartments (water, sediments, plant roots, fish) were analyzed by gas chromatography-inductively coupled plasma-mass spectrometry (GC-ICP-MS). In addition, sediment, plants, and fish gut microbiota were studied by MiSEQ sequencing. Some strains were isolated and tested for their ability to methylate Hg. The results revealed 199MeHg production in plant roots and the presence of this form in fish (tissues and gut), highlighting a MeHg trophic transfer. Moreover, methylator bacteria were identified from the gut contents of the fish when they were in the presence of plants. Some of them were related to bacteria found in the plant roots. On the basis of these results, the transfer of MeHg and bacteria from plants to fish is highlighted; in addition, Hg methylation is strongly suspected in the fish gut, potentially increasing the Hg bioaccumulation.
DERN: Deep Ensemble Learning Model for Short- and Long-Term Prediction of Baltic Dry Index
Authors: Kamal Imam Mustafa , Bae Hyerim , Sunghyun Sim , Yun Heesung
Published: February 2020

The Baltic Dry Index (BDI) is a commonly utilized indicator of global shipping and trade activity. It influences stakeholders’ and ship-owners’ decisions respecting investments, chartering, operational plans, and export and import activities. Accurate prediction of the BDI is very challenging due to its volatility, non-stationarity, and complexity. To help stakeholders and ship-owners make sound short- and long-term maritime business decisions and avoid market risk, we performed short- and long-term predictions of BDI using an ensemble deep-learning approach. In this study, we propose to apply recurrent neural network models for BDI prediction. The state-of-the-art of sequential deep-learning models such as RNN, LSTM, and GRU are employed to predict one- and multi-step-ahead BDI values. In order to increase the accuracy, we assemble the models. In experiments, we compared our results with those of traditional methods such as ARIMA and MLP. The results showed that our proposed method outperforms ARIMA, MLP, RNN, LSTM, and GRU in both short- and long-term prediction of BDI.
X-Ray Bone Fracture Classification Using Deep Learning: A Baseline for Designing a Reliable Approach
Authors: Tanzi Leonardo , Vezzetti Enrico , Moreno Rodrigo , Moos Sandro
Published: February 2020

In recent years, bone fracture detection and classification has been a widely discussed topic and many researchers have proposed different methods to tackle this problem. Despite this, a universal approach able to classify all the fractures in the human body has not yet been defined. We aim to analyze and evaluate a selection of papers, chosen according to their representative approach, where the authors applied different deep learning techniques to classify bone fractures, in order to select the strengths of each of them and try to delineate a generalized strategy. Each study is summarized and evaluated using a radar graph with six values: area under the curve (AUC), test accuracy, sensitivity, specificity, dataset size and labelling reliability. Plus, we defined the key points which should be taken into account when trying to accomplish this purpose and we compared each study with our baseline. In recent years, deep learning and, in particular, the convolution neural network (CNN), has achieved results comparable to those of humans in bone fracture classification. Adopting a correct generalization, we are reasonably sure that a computer-aided diagnosis (CAD) system, correctly designed to assist doctors, would save a considerable amount of time and would limit the number of wrong diagnoses.
Characterization and Defect Analysis of Machined Regions in Al-SiC Metal Matrix Composites Using an Abrasive Water Jet Machining Process
Authors: Mayuet Ares Pedro F. , Rodríguez-Parada Lucía , Gómez-Parra Álvaro , Batista Ponce Moises
Published: February 2020

Metal matrix composite (MMC) materials are increasingly used in industrial sectors such as energy, structural, aerospace, and automotive. This is due to the improvement of properties by the addition of reinforcements. Thus, it is possible to obtain properties of higher strength, better rigidity, controlled thermal expansion, and elevated wear resistance. However, due to the extreme hardness achieved during their manufacture, these composites pose a challenge to the conventional machining industry due to the rapid deterioration experienced by cutting tools. This article therefore proposes the use of an unconventional machining method that is becoming increasingly widely used: abrasive water jet cutting. This process is characterized by high production rates, absence of wear, and environmental friendliness, among other advantages. Experimental tests were carried out in order to analyze results that minimize the formation of defects in the machining of metal matrix composite consisting of aluminium matrix with silicon carbide (Al-SiC MMC). To this end, results were analyzed using Scanning Optical and Electron Microscope (SOM/SEM) techniques, the taper angle was calculated, and areas with different surface quality were detected by measuring the roughness.
Analysis of Energy Consumption in Different European Cities: The Adaptive Comfort Control Implemented Model (ACCIM) Considering Representative Concentration Pathways (RCP) Scenarios
Authors: Sánchez-García Daniel , Bienvenido-Huertas David , Pulido-Arcas Jesús A. , Rubio-Bellido Carlos
Published: February 2020

