bluuebunny/crossref_metadata_2025 huggingface dataset:
Indoors or Outdoors? An International Exploration of Owner Demographics and Decision Making Associated with Lifestyle of Pet Cats
Authors: Foreman-Worsley Rachel , Finka Lauren R. , Ward Samantha J. , Farnworth Mark J.
Published: January 2021

Outdoor access for owned domestic cats (Felis catus) is a divisive issue. Cat safety, mental and physical wellbeing, infectious diseases, and wildlife depredation are cited as factors influencing owners; however, the degree of consideration each factor receives has not been quantified. This study (i) analysed which demographic variables are associated with greater odds of cats having indoor or outdoor lifestyles, (ii) identified which factors owners consider when making a choice on lifestyle and any regional variations, and (iii) identified if owners consider the different lifestyle options available and recognise their associated benefits. A series of online surveys were used for data collection. Binary logistic regression models were used to generate odds ratios assessing if demographic variables were significantly associated with cat lifestyle. Quantitative analysis of factors considered when deciding on cat lifestyle was accompanied by a thematic analysis of rich-text open-ended responses, providing nuanced insight into the rationale and elucidating additional factors considered. Of the demographic variables tested, 10/12 were significantly associated with lifestyle. Variables with higher odds of indoor-only lifestyles were owners being 26–35 years old, multi-cat households, junior cats, pedigree cats or unknown pedigree status, cats with health issues, living in city centres or urban areas, or living in the United States, Canada, Australia, or New Zealand. Variables with higher odds of indoor-outdoor lifestyles were owners being 46–55 years old or 56+ years old, households with residents 17 years old or under, male cats, and cats being mature or senior. Road traffic concerns were the most cited reason for keeping indoor-only cats across all global regions. The second-most cited reason varied regionally. For Europe, it was protection from people. For the USA and Canada, the reason was protection from wildlife, and for Australia and New Zealand, to prevent hunting. Indoor-outdoor cat owners cited most frequently the benefits to their cat’s mental health. Over two-thirds of owners did not consider the alternative lifestyle for their cat. These data give insight into the priorities of cat owners with regards to feline wellbeing, feline safety, and wildlife depredation, helpful for individuals or organisations working with human behaviour change. They provide evidence that the numbers of indoor-only cats are likely to rise with increasing urbanisation. Finally, the data identify cat populations who may be at risk of compromised welfare due to unsuitable, or under-researched, lifestyles.
The Age-Related Cryptosporidium Species Distribution in Asymptomatic Cattle from North-Western Spain
Authors: Díaz Pablo , Navarro Esther , Remesar Susana , García-Dios David , Martínez-Calabuig Néstor , Prieto Alberto , López-Lorenzo Gonzalo , López Ceferino Manuel , Panadero Rosario , Fernández Gonzalo , Díez-Baños Pablo , Morrondo Patrocinio
Published: January 2021

An age-related distribution of Cryptosporidium species has been reported in cattle, with C. parvum being predominant in suckling calves, C. bovis and C. ryanae being predominant in post-weaned calves and C. andersoni being predominant in adults. However, variants to this pattern have recently been reported. Thus, fecal samples (n = 594) from asymptomatic cattle were collected in north-western Spain. Animals were classified as <1 month (G1), 1–2 months (G2), 2–12 months (G3), 12–24 months (G4) and >2 years (G5). Cryptosporidium detection and species identification were performed by SSU rRNA PCR. Individual Cryptosporidium prevalence was 16.7%; it significantly decreased with age. Cryptosporidium parvum was predominant in G1 and C. bovis was predominant in the rest of the age classes; C. bovis and C. ryanae were especially prevalent in G2 and G3. Cryptosporidium occultus was not found in suckling calves. Finally, C. andersoni and C. xiaoi were occasionally detected in G5. The presence of C. parvum in all age classes implies significant animal and public health concerns. The predominance of C. bovis in cattle older than 1 month supports the idea that the age-related pattern of Cryptosporidium species described in cattle is not fully consistent, and thus further studies are still needed to identify those factors determining the species distribution.
Egg Quality from Nera Atriana, a Local Poultry Breed of the Abruzzo Region (Italy), and ISA Brown Hens Reared under Free Range Conditions
Authors: Ianni Andrea , Bartolini Dayana , Bennato Francesca , Martino Giuseppe
Published: January 2021

