bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Healthcare Expenditures on Healthcare Outcomes in the Middle East and North Africa (MENA) Region: A Cross-Country Comparison, 1995–2015
Authors: Balkhi Bander , Alshayban Dhfer , Alotaibi Nawaf M.
Published: February 2021

The association between healthcare expenditures and outcomes, mainly mortality and life expectancy, is complex. The real explanation for this association is not clear, especially in the Middle East and North Africa (MENA) region. This study assesses the impact of health expenditures on improving healthcare systems and health status and finds a relationship between health expenditures and health outcomes across different region. Annual time series data on healthcare spending and outcomes from 1995 to 2015 were used for MENA region in comparison to developed and developing countries. Health expenditure was adjusted by the consumer price index equation to the 2015 US dollar eliminate the impact of inflation on our results. For many countries, spending on healthcare continues to rise, Among MENA countries, we found that the United Arab Emirates and Kuwait spent more per capita on health, $1,711 and $1,420, respectively, than any other countries in the region. Although this study demonstrated a relationship between total healthcare expenditure and outcomes, some countries spend more on healthcare but have shorter life expectancy. In most countries, efficient and effective utilization of healthcare resources is the key strategy for improving health outcomes in any country. The lack of a positive correlation between healthcare spending and life expectancy may indicate that health resources are not allocated effectively. In those cases, increasing health spending does not guarantee that there is any kind of improvement in healthcare.
Mental Health of Physicians During COVID-19 Outbreak in Bangladesh: A Web-Based Cross-Sectional Survey
Authors: Khatun Most. Farida , Parvin Most. Firoza , Rashid Md. Mamun-ur , Alam Md. Shah , Kamrunnahar Most. , Talukder Ashis , Rahman Razu Shaharior , Ward Paul R. , Ali Mohammad
Published: February 2021

There have been numerous studies about the health implication of COVID-19 on patients, but little attention has been paid to the impacts of the pandemic on physicians. Our paper attends to this gap by exploring the mental health of physicians in Bangladesh during the COVID-19 pandemic. This is particularly important since the mental health of physicians impacts not only on themselves, but also their professional performance and hence the care of patients. This study examined physicians' mental health outcomes by evaluating the prevalence and associated potential risk factors of anxiety and depression. Using a web-based cross-sectional survey, we collected data from 114 physicians. Seven-item Generalized Anxiety Disorder (GAD-7) scale and Nine-item Patient Health Questionnaire (PHQ-9) were used to measure the anxiety and depression, respectively. Multivariate logistic regression models were used to explore the potential risk factors related to anxiety and depression. The prevalence of anxiety and depression were 32.5 and 34.2%, respectively. Findings revealed that marital status, work per day and current job location were the main risk factors for anxiety while sex, age, and marital status were the main risk factors for depression. Our results highlight the need to implement policies and strategies for positively impacting the mental health of physicians during and after the COVID-19 pandemic.
Entrapment Between Narratives: The Millennial Voice and Degendering Organizational Resilience
Authors: Witmer Hope
Published: February 2021

The Covid-19 pandemic pushes organizations to innovate, adapt, and be responsive to new conditions. These demands are exacerbated as organizations respond to the triple sustainability challenge of social and environmental issues alongside economic recovery. These combined factors highlight the need for an inclusive definition of organizational resilience, the increased agility to adapt, learn, and transform to rapidly shifting external and internal conditions. This paper explores a gendered perspective of organizational resilience and the implications for degendering the concept to incorporate masculine and feminine constructs equally valuable to the theory and practices of organizational resilience during times of crisis. Viewing the organizational demands of crisis and the expectations of the millennial workforce through the degendering lens elucidates conceptualizations of gender constructions and power that limit inclusive practices and processes of organizational resilience. Data was used from focus groups of men and women between the ages of 21–35 (millennials) who have experience in the workplace and a shared knowledge of sustainability including social aspects of gender equity and inclusion. The Degendering Organizational Resilience model (DOR) was used for analysis to reveal barriers to inclusive, resilient organizational practices. The data was organized according to the three aspects of the DOR, power structures, gendering practices, and language. A unique contribution of this study is that it explores a cross-cultural gender perspective of organizational resilience focused on a specific cohort group, the millennials. Based on the findings three organizational recommendations for practice were identified. These include recommendations for policies and practices that deconstruct inequitable practices and co-create more agile structures, practices, and narratives for sustainable and resilient organizations.
Pregnancy During the Global COVID-19 Pandemic: Canadian Experiences of Care
Authors: Rudrum Sarah
Published: February 2021