Reports of Intergovernmental Panel on Climate Change have set various greenhouse gas emissions scenarios, through which the evolution of the temperature of the planet can be estimated throughout the 21st century. The reduction of the emissions from the different activities carried out by mankind is crucial to mitigate greenhouse gas emissions. One of the most significant activities is users’ behaviour within buildings, particularly the use of Heating, Ventilation and Air-Conditioning systems. Modifying users’ behaviour patterns to guarantee acceptable thermal conditions inside buildings could lead to considerable energy saving percentages, and adaptive thermal comfort models could be an opportunity to achieve important savings. For this reason, this study analyzes the potential to apply adaptive thermal comfort models to use artificial air-conditioning systems by modifying setpoint temperatures. The analysis was conducted in five major European cities (Barcelona, Berlin, Bern, Rome, and Vienna) and in five climate change scenarios in the year 2050. The results showed that, in general, the energy saving achieved by adaptive strategies was larger in the cities with a greater cooling demand. Also, in both Representative Concentration Pathways (RCP) of the Fifth Assessment Report (AR5) considered, the energy saving were decreased in the cities of Barcelona and Rome, with values lower than those of the Fourth Assessment Report (AR4) scenarios considered, whereas in the cities of Berlin, Bern, and Vienna, the saving in the RCP scenarios is greater than those in the other scenarios.
Effects of Different InGaN/GaN Electron Emission Layers/Interlayers on Performance of a UV-A LED
Authors: Kim Dohyun , Song Keun , Jung UiJin , Kim Subin , Shin Dong , Park Jinsub
Published: February 2020

In this study, we investigated the effects of InGaN/GaN-based interlayer (IL) and electron emitting layer (EEL) consisting of a GaN barrier layer grown with different metal-organic (MO) precursors of gallium (Ga), which were grown underneath the active layer. The growth behavior of GaN with triethyl Ga (TEGa) showed an increasing growth time due to a lower growth rate compared with GaN grown with trimethyl Ga (TMGa), resulting in the formation of columnar domains and grain boundary with reduced defect. UV-A light emitting diode (LED) chips with three types of ILs and EELs, grown with different MO sources, were fabricated and evaluated by light output power (LOP) measurements. The LOP intensity of UVLED-III with the GaN barrier layer-based IL and EEL grown by TEGa was enhanced by 1.5 times compared to that of the IL and EEL grown with TMGa at 300 mA current injection. Use of the GaN barrier layer in ILs and EELs grown by TEGa improved the crystal quality of the post grown InGaN/GaN multiple quantum well, which reduces leakage current. Therefore, for the UV-A LED with ILs and EELs grown with TEGa MO precursors, electrical and optical properties were improved significantly.
Efficient Seismic Fragility Analysis for Large-Scale Piping System Utilizing Bayesian Approach
Authors: Kwag Shinyoung , Ryu YongHee , Ju Bu-Seog
Published: February 2020

In the event of an earthquake, it is essential to accurately assess the seismic fragility of piping systems to ensure the continued safety of society. When evaluating the seismic fragility of a piping system, which is generally a secondary structural system, this should mainly be an integrated model that includes both the primary structural frames and the secondary ones, unlike the primary structural system of a building. Hence, the piping seismic fragility evaluation has an issue in that it takes considerable computational time because numerical analyses must be performed on a relatively complex model. Given this background, the purpose of this study is to propose an efficient piping seismic fragility analysis method by utilizing the existing seismic fragility analysis method and the Bayesian updating concept. In order to verify the validity of the proposed method, it was applied to a building–piping coupled structural system example, and its results were analyzed and compared with the results of the existing method in terms of accuracy and efficiency. As a result, the proposed method showed a similar accuracy compared with the existing method while significantly reducing the numerical cost of nonlinear seismic response analyses necessary for these results.
A Protection Scheme for a Power System with Solar Energy Penetration
Authors: Ram Ola Sheesh , Saraswat Amit , Goyal Sunil Kumar , Jhajharia S. K. , Khan Baseem , Mahela Om Prakash , Haes Alhelou Hassan , Siano Pierluigi
Published: February 2020