The selection and diffusion in the poultry sector of hybrid breeds able to produce higher amount of meat and eggs, led over time to the erosion of genetic resources. One of the strategies that can be applied in order to stem such phenomenon, concerns the valorization of the animal products, meat or eggs, obtained from indigenous poultry breeds. Therefore, the aim of this study is to characterize the qualitative aspects of eggs obtained from the Nera Atriana hen, an Italian indigenous laying hen characteristic of the Abruzzo region, making a direct comparison with a commercial hybrid reared in the same environment and applying the same feeding protocol. The trial was conducted for a period of 5 months (from March to July 2019), in which 6 egg samplings were performed (one at the beginning and additional 5 on a monthly basis); each sampling involved the collection of 15 eggs per group of animals for a total of 90 eggs per genotype. Eggs were specifically subjected to evaluations of the physical parameters, including the yolk color, and analyses aimed at determining the content of total lipids, cholesterol, and β-carotene. In addition to this, the fatty acids profile and the electrophoretic pattern of the globular proteins of the yolk were characterized. Eggs from hybrid hens were characterized by higher total weight with significantly higher values specifically associated to albumen and yolk weight and to the albumen percentage. In the eggs obtained from the local hen, higher relative percentages were instead found in the quantity of shell and yolk; furthermore, in the same samples was observed a higher yolk redness, a cholesterol concentration tending to be lower although not significant (p = 0.0521), and a greater amount of saturated fatty acids which could justify a lower susceptibility of the food to oxidative processes following transformation with heat treatments. With regard to the fatty acid composition, differences were specifically observed for palmitic (C16:0) and palmitoleic (C16:1 cis-9) acids that showed higher relative percentages in eggs from local breed, and for the oleic acid (C18:1 cis-9) which was more represented in eggs from commercial hens. In conclusion, some interesting nutritional features, in a preliminary way, have been highlighted that could lead the consumer to prefer these “niche” products over those obtained from commercial hybrids.
The Resistance to Host Antimicrobial Peptides in Infections Caused by Daptomycin-Resistant Staphylococcus aureus
Authors: Bhuiyan Md Saruar , Jiang Jhih-Hang , Kostoulias Xenia , Theegala Ravali , Lieschke Graham J. , Peleg Anton Y.
Published: January 2021

Daptomycin is an important antibiotic for the treatment of infections caused by Staphylococcus aureus. The emergence of daptomycin resistance in S. aureus is associated with treatment failure and persistent infections with poor clinical outcomes. Here, we investigated host innate immune responses against clinically derived, daptomycin-resistant (DAP-R) and -susceptible S. aureus paired isolates using a zebrafish infection model. We showed that the control of DAP-R S. aureus infections was attenuated in vivo due to cross-resistance to host cationic antimicrobial peptides. These data provide mechanistic understanding into persistent infections caused by DAP-R S. aureus and provide crucial insights into the adaptive evolution of this troublesome pathogen.
Embryo and Its Mitochondria
Authors: May-Panloup Pascale , Boguenet Magalie , El Hachem Hady , Bouet Pierre-Emmanuel , Reynier Pascal
Published: January 2021

The mitochondria, present in almost all eukaryotic cells, produce energy but also contribute to many other essential cellular functions. One of the unique characteristics of the mitochondria is that they have their own genome, which is only maternally transmitted via highly specific mechanisms that occur during gametogenesis and embryogenesis. The mature oocyte has the highest mitochondrial DNA copy number of any cell. This high mitochondrial mass is directly correlated to the capacity of the oocyte to support the early stages of embryo development in many species. Indeed, the subtle energetic and metabolic modifications that are necessary for each of the key steps of early embryonic development rely heavily on the oocyte’s mitochondrial load and activity. For example, epigenetic reprogramming depends on the metabolic cofactors produced by the mitochondrial metabolism, and the reactive oxygen species derived from the mitochondrial respiratory chain are essential for the regulation of cell signaling in the embryo. All these elements have also led scientists to consider the mitochondria as a potential biomarker of oocyte competence and embryo viability, as well as a key target for future potential therapies. However, more studies are needed to confirm these findings. This review article summarizes the past two decades of research that have led to the current understanding of mitochondrial functions in reproduction
An Unsupervised Prediction Model for Salmonella Detection with Hyperspectral Microscopy: A Multi-Year Validation
Authors: Eady Matthew , Park Bosoon
Published: January 2021

Hyperspectral microscope images (HMIs) have been previously explored as a tool for the early and rapid detection of common foodborne pathogenic bacteria. A robust unsupervised classification approach to differentiate bacterial species with the potential for single cell sensitivity is needed for real-world application, in order to confirm the identity of pathogenic bacteria isolated from a food product. Here, a one-class soft independent modelling of class analogy (SIMCA) was used to determine if individual cells are Salmonella positive or negative. The model was constructed and validated with a spectral library built over five years, containing 13 Salmonella serotypes and 14 non-Salmonella foodborne pathogens. An image processing method designed to take less than one minute paired with the one-class Salmonella prediction algorithm resulted in an overall classification accuracy of 95.4%, with a Salmonella sensitivity of 0.97, and specificity of 0.92. SIMCA’s prediction accuracy was only achieved after a robust model incorporating multiple serotypes was established. These results demonstrate the potential for HMI as a sensitive and unsupervised presumptive screening method, moving towards the early (<8 h) and rapid (<1 h) identification of Salmonella from food matrices.
Modeling and Control of an Underactuated System for Dynamic Body Weight Support
Authors: Gembalczyk Grzegorz , Gierlak Piotr , Duda Slawomir
Published: January 2021