Drawing on journal entries written by a cohort of pregnant Canadians, this article explores how responses to the COVID-19 pandemic shaped access to and experiences of maternity care. Variance in practices among jurisdictions and among provider groups meant that participants had diverse experiences. Nevertheless, I identify clear shared concerns, including fear over giving birth with no familial support, the need for better communications, and challenges entailed when needing to switch providers or travel for care during a state of emergency. Despite a universal health care system, there are gaps and inequities in access to appropriate maternity care in Canada; the pandemic exposed existing access challenges.
Dose-Effect of Zearalenone on the Localization and Expression of Growth Hormone, Growth Hormone Receptor, and Heat Shock Protein 70 in the Ovaries of Post-weaning Gilts
Authors: Song Tingting , Liu Xiufeng , Yuan Xuejun , Yang Weiren , Liu Faxiao , Hou Yanmeng , Huang Libo , Jiang Shuzhen
Published: February 2021

Zearalenone (ZEA) has an estrogen-like effect, which can injure the reproductive system of animals, causing infertility, and abortion in sows. However, the underlying mechanisms are still not clear. The objective of this study was to assess the effects of ZEA on the localization and expression of growth hormone (GH), growth hormone receptor (GHR), and heat shock protein 70 (Hsp70) in the ovaries of post-weaning gilts. Forty healthy post-weaning gilts were randomly provided one of four diets: normal basal diet supplemented with 0 (control), 0.5 (ZEA0.5), 1.0 (ZEA1.0), and 1.5 (ZEA1.5) mg ZEA/kg. Gilts were housed and fed individually for 35 days; the ovaries were collected after euthanasia for antioxidant index, relative mRNA and protein expression, and immunohistochemical analyses of GH, GHR, and Hsp70. The results revealed that the glutathione peroxidase and total superoxide dismutase levels decreased (p < 0.05), whereas the malondialdehyde level increased (p < 0.05) with increasing ZEA content. The localization pattern of GH, GHR, and Hsp70 in ZEA-treated gilts was the same as that in the control; however, the localization of yellow and brown immunoreactive substances of GH, GHR, and Hsp70 was stronger in the ZEA groups than in the control. The relative mRNA and protein expression of GHR and Hsp70 was the highest in the ZEA1.0 group (p < 0.05), whereas that of GH was the highest in the ZEA0.5 group (p < 0.05). The mRNA and protein expression of GH was lower in the ZEA1.5 group than in the control (p < 0.05). Hsp70 results showed adverse responses to increasing ZEA levels in gilt ovaries, suggesting that Hsp70 played an important role in alleviating ZEA-induced oxidative stress.
The Common Warehouse Model and Profit Distribution of the Express Industry
Authors: Wang Li , Wang Xi , Cai Xilong
Published: February 2021

The sharing mode of the logistics industry can effectively solve the new problems arising from the rapid development of the express industry. However, only when the interests are reasonably distributed can the sharing mode be implemented for a long time. This paper discusses the connotation of unified warehouse and distribution, designs the operation mode of a unified warehouse and distribution, and solves the profit distribution problem of a unified warehouse and distribution alliance based on the improved Shapley value method. Firstly, the traditional Shapley value method is improved by using a comprehensive correction factor, including the proportions of investment, risk, and innovative research contributions. Secondly, each factor’s weight is determined by the analytic hierarchy process (AHP), and the profits are distributed according to the contribution of each express enterprise to the alliance. Finally, an example is given to verify the validity of the modified algorithm. It proves that the modified Shapley value method can effectively solve the problem of profit distribution.
Design, Modeling, and Control of a Single Leg for a Legged-Wheeled Locomotion System with Non-Rigid Joint
Authors: Pinto Vítor H. , Gonçalves José , Costa Paulo
Published: February 2021

This article presents an innovative legged-wheeled system, designed to be applied in a hybrid robotic vehicle’s locomotion system, as its driving member. The proposed system will be capable to combine the advantages of legged and wheeled locomotion systems, having 3DOF connected through a combination of both rigid and non-rigid joints. This configuration provides the vehicle the ability to absorb impacts and selected external disturbances. A state space approach was adopted to control the joints, increasing the system’s stability and adaptability. Throughout this article, the entire design process of this robotic system will be presented, as well as its modeling and control. The proposed system’s design is biologically inspired, having as reference the human leg, resulting in the development of a prototype. The results of the testing process with the proposed prototype are also presented. This system was designed to be modular, low-cost, and to increase the autonomy of typical autonomous legged-wheeled locomotion systems.
Antioxidants Promote Intestinal Tumor Progression in Mice
Authors: Zou Zhiyuan V. , Le Gal Kristell , El Zowalaty Ahmed E. , Pehlivanoglu Lara E. , Garellick Viktor , Gul Nadia , Ibrahim Mohamed X. , Bergh Per-Olof , Henricsson Marcus , Wiel Clotilde , Akyürek Levent M. , Bergo Martin O. , Sayin Volkan I. , Lindahl Per
Published: February 2021

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.
Antioxidant, Pancreatic Lipase Inhibitory, and Tyrosinase Inhibitory Activities of Extracts of the Invasive Plant Spartina anglica (Cord-Grass)
Authors: Kim Geum Jin , Park Songhee , Kim Eonmi , Kwon Hyukbean , Park Hae-Jin , Nam Joo-Won , Roh Seong-Soo , Choi Hyukjae
Published: February 2021