As renewable energy (RE) penetration has a continuously increasing trend, the protection of RE integrated power systems is a critical issue. Recently, power networks developed for grid integration of solar energy (SE) have been designed with the help of multi-tapped lines to integrate small- and medium-sized SE plants and simultaneously supplying power to the loads. These tapped lines create protection challenges. This paper introduces an algorithm for the recognition of faults in the grid to which a solar photovoltaic (PV) system is integrated. A fault index (FI) was introduced to identify faults. This FI was calculated by multiplying the Wigner distribution (WD) index and Alienation (ALN) index. The WD-index was based on the energy density of the current signal evaluated using Wigner distribution function. The ALN-index was evaluated using sample-based alienation coefficients of the current signal. The performance of the algorithm was validated for various scenarios with different fault types at various locations, different fault incident angles, fault impedances, sampling frequencies, hybrid line consisting of overhead (OH) line and underground (UG) cable sections, different types of transformer windings and the presence of noise. Two phase faults with and without the involvement of ground were differentiated using the ground fault index based on the zero sequence current. This study was performed on the IEEE-13 nodes test network to which a solar PV plant with a capacity of 1 MW was integrated. The performance of the algorithm was also tested on the western part of utility grid in the Rajasthan State in India where solar PV energy integration is high. The performance of the algorithm was effectively established by comparing it with the discrete Wavelet transform (DWT), Wavelet packet transform (WPT) and Stockwell transform-based methods.
Inverse Halftoning Methods Based on Deep Learning and Their Evaluation Metrics: A Review
Authors: Li Mei , Zhang Erhu , Wang Yutong , Duan Jinghong , Jing Cuining
Published: February 2020

Inverse halftoning is an ill-posed problem that refers to the problem of restoring continuous-tone images from their halftone versions. Although much progress has been achieved over the last decades, the restored images still suffer from detail loss and visual artifacts. Recent studies show that inverse halftoning methods based on deep learning are superior to other traditional methods, and thus this paper aimed to systematically review the inverse halftone methods based on deep learning, so as to provide a reference for the development of inverse halftoning. In this paper, we firstly proposed a classification method for inverse halftoning methods on the basis of the source of halftone images. Then, two types of inverse halftoning methods for digital halftone images and scanned halftone images were investigated in terms of network architecture, loss functions, and training strategies. Furthermore, we studied existing image quality evaluation including subjective and objective evaluation by experiments. The evaluation results demonstrated that methods based on multiple subnetworks and methods based on multi-stage strategies are superior to other methods. In addition, the perceptual loss and the gradient loss are helpful for improving the quality of restored images. Finally, we gave the future research directions by analyzing the shortcomings of existing inverse halftoning methods.
Experimental and Numerical Investigations on the Local Direct Leakage Process of Rotary Regenerative Air Preheater
Authors: Zhu Hua , Li Dechao , Pu Henglin , Wang Limin , He Yang , Bu Yufan , Che Defu
Published: February 2020

An inherent defect of the operating rotary air preheaters (RAPH) is known as leakage, which seriously hinders the efficient and safe operation of RAPH. It is significant for the estimation of the direct leakage to determine the effects of different structure parameters of sealing sheets and different operation parameters of a RAPH. A direct leakage set-up was built and a three-dimensional numerical model was established to explore the local direct air leaking process of rotary regenerative air preheater and study the effects of geometrical and operational parameters on the leakage. The numerical simulation using the transition k-kl-ω turbulence model was verified by the experimental results. The results show that the local direct air leakage mainly depends on the total pressure difference between the two sides of the seal instead of the one-side pressure. The air leakage can be significantly reduced by narrowing the leakage gap. The increase in the number of sealing sheets can reduce the air leakage own to the increase in the leakage resistance. The increase in the spacing between the adjacent sealing sheets can enlarge the recirculation zone and increase the energy loss of mainstream, greatly reducing the local direct air leakage. Due to the different size recirculation zone formation and streamline curvature induced by sealing sheet, the effect of bending angle on the direct air leakage varies. To obtain lower leakage rate, it is recommended for the rotor of tri-sectional air preheater to pass through flue gas section, secondary-air section, and primary-air section in sequence.
Solid γ-Cyclodextrin Inclusion Compound with Gingerols, a Multi-Component Guest: Preparation, Properties and Application in Yogurt
Authors: Pais Joana M. , Pereira Bruna , Paz Filipe A. Almeida , Cardoso Susana M. , Braga Susana S.
Published: February 2020