This article concerns the stability analysis of a control system for a dynamic body weight support system in a rehabilitation device for the re-education of human gait. The paper presents a physical model of the device, which characterizes the most important physical phenomena associated with the movement of the system, i.e., inertia, damping, and elasticity. The device has one active and one passive element. They are connected by a connector with elastic and damping properties. This solution provides the kinematic chain required due to interactions with humans, while at the same time ensures that the device is an underactuated system. The article also presents the methodology used to verify the stability of the control system while acting as an active body weight support system. The paper formulates the mathematical model of the system that was used in the synthesis of control using the Lyapunov theory of stability. The results of simulation and experimental tests are also presented.
Game Approach to HDR-TS-PV Hybrid Power System Dispatching
Authors: Si Yang , Chen Laijun , Zhang Xuelin , Chen Xiaotao , Zheng Tianwen , Mei Shengwei
Published: January 2021

Hot dry rock (HDR) power stations have the potential to serve as an energy storage system for large-scale photovoltaic (PV) plants. For flexible operation, thermal storage (TS) power stations are required to coordinate with HDR power stations. In this study, a hybrid power system is constructed by combining the HDR, TS, and PV plants. Game theory is then introduced into the optimal dispatch of the hybrid power system. Considering HDR, TS, and PV as players, non-cooperative and cooperative game dispatching models are established and verified by a case in the Gonghe basin of Qinghai. Finally, the stability of the coalitions and the rationality of allocation of the hybrid power system is verified, and the sensitivity of critical parameters is analyzed. The results demonstrate that the overall payoff of the hybrid power system is increased by 10.15%. The payoff of the HDR power station is increased by 16.5%. The TS power station has obtained 50% of the total extra profits. The PV plant reduces the impact on the grid to obtain the priority of grid connection. Based on these results, a theoretical basis can be provided for developing generation systems based on the HDR resources in the Gonghe Basin.
Numerical Study on Track–Bridge Interaction of Integral Railway Rigid-Frame Bridge
Authors: Liu Wenshuo , Lai Hao , Dai Gonglian , Rao Shiwei , Wang Dezhi , Wu Bing
Published: January 2021

Track–bridge interaction (TBI) is an increasingly essential consideration for the design and operation of railway bridges, especially for the innovative bridge structure systems that constantly spring up over the years. This paper focuses on the characteristics of additional forces in continuous welded rails (CWRs) on the 3 × 70 m integral rigid-frame bridge of the Fuzhou–Xiamen High-Speed Railway, which is a novel high-speed railway (HSR) bridge structure system in China. The differential equations of rail stress and displacement are first investigated and an integrative analysis model comprising of rail, track, bridge and piers is then established. Secondly, the characteristics of representative additional forces are illustrated and the influences of different design parameters are discussed in detail. Furthermore, suitable rail fasteners, optimal layout schemes of adjacent bridges and reasonable stiffness of piers are also studied. The results indicate that the additional expansion force accounts for the largest proportion of additional forces in integral rigid-frame bridges and that resistance reduction obviously weakens the various additional forces caused by the TBI effect, while the broken gap of the rail increases greatly. Small resistance fasteners are recommended to be applied onto this new type of HSR line as these provide reductions in additional stresses of CWRs compared to WJ-8 fasteners. The additional rail stresses after adopting an adjacent span scheme of 4 × 32 m simply supported beams are less than the corresponding stresses in other schemes. The results also show that there is a strong correlation between the minimum threshold value of the pier stiffness and the longitudinal resistance of HSR lines for the integral rigid-frame bridge. This work could serve as a valuable reference for detailed design and safety evaluation of integral rigid-frame bridges.
HPC Cloud Architecture to Reduce HPC Workflow Complexity in Containerized Environments
Authors: Li Guohua , Woo Joon , Lim Sang Boem
Published: January 2021