Gingerols from the rhizome of fresh ginger (Zingiber officinale) were obtained by a simple extraction, followed by purification. The gingerols extract was composed of 6-gingerol (54%), 8-gingerol (20%), and 10-gingerol (26%). It was included into γ-cyclodextrin by classic co-dissolution procedures. Solid-state characterisation of γ-cyclodextrin·gingerols shows that this inclusion compound features 1:1 host-to-guest stoichiometry and that it is a microcrystalline powder with a crystalline cell that belongs to the tetragonal space group 4212, having the host molecules stacked in infinite channels where the gingerols are accommodated. In chimico studies with ABTS•+ scavenging, NO• scavenging, β-carotene peroxidation, and 5-LOX inhibition show that γ-cyclodextrin is a suitable carrier for gingerols, because it does not alter their reactivity towards these substances. Yogurt was tested as a matrix for the incorporation of gingerols and γ-cyclodextrin·gingerols into foodstuff. The colour of the fortified yogurt suffered little alterations. In the case of yogurt with the inclusion compound, γ-cyclodextrin·gingerols, as fortificant, these alterations were not perceptible to the naked eye. Moreover, yogurt with γ-cyclodextrin·gingerols showed a good antioxidant activity, thus being suitable for use in nutraceutical applications.
Antiproliferative Effect of Acridine Chalcone Is Mediated by Induction of Oxidative Stress
Authors: Takac Peter , Kello Martin , Vilkova Maria , Vaskova Janka , Michalkova Radka , Mojzisova Gabriela , Mojzis Jan
Published: February 2020

Chalcones are naturally occurring phytochemicals with diverse biological activities including antioxidant, antiproliferative, and anticancer effects. Some studies indicate that the antiproliferative effect of chalcones may be associated with their pro-oxidant effect. In the present study, we evaluated contribution of oxidative stress in the antiproliferative effect of acridine chalcone 1C ((2 E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one) in human colorectal HCT116 cells. We demonstrated that chalcone 1C induced oxidative stress via increased reactive oxygen/nitrogen species (ROS/RNS) and superoxide production with a simultaneous weak adaptive activation of the cellular antioxidant defence mechanism. Furthermore, we also showed chalcone-induced mitochondrial dysfunction, DNA damage, and apoptosis induction. Moreover, activation of mitogen activated phosphokinase (MAPK) signalling pathway in 1C-treated cancer cells was also observed. On the other hand, co-treatment of cells with strong antioxidant, N-acetyl cysteine (NAC), significantly attenuated all of the above-mentioned effects of chalcone 1C, that is, decreased oxidant production, prevent mitochondrial dysfunction, DNA damage, and induction of apoptosis, as well as partially preventing the activation of MAPK signalling. Taken together, we documented the role of ROS in the antiproliferative/pro-apoptotic effects of acridine chalcone 1C. Moreover, these data suggest that this chalcone may be useful as a promising anti-cancer agent for treating colon cancer.
Patient Derived Models to Study Head and Neck Cancer Radiation Response
Authors: Cosper Pippa F. , Abel Lindsey , Lee Yong-Syu , Paz Cristina , Kaushik Saakshi , Nickel Kwangok P. , Alexandridis Roxana , Scott Jacob G. , Bruce Justine Y. , Kimple Randall J.
Published: February 2020

Patient-derived model systems are important tools for studying novel anti-cancer therapies. Patient-derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for the study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient-derived models for radiation research, including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.
Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression
Authors: Chen Li-Mei , Tseng Hong-Yu , Chen Yen-An , Al Haq Aushia Tanzih , Hwang Pai-An , Hsu Hsin-Ling
Published: February 2020

Reactive oxygen species (ROS) produced during intracellular metabolism or triggered by extrinsic factors can promote neoplastic transformation and malignant microenvironment that mediate tumor development. Oligo-Fucoidan is a sulfated polysaccharide isolated from the brown seaweed. Using human THP-1 monocytes and murine Raw264.7 macrophages as well as human HCT116 colorectal cancer cells, primary C6P2-L1 colorectal cancer cells and human MDA-MB231 breast cancer cells, we investigated the effect of Oligo-Fucoidan on inhibiting M2 macrophage differentiation and its therapeutic potential as a supplement in chemotherapy and tumor prevention. We now demonstrate that Oligo-Fucoidan is an antioxidant that suppresses intracellular ROS and mitochondrial superoxide levels in monocytes/macrophages and in aggressive cancer cells. Comparable to ROS inhibitors (DPI and NAC), Oligo-Fucoidan directly induced monocyte polarization toward M1-like macrophages and repolarized M2 macrophages into M1 phenotypes. DPI and Oligo-Fucoidan also cooperatively prevented M2 macrophage invasiveness. Indirectly, M1 polarity was advanced particularly when DPI suppressed ROS generation and supplemented with Oligo-Fucoidan in the cancer cells. Moreover, cisplatin chemoagent polarized monocytes and M0 macrophages toward M2-like phenotypes and Oligo-Fucoidan supplementation reduced these side effects. Furthermore, Oligo-Fucoidan promoted cytotoxicity of cisplatin and antagonized cisplatin effect on cancer cells to prevent M2 macrophage differentiation. More importantly, Oligo-Fucoidan inhibited tumor progression and M2 macrophage infiltration in tumor microenvironment, thus increasing of anti-tumor immunity.
Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma
Authors: Schiffmann Lars M. , Loeser Heike , Jacob Anne Sophie , Maus Martin , Fuchs Hans , Zhao Yue , Tharun Lars , Essakly Ahlem , Iannos Damanakis Alexander , Zander Thomas , Büttner Reinhard , Schröder Wolfgang , Bruns Christiane , Quaas Alexander , Gebauer Florian
Published: February 2020

Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.
Identification of an Upper Limit of Tumor Burden for Downstaging in Candidates with Hepatocellular Cancer Waiting for Liver Transplantation: A West–East Collaborative Effort
Authors: Lai Quirino , Vitale Alessandro , Halazun Karim , Iesari Samuele , Viveiros André , Bhangui Prashant , Mennini Gianluca , Wong Tiffany , Uemoto Shinji , Lin Chih-Che , Mittler Jens , Ikegami Toru , Zhe Yang , Zheng Shu-Sen , Soejima Yuji , Hoppe-Lotichius Maria , Chen Chao-Long , Kaido Toshimi , Lo Chung Mau , Rossi Massimo , Soin Arvinder Singh , Finkenstedt Armin , Emond Jean C. , Cillo Umberto , Lerut Jan
Published: February 2020

Since the introduction of Milan Criteria, all scoring models describing the prognosis of hepatocellular cancer (HCC) after liver transplantation (LT) have been exclusively based on characteristics available at surgery, therefore neglecting the intention-to-treat principles. This study aimed at developing an intention-to-treat model through a competing-risk analysis. Using data available at first referral, an upper limit of tumor burden for downstaging was identified beyond which successful LT becomes an unrealistic goal. Twelve centers in Europe, United States, and Asia (Brussels, Sapienza Rome, Padua, Columbia University New York, Innsbruck, Medanta-The Medicity Dehli, Hong Kong, Kyoto, Kaohsiung Taiwan, Mainz, Fukuoka, Shulan Hospital Hangzhou) created a Derivation (n = 2318) and a Validation Set (n = 773) of HCC patients listed for LT between January 2000–March 2017. In the Derivation Set, the competing-risk analysis identified two independent covariables predicting post-transplant HCC-related death: combined HCC number and diameter (SHR = 1.15; p < 0.001) and alpha-fetoprotein (AFP) (SHR = 1.80; p < 0.001). WE-DS Model showed good diagnostic performances at internal and external validation. The identified upper limit of tumor burden for downstaging was AFP ≤ 20 ng/mL and up-to-twelve as sum of HCC number and diameter; AFP = 21–200 and up-to-ten; AFP = 201–500 and up-to-seven; AFP = 501–1000 and up-to-five. The WE-DS Model proposed here, based on morphologic and biologic data obtained at first referral in a large international cohort of HCC patients listed for LT, allowed identifying an upper limit of tumor burden for downstaging beyond which successful LT, following downstaging, results in a futile transplantation.
A ”Clickable” Probe for Active MGMT in Glioblastoma Demonstrates Two Discrete Populations of MGMT
Authors: Raghavan Sudhir , Baskin David S. , Sharpe Martyn A.
Published: February 2020