The complexity of high-performance computing (HPC) workflows is an important issue in the provision of HPC cloud services in most national supercomputing centers. This complexity problem is especially critical because it affects HPC resource scalability, management efficiency, and convenience of use. To solve this problem, while exploiting the advantage of bare-metal-level high performance, container-based cloud solutions have been developed. However, various problems still exist, such as an isolated environment between HPC and the cloud, security issues, and workload management issues. We propose an architecture that reduces this complexity by using Docker and Singularity, which are the container platforms most often used in the HPC cloud field. This HPC cloud architecture integrates both image management and job management, which are the two main elements of HPC cloud workflows. To evaluate the serviceability and performance of the proposed architecture, we developed and implemented a platform in an HPC cluster experiment. Experimental results indicated that the proposed HPC cloud architecture can reduce complexity to provide supercomputing resource scalability, high performance, user convenience, various HPC applications, and management efficiency.
Automatic Detection of Linear Thermal Bridges from Infrared Thermal Images Using Neural Network
Authors: Kim Changmin , Choi Jae-Sol , Jang Hyangin , Kim Eui-Jong
Published: January 2021

Detecting thermal bridges in building envelopes should be a priority to improve the thermal performance of buildings. Recently, thermographic surveys are being used to detect thermal bridges. However, conventional methods of detecting thermal bridges from thermal images rely on the subjective judgment of audits. Research has been conducted to automatically detect thermal bridges from thermal images to improve problems caused by such subjective judgment, but most of these studies are still in the early stage. Therefore, this study proposes a linear thermal bridge detection method based on image processing and machine learning. The proposed method includes thermal anomaly area clustering, feature extraction, and an artificial-neural-network-based thermal bridge detection. The proposed method was validated by detecting the thermal bridges in actual buildings. As a result, the average precision, recall, and F-score were 89.29%, 87.29, and 87.63%, respectively.
Analysis of the Propagation in High-Speed Interconnects for MIMICs by Means of the Method of Analytical Preconditioning: A New Highly Efficient Evaluation of the Coefficient Matrix
Authors: Lucido Mario
Published: January 2021

The method of analytical preconditioning combines the discretization and the analytical regularization of a singular integral equation in a single step. In a recent paper by the author, such a method has been applied to a spectral domain integral equation formulation devised to analyze the propagation in polygonal cross-section microstrip lines, which are widely used as high-speed interconnects in monolithic microwave and millimeter waves integrated circuits. By choosing analytically Fourier transformable expansion functions reconstructing the behavior of the fields on the wedges, fast convergence is achieved, and the convolution integrals are expressed in closed form. However, the coefficient matrix elements are one-dimensional improper integrals of oscillating and, in the worst cases, slowly decaying functions. In this paper, a novel technique for the efficient evaluation of such kind of integrals is proposed. By means of a procedure based on Cauchy integral theorem, the general coefficient matrix element is written as a linear combination of fast converging integrals. As shown in the numerical results section, the proposed technique always outperforms the analytical asymptotic acceleration technique, especially when highly accurate solutions are required.
Slotting Optimization Model for a Warehouse with Divisible First-Level Accommodation Locations
Authors: Viveros Pablo , González Katalina , Mena Rodrigo , Kristjanpoller Fredy , Robledo Javier
Published: January 2021

Efficiency in supply chains is critically affected by the performance of operations within warehouses. For this reason, the activities related to the disposition and management of inventories are crucial. This work addresses the multi-level storage locations assignment problem for SKU pallets, considering divisible locations in the first level to improve the picking operation and reduce the travel times associated with the routes of the cranes. A mathematical programming model is developed considering the objective of minimizing the total travel distance, and in the background, maximizing the use of storage capacity. To solve this complex problem, we consider its decomposition into four subproblems, which are solved sequentially. To evaluate the performance of the model, two analysis scenarios based on different storage strategies are proposed to evaluate both the entry and exit distance of pallets, as well as the cost associated with the movements.
Particulate Matter Profiles along the Rack Railway Route Using Low-Cost Sensor
Authors: Samad Abdul , Maali Anas , Laquai Bernd , Vogt Ulrich
Published: January 2021

Air pollution due to Particulate Matter (PM) is an increasing concern of global extent. It has been the focus of many research projects worldwide and the latest low-cost technology is offering an ease and cheap way to monitor PM concentration. In this research, a low-cost PM monitoring platform was built with the objectives of evaluating its feasibility and its performance in mobile measurements, as well as characterizing the concentration profiles of PM along the measurement route. The rack railway in Stuttgart was utilized as means of transportation for this low-cost monitoring system with which the temporal and spatial distribution of the PM10, PM2.5 and PM1 concentration along the route was attained. The measurements were conducted for around two months from mid of January until mid of March 2019, during the operation hours of the rack railway. The results showed that the PM concentrations were dominated by fine particulate matter (PM2.5 and PM1) along the route of the rack railway. Higher PM concentrations were measured near the federal highway and high traffic area as compared to the residential area. An overestimation of PM concentration using low-cost sensor platform was observed during high relative humidity conditions as compared to the professional aerosol spectrometers.
Lithium-Ion Batteries: Latest Advances and Prospects
Authors: Rahimi Mohammad
Published: January 2021

The anthropogenic release of greenhouse gases, especially carbon dioxide (CO2), has resulted in a notable climate change and an increase in global average temperature since the mid-20th century [...]
Innocuous, Highly Conductive, and Affordable Thermal Interface Material with Copper-Based Multi-Dimensional Filler Design
Authors: Kim Woochang , Kim Chihyun , Lee Wonseok , Park Jinsung , Kim Duckjong
Published: January 2021

Thermal interface materials (TIMs), typically composed of a polymer matrix with good wetting properties and thermally conductive fillers, are applied to the interfaces of mating components to reduce the interfacial thermal resistance. As a filler material, silver has been extensively studied because of its high intrinsic thermal conductivity. However, the high cost of silver and its toxicity has hindered the wide application of silver-based TIMs. Copper is an earth-abundant element and essential micronutrient for humans. In this paper, we present a copper-based multi-dimensional filler composed of three-dimensional microscale copper flakes, one-dimensional multi-walled carbon nanotubes (MWCNTs), and zero-dimensional copper nanoparticles (Cu NPs) to create a safe and low-cost TIM with a high thermal conductivity. Cu NPs synthesized by microwave irradiation of a precursor solution were bound to MWCNTs and mixed with copper flakes and polyimide matrix to obtain a TIM paste, which was stable even in a high-temperature environment. The cross-plane thermal conductivity of the copper-based TIM was 36 W/m/K. Owing to its high thermal conductivity and low cost, the copper-based TIM could be an industrially useful heat-dissipating material in the future.
Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders
Authors: Devi Shweta , Kumar Vijay , Singh Sandeep Kumar , Dubey Ashish Kant , Kim Jong-Joo
Published: January 2021

Neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.
The Influence of Video Format on Engagement and Performance in Online Learning
Authors: Lackmann Sergej , Léger Pierre-Majorique , Charland Patrick , Aubé Caroline , Talbot Jean
Published: January 2021

Millions of students follow online classes which are delivered in video format. Several studies examine the impact of these video formats on engagement and learning using explicit measures and outline the need to also investigate the implicit cognitive and emotional states of online learners. Our study compared two video formats in terms of engagement (over time) and learning in a between-subject experiment. Engagement was operationalized using explicit and implicit neurophysiological measures. Twenty-six (26) subjects participated in the study and were randomly assigned to one of two conditions based on the video shown: infographic video or lecture capture. The infographic video showed animated graphics, images, and text. The lecture capture showed a professor, providing a lecture, filmed in a classroom setting. Results suggest that lecture capture triggers greater emotional engagement over a shorter period, whereas the infographic video maintains higher emotional and cognitive engagement over longer periods of time. Regarding student learning, the infographic video contributes to significantly improved performance in matters of difficult questions. Additionally, our results suggest a significant relationship between engagement and student performance. In general, the higher the engagement, the better the student performance, although, in the case of cognitive engagement, the link is quadratic (inverted U shaped).
Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology
Authors: Spronck Elisabeth , Vallès Astrid , Lampen Margit , Montenegro-Miranda Paula , Keskin Sonay , Heijink Liesbeth , Evers Melvin , Petry Harald , Deventer Sander , Konstantinova Pavlina , Haan Martin
Published: January 2021

Huntington disease (HD) is a fatal, neurodegenerative genetic disorder with aggregation of mutant Huntingtin protein (mutHTT) in the brain as a key pathological mechanism. There are currently no disease modifying therapies for HD; however, HTT-lowering therapies hold promise. Recombinant adeno-associated virus serotype 5 expressing a microRNA that targets HTT mRNA (AAV5-miHTT) is in development for the treatment of HD with promising results in rodent and minipig HD models. To support a clinical trial, toxicity studies were performed in non-human primates (NHP, Macaca fascicularis) and Sprague-Dawley rats to evaluate the safety of AAV5-miHTT, the neurosurgical administration procedure, vector delivery and expression of the miHTT transgene during a 6-month observation period. For accurate delivery of AAV5-miHTT to the striatum, real-time magnetic resonance imaging (MRI) with convection-enhanced delivery (CED) was used in NHP. Catheters were successfully implanted in 24 NHP, without neurological symptoms, and resulted in tracer signal in the target areas. Widespread vector DNA and miHTT transgene distribution in the brain was found, particularly in areas associated with HD pathology. Intrastriatal administration of AAV5-miHTT was well tolerated with no clinically relevant changes in either species. These studies demonstrate the excellent safety profile of AAV5-miHTT, the reproducibility and tolerability of intrastriatal administration, and the delivery of AAV5-miHTT to the brain, which support the transition of AAV5-miHTT into clinical studies.
Mechanisms of Nerve Damage in Neuropathies Associated with Hematological Diseases: Lesson from Nerve Biopsies
Authors: Briani Chiara , Ferrari Sergio , Campagnolo Marta , Tagliapietra Matteo , Castellani Francesca , Salvalaggio Alessandro , Mariotto Sara , Visentin Andrea , Cavallaro Tiziana
Published: January 2021