Various pathways can repair DNA alkylation by chemotherapeutic agents such as temozolomide (TMZ). The enzyme O6-methylguanine methyltransferase (MGMT) removes O6-methylated DNA adducts, leading to the failure of chemotherapy in resistant glioblastomas. Because of the anti-chemotherapeutic activities of MGMT previously described, estimating the levels of active MGMT in cancer cells can be a significant predictor of response to alkylating agents. Current methods to detect MGMT in cells are indirect, complicated, time-intensive, or utilize molecules that require complex and multistep chemistry synthesis. Our design simulates DNA repair by the transfer of a clickable propargyl group from O6-propargyl guanine to active MGMT and subsequent attachment of fluorescein-linked PEG linker via ”click chemistry.” Visualization of active MGMT levels reveals discrete active and inactive MGMT populations with biphasic kinetics for MGMT inactivation in response to TMZ-induced DNA damage.
Loss of CDKN1A mRNA and Protein Expression Are Independent Predictors of Poor Outcome in Chromophobe Renal Cell Carcinoma Patients
Authors: Ohashi Riuko , Angori Silvia , Batavia Aashil A. , Rupp Niels J. , Ajioka Yoichi , Schraml Peter , Moch Holger
Published: February 2020

Chromophobe renal cell carcinoma (chRCC) patients have good prognosis. Only 5%–10% patients die of metastatic disease after tumorectomy, but tumor progression cannot be predicted by histopathological parameters alone. chRCC are characterized by losses of many chromosomes, whereas gene mutations are rare. In this study, we aim at identifying genes indicating chRCC progression. A bioinformatic approach was used to correlate chromosomal loss and mRNA expression from 15287 genes from The Cancer Genome Atlas (TCGA) database. All genes in TCGA chromophobe renal cancer dataset (KICH) for which a significant correlation between chromosomal loss and mRNA expression was shown, were identified and their associations with outcome was assessed. Genome-wide DNA copy-number alterations were analyzed by Affymetrix OncoScan® CNV FFPE Microarrays in a second cohort of Swiss chRCC. In both cohorts, tumors with loss of chromosomes 2, 6, 10, 13, 17 and 21 had signs of tumor progression. There were 4654 genes located on these chromosomes, and 13 of these genes had reduced mRNA levels, which was associated with poor outcome in chRCC. Decreased CDKN1A expression at mRNA (p = 0.02) and protein levels (p = 0.02) were associated with short overall survival and were independent predictors of prognosis (p < 0.01 and <0.05 respectively). CDKN1A expression status is a prognostic biomarker independent of tumor stage. CDKN1A immunohistochemistry may be used to identify chRCC patients at greater risk of disease progression.
A Comprehensive Analysis of FUT8 Overexpressing Prostate Cancer Cells Reveals the Role of EGFR in Castration Resistance
Authors: Höti Naseruddin , Lih Tung-Shing , Pan Jianbo , Zhou Yangying , Yang Ganglong , Deng Ashely , Chen Lijun , Dong Mingmimg , Yang Ruey-Bing , Tu Cheng-Fen , Haffner Michael C. , Kay Li Qing , Zhang Hui
Published: February 2020

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes.
Transcriptome Analysis Identifies ALCAM Overexpression as a Prognosis Biomarker in Laryngeal Squamous Cell Carcinoma
Authors: Nicolau-Neto Pedro , de Souza-Santos Paulo Thiago , Severo Ramundo Mariana , Valverde Priscila , Martins Ivanir , Costa Santos Izabella , Dias Fernando , de Almeida Simão Tatiana , Ribeiro Pinto Luis Felipe
Published: February 2020

Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most incident tumors in the world, especially in developing countries, such as Brazil. Different from other tumors, LSCC prognosis did not improve during the past four decades. Therefore, the objective of this study was to develop biomarkers that can predict LSCC patient’s prognosis. Results: Transcriptome analysis pointed out 287 overexpressed genes in LSCC in comparison to adjacent mucosa. Among these, a gene-pattern signature was created with 24 genes associated with prognosis. The Bayesian clustering of both Brazil and The Cancer Genome Atlas (TCGA) data pointed out clusters of samples possessing significative differences in the prognosis, and the expression panel of three genes (ALCAM, GBP6, and ME1) was capable to distinguish patients with worse prognosis with an accuracy of 97%. Survival analyses with TCGA data highlighted ALCAM gene expression as an independent prognostic factor for LSCC. This was further confirmed through immunohistochemistry, using a validation set of Brazilian patients. ALCAM expression was not associated with prognosis for other head and neck tumor sites. Conclusion: ALCAM overexpression seems to be an independent prognosis biomarker for LSCC patients.
Multicenter External Validation of the Liverpool Uveal Melanoma Prognosticator Online: An OOG Collaborative Study
Authors: Cunha Rola Alda , Taktak Azzam , Eleuteri Antonio , Kalirai Helen , Heimann Heinrich , Hussain Rumana , Bonnett Laura J. , Hill Christopher J. , Traynor Matthew , Jager Martine J. , Marinkovic Marina , Luyten Gregorius P.M. , Dogrusöz Mehmet , Kilic Emine , de Klein Annelies , Smit Kyra , van Poppelen Natasha M , Damato Bertil E. , Afshar Armin , Guthoff Rudolf F. , Scheef Björn O. , Kakkassery Vinodh , Saakyan Svetlana , Tsygankov Alexander , Mosci Carlo , Ligorio Paolo , Viaggi Silvia , Le Guin Claudia H.D. , Bornfeld Norbert , Bechrakis Nikolaos E. , Coupland Sarah E.
Published: February 2020

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3’s performance using discrimination and calibration methods. LUMPO3’s ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.
Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma
Authors: Dimri Manali , Satyanarayana Ande
Published: February 2020

Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.
Decreased Cytoplasmic Expression of ADAMTS14 Is Correlated with Reduced Survival Rates in Oral Squamous Cell Carcinoma Patients
Authors: Lin Yueh-Min , Lin Chiao-Wen , Lu Jeng-Wei , Yeh Kun-Tu , Lin Shu-Hui , Yang Shun-Fa
Published: February 2020

A disintegrin and metalloproteinase with thrombospondin motif 14 (ADAMTS14) is a member of the zinc-dependent protease family that is implicated in the occurrence and progression of tumors. Oral cancer (OC) is a common cancer worldwide, but it is particularly prevalent in Taiwan. However, whether the expression of ADAMTS14 is correlated with the carcinogenesis and progression of oral squamous cell carcinoma (OSCC) has not yet been investigated. In this study, we used immunohistochemistry (IHC) to examine 250 OSCC specimens in order to identify correlations between the cytoplasmic expression of ADAMTS14 and (1) clinicopathological features of OSCC as well as (2) clinical outcomes of OSCC. Our results indicate that cytoplasmic expression of ADAMTS14 was lower in OSCC tissues than in normal tissues. In analyzing correlations between ADAMTS14 expression and clinicopathological features, we found that negative cytoplasmic expression of ADAMTS14 was significantly associated with higher frequencies of lymph node metastasis and more advanced AJCC stages (III/IV). Kaplan–Meier survival analysis revealed that negative cytoplasmic expression of ADAMTS14 was also associated with significantly worse OSCC survival. Univariate and multivariate analyses confirmed that cytoplasmic expression of ADAMTS14 was associated with lymph node metastasis, tumor stage, and tumor grade and also indicated that cytoplasmic ADAMTS14 expression may be an independent prognostic factor for OSCC. This is the first study to report that the cytoplasmic expression level of ADAMTS14 is associated with OSCC prognosis and tumor progression. Our data indicate that ADAMTS14 can serve as a prognostic marker and a potential therapeutic target for OSCC.