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.
Elevated Circulating Microparticle Subpopulations in Incidental Cerebral White Matter Hyperintensities: A Multimodal Study
Authors: Che Mohd Nassir Che Mohd Nasril , Mohamad Ghazali Mazira , Ahmad Safri Amanina , Jaffer Usman , Abdullah Wan Zaidah , Idris Nur Suhaila , Muzaimi Mustapha
Published: January 2021

Asymptomatic (or “silent”) manifestations of cerebral small vessel disease (CSVD) are widely recognized through incidental findings of white matter hyperintensities (WMHs) as a result of magnetic resonance imaging (MRI). This study aims to examine the potential associations of surrogate markers for the evaluation of white matter integrity in CSVD among asymptomatic individuals through a battery of profiling involving QRISK2 cardiocerebrovascular risk prediction, neuroimaging, neurocognitive evaluation, and microparticles (MPs) titers. Sixty asymptomatic subjects (mean age: 39.83 ± 11.50 years) with low to moderate QRISK2 scores were recruited and underwent neurocognitive evaluation for memory and cognitive performance, peripheral venous blood collection for enumeration of selected MPs subpopulations, and 3T MRI brain scan with specific diffusion MRI (dMRI) sequences inclusive of diffusion tensor imaging (DTI). WMHs were detected in 20 subjects (33%). Older subjects (mean age: 46.00 ± 12.00 years) had higher WMHs prevalence, associated with higher QRISK2 score and reduced processing speed. They also had significantly higher mean percentage of platelet (CD62P)- and leukocyte (CD62L)-derived MPs. No association was found between reduced white matter integrity—especially at the left superior longitudinal fasciculus (LSLF)—with age and neurocognitive function; however, LSLF was associated with higher QRISK2 score, total MPs, and CD62L- and endothelial cell-derived MPs (CD146). Therefore, this study establishes these multimodal associations as potential surrogate markers for “silent” CSVD manifestations in the well-characterized cardiocerebrovascular demographic of relatively young, neurologically asymptomatic adults. Furthermore, to the best of our knowledge, this study is the first to exhibit elevated MP counts in asymptomatic CSVD (i.e., CD62P and CD62L), which warrants further delineation.
Erratum: Wagner, A.E., et al. SP8 Promotes an Aggressive Phenotype in Hepatoblastoma via FGF8 Activation. Cancers 2020, 12, 2294
Authors: Wagner Alexandra Elisabeth , Schwarzmayr Thomas , Häberle Beate , Vokuhl Christian , Schmid Irene , Kaller Markus , Hermeking Heiko , von Schweinitz Dietrich , Kappler Roland
Published: January 2021

Two contributors’ names were missing in the original version of the authorship of the paper [...]
Bone Marrow Adipocytes: A Link between Obesity and Bone Cancer
Authors: Reagan Michaela R. , Fairfield Heather , Rosen Clifford J.
Published: January 2021

Cancers that grow in the bone marrow are for most patients scary, painful, and incurable. These cancers are especially hard to treat due to the supportive microenvironment provided by the bone marrow niche in which they reside. New therapies designed to target tumor cells have extended the life expectancy for these patients, but better therapies are needed and new ideas for how to target these cancers are crucial. This need has led researchers to interrogate whether bone marrow adipocytes (BMAds), which increase in number and size during aging and in obesity, contribute to cancer initiation or progression within the bone marrow. Across the globe, the consensus in the field is a unified “yes”. However, how to target these adipocytes or the factors they produce and how BMAds interact with different tumor cells are open research questions. Herein, we review this research field, with the goal of accelerating research in the network of laboratories working in this area and attracting bright scientists with new perspectives and ideas to the field in order to bring about better therapies for patients with bone cancers.
Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells
Authors: Jakobsen Theresa , Dahl Mette , Dimopoulos Konstantinos , Grønbæk Kirsten , Kjems Jørgen , Kristensen Lasse Sommer
Published: January 2021

Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, may induce significant remissions in multiple myeloma (MM) patients, but relapses are frequently observed and the underlying molecular mechanisms for this are not completely understood. Circular RNAs (circRNAs) constitute an emerging class of non-coding RNAs with important roles in cancer. Here, we profiled genome-wide expression patterns of circRNAs in IMiD-sensitive MM cells and their resistant counterparts as well as in IMiD-resistant cells treated with specific epigenetic drugs alone or in combination. We found that genome-wide circRNA expression patterns reflect IMiD sensitivity and ciRS-7 (also known as CDR1as) was the most downregulated circRNA upon acquired resistance. The depletion of ciRS-7 correlated with increased methylation levels of the promoter CpG island of its host gene, LINC00632. Expression of LINC00632 and ciRS-7 was partly restored by treatment with a combination of an EZH2 inhibitor (EPZ-6438) and a DNA methyl transferase inhibitor (5-azacytidine), which also restores the IMiD sensitivity of the cells. However, knockdown of ciRS-7 did not affect IMiD sensitivity and we found that ciRS-7 also becomes epigenetically silenced after prolonged cell culture without drug-exposure. In conclusion, we found that genome-wide circRNA expression patterns reflect IMiD sensitivity in an in vitro model of acquired resistance.
Regional Responses in Radiation-Induced Normal Tissue Damage
Authors: Voshart Daniëlle C. , Wiedemann Julia , van Luijk Peter , Barazzuol Lara
Published: January 2021

Normal tissue side effects remain a major concern in radiotherapy. The improved precision of radiation dose delivery of recent technological developments in radiotherapy has the potential to reduce the radiation dose to organ regions that contribute the most to the development of side effects. This review discusses the contribution of regional variation in radiation responses in several organs. In the brain, various regions were found to contribute to radiation-induced neurocognitive dysfunction. In the parotid gland, the region containing the major ducts was found to be critical in hyposalivation. The heart and lung were each found to exhibit regional responses while also mutually affecting each other’s response to radiation. Sub-structures critical for the development of side effects were identified in the pancreas and bladder. The presence of these regional responses is based on a non-uniform distribution of target cells or sub-structures critical for organ function. These characteristics are common to most organs in the body and we therefore hypothesize that regional responses in radiation-induced normal tissue damage may be a shared occurrence. Further investigations will offer new opportunities to reduce normal tissue side effects of radiotherapy using modern and high-precision technologies.
In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors
Authors: Roze Joline , Sendino Garví Elena , Stelloo Ellen , Stangl Christina , Sereno Ferdinando , Duran Karen , Groeneweg Jolijn , Paijens Sterre , Nijman Hans , van Meurs Hannah , van Lonkhuijzen Luc , Piek Jurgen , Lok Christianne , Jonges Geertruida , Witteveen Petronella , Verheijen René , van Haaften Gijs , Zweemer Ronald , Monroe Glen
Published: January 2021

Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.
Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer
Authors: Khatpe Aditi , Adebayo Adedeji , Herodotou Christopher , Kumar Brijesh , Nakshatri Harikrishna
Published: January 2021

Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.
HER2-Positive Breast Cancer Patients with Pre-Treatment Axillary Involvement or Postmenopausal Status Benefit from Neoadjuvant Rather than Adjuvant Chemotherapy Plus Trastuzumab Regimens
Authors: Laas Enora , Bresset Arnaud , Féron Jean-Guillaume , Le Gal Claire , Darrigues Lauren , Coussy Florence , Grandal Beatriz , Laot Lucie , Pierga Jean-Yves , Reyal Fabien , Hamy Anne-Sophie
Published: January 2021

Background: No survival benefit has yet been demonstrated for neoadjuvant chemotherapy (NAC) against HER2-positive tumors in patients with early breast cancer (BC). The objective of this study was to compare the prognosis of HER2-positive BC patients treated with NAC to that of patients treated with adjuvant chemotherapy (AC). Materials and methods: We retrospectively analyzed disease-free (DFS) and overall survival (OS) in 202 HER2-positive patients treated with NAC and 701 patients treated with AC. All patients received trastuzumab in addition to chemotherapy. Patient data were weighted by a propensity score to overcome selection bias. Results: After inverse probability of treatment weights (IPTW) adjustment, no difference in DFS (p = 0.3) was found between treatments for the total population. However, after multivariate analysis, an interaction was found between cN status and chemotherapy strategy (IPTW-corrected corrected Hazard ratio cHR = 0.52, 95% CI (0.3–0.9), pinteraction = 0.08) and between menopausal status and chemotherapy (CT) strategy (cHR = 0.35, 95%CI (0.18–0.7)) pinteraction < 0.01). NAC was more beneficial than AC strategy in cN-positive patients and in postmenopausal patients. Moreover, after IPTW adjustment, the multivariate analysis showed that the neoadjuvant strategy conferred a significant OS benefit (cHR = 0.09, 95%CI [0.02–0.35], p < 0.001). Conclusion: In patients with HER2-positive BC, the NAC strategy is more beneficial than the AC strategy, particularly in cN-positive and postmenopausal patients. NAC should be used as a first-line treatment for HER2-positive tumors.
Cancer Stem Cells—Key Players in Tumor Relapse
Authors: Marzagalli Monica , Fontana Fabrizio , Raimondi Michela , Limonta Patrizia
Published: January 2021

Tumor relapse and treatment failure are unfortunately common events for cancer patients, thus often rendering cancer an uncurable disease. Cancer stem cells (CSCs) are a subset of cancer cells endowed with tumor-initiating and self-renewal capacity, as well as with high adaptive abilities. Altogether, these features contribute to CSC survival after one or multiple therapeutic approaches, thus leading to treatment failure and tumor progression/relapse. Thus, elucidating the molecular mechanisms associated with stemness-driven resistance is crucial for the development of more effective drugs and durable responses. This review will highlight the mechanisms exploited by CSCs to overcome different therapeutic strategies, from chemo- and radiotherapies to targeted therapies and immunotherapies, shedding light on their plasticity as an insidious trait responsible for their adaptation/escape. Finally, novel CSC-specific approaches will be described, providing evidence of their preclinical and clinical applications.
Long-Term Experience with Radiofrequency-Induced Hyperthermia Combined with Intravesical Chemotherapy for Non-Muscle Invasive Bladder Cancer
Authors: Brummelhuis Iris S. G. , Wimper Yvonne , Witjes-van Os Hilde G. J. M. , Arends Tom J. H. , van der Heijden Antoine G. , Witjes J. Alfred
Published: January 2021

Background: The recurrence rate of non-muscle invasive bladder cancer (NMIBC) is high, despite intravesical treatments. Importantly, patients are frequently unfit or unwilling to undergo a recommended radical cystectomy when standard intravesical treatments fail, due to the substantial risk of morbidity and mortality. For these patients, radiofrequency-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We aim to determine treatment outcomes and assess the effect of (ablative) dose. Methods: 299 intensively pretreated patients treated with RF-CHT were included in safety analysis. Of these, 274 patients who fulfilled induction treatments were included in efficacy analysis. Six-month complete response (CR) and durable response were reported for (concomitant) carcinoma in situ (CIS) patients and recurrence-free survival (RFS) for papillary patients. Results: For CIS, six-month CR-rate was 56.0%; and durable response rates were 79.7%, 66.5%, and 40.3% at one-, two- and five-year, respectively. RFS rates for papillary patients were 77.9%, 57.5%, and 37.2%, respectively. Patients treated with ablative dose are less likely to develop recurrence (adjusted Hazard Ratio 0.54, p = 0.01), compared to adjuvant dose. Conclusions: RF-CHT is effective in NMIBC patients in whom standard intravesical treatments have failed and should be considered in patients who are unwilling or unfit to undergo radical cystectomy. Patients with CIS or residual papillary tumor at baseline benefit from ablative dose.
The Role of Neoadjuvant Chemotherapy in Repeat Local Treatment of Recurrent Colorectal Liver Metastases: A Systematic Review and Meta-Analysis
Authors: Dijkstra Madelon , Nieuwenhuizen Sanne , Puijk Robbert S. , Geboers Bart , Timmer Florentine E. F. , Schouten Evelien A. C. , Scheffer Hester J. , de Vries Jan J. J. , Ket Johannes C. F. , Versteeg Kathelijn S. , Meijerink Martijn R. , van den Tol M. Petrousjka
Published: January 2021

The additive value of neoadjuvant chemotherapy (NAC) prior to repeat local treatment of patients with recurrent colorectal liver metastases (CRLM) is unclear. A systematic search was performed in PubMed, Embase, Web of Science, and an additional search in Google Scholar to find articles comparing repeat local treatment by partial hepatectomy and/or thermal ablation with versus without NAC. The search included randomized trials and comparative observational studies with univariate/multivariate analysis and/or matching as well as (inter)national guidelines assessed using the AGREE II instrument. The search identified 21,832 records; 172 were selected for full-text review; 20 were included: 20 comparative observational studies were evaluated. Literature to evaluate the additive value of NAC prior to repeat local treatment was limited. Outcomes of NAC were often reported as subgroup analyses and reporting of results was frequently unclear. Assessment of the seven studies that qualified for inclusion in the meta-analysis showed conflicting results. Only one study reported a significant difference in overall survival (OS) favoring NAC prior to repeat local treatment. However, further analysis revealed a high risk for residual bias, because only a selected group of chemo-responders qualified for repeat local treatment, disregarding the non-responders who did not qualify. All guidelines that specifically mention recurrent disease (3/3) recommend repeat local treatment; none provide recommendations about the role of NAC. The inconclusive findings of this meta-analysis do not support recommendations to routinely favor NAC prior to repeat local treatment. This emphasizes the need to investigate the additive value of NAC prior to repeat local treatment of patients with recurrent CRLM in a future phase 3 randomized controlled trial (RCT).