Since 2016, the invasive halophyte Spartina anglica has been colonizing mudflats along the western coast of South Korea. In order to minimize costs on S. anglica expansion management and waste-treatment of collected biomass, the potential application of the collected biomass of S. anglica was investigated. Ethanolic extracts and subfractions thereof (hexanes, methylene chloride, ethyl acetate, 1-butanol, and water-soluble) of the aerial and belowground parts of S. anglica showed free radical-scavenging [2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)], tyrosinase inhibitory, and pancreatic lipase inhibitory activities. An ethyl acetate fraction derived from aerial parts (EA-a) showed the most potent radical-scavenging and pancreatic lipase inhibitory activities, whereas tyrosinase inhibition was mainly observed in the methylene chloride soluble fractions (MC-bg) and other lipophilic fractions (ethyl acetate and hexanes layers) obtained from belowground parts. The major EA-a compound isolated and identified was 1,3-di-O-trans-feruloyl quinic acid (1) based on spectroscopic analysis, whereas the two major MC-bg compounds were identified as p-hydroxybenzaldehyde (2) and N-trans-feruloyltyramine (3). Compounds 1 and 3 scavenged both DPPH and ABTS radicals, whereas 1 and 2 inhibited pancreatic lipase activity. These results indicate that extracts and fractions of S. anglica have antioxidant, anti-obesity, and whitening properties with potential pharmaceutical, cosmeceutical, and functional food applications.
Responses of Primary Productivity and Phytoplankton Community to the Atmospheric Nutrient Deposition in the East China Sea
Authors: Ma Qingwei , Chen Ying , Wang Fanghui , Li Haowen
Published: February 2021

Atmospheric deposition of nutrients to the surface seawater may significantly affect marine phytoplankton growth. Two in situ bioassay experiments were performed in the East China Sea (ECS) by adding nutrients (N, P, and Si) and atmospheric aerosols into the surface seawater. Chlorophyll a (Chl a) concentrations were largely enhanced by simultaneous input of N and P with the maximal increase of 0.68–0.78 μg Chl a per μmol N addition. This Chl a increment was significantly lower (0.19–0.47 μg) in aerosol treatments as a result of initial N-replete condition (N/P ratio ~50) and extremely high N/P ratio in aerosols (>300). Among the multiple influencing factors, atmospheric dry flux of NH4+ + NO3− (AN) was found to be an effective predictor for springtime Chl a in the ECS with a time lag of three days and were strongly correlated with Chl a concentrations on day 3 (r = 0.81, p < 0.001), which might be partly explained by the asynchronous supplies of N (atmospheric deposition) and P (subsurface water). Although dinoflagellates dominated the phytoplankton community in both initial seawaters, additions of P and N + P + Si profoundly enhanced the cell densities and dominance of diatom species Thalassiosira sp. and Nitzschia closterium in the 2012 and 2014 bioassay experiments, respectively. Moreover, the percentage of dinoflagellates were promoted by adding higher NH4+/NO3− ratio (6/4 vs. 1/9) when silicate was at a low concentration (~2 μmol L−1). Atmospheric deposition is likely to be an important N source supporting the high primary production in the ECS and its supply of excess N relative to P may influence dominant phytoplankton groups.
Sliding Mode Control with Application to Fault-Tolerant Control: Assessment and Open Problems
Authors: Zenteno-Torres Jazmín , Cieslak Jérôme , Dávila Jorge , Henry David
Published: February 2021

This paper is prepared within a collaboration between the Instituto Politécnico Nacional, which is a Mexican research institute that manages research on sliding-mode control theory, and the ARIA research team of the Intégration du Matériau au Système Lab., a French research group that engages research on model-based fault diagnosis and fault-tolerant control theories. The paper reviews the application of sliding mode control techniques to fault tolerant control and provides perspectives leading to posing some open problems. Operating principles, definitions of the basic concepts are recalled along with the control objectives and design procedures. The evolution of the sliding mode control technique through five generations (as classified by Fridman, Moreno and co-workers) is reviewed. Their respective design procedures, limitations, and robustness properties are also highlighted. The application of the five generations of sliding-mode controllers to fault-tolerant control is discussed. The focus is on some open problems that are judged to commonly be overlooked. Some applications in real-world systems are also presented.
An Atherogenic Diet Disturbs Aquaporin 5 Expression in Liver and Adipocyte Tissues of Apolipoprotein E-Deficient Mice: New Insights into an Old Model of Experimental Atherosclerosis
Authors: da Silva Inês V. , Whalen Courtney A. , Mattie Floyd J. , Florindo Cristina , Huang Neil K. , Heil Sandra G. , Neuberger Thomas , Ross A. Catharine , Soveral Graça , Castro Rita
Published: February 2021

The dysfunction of vascular endothelial cells is profoundly implicated in the pathogenesis of atherosclerosis and cardiovascular disease, the global leading cause of death. Aquaporins (AQPs) are membrane channels that facilitate water and glycerol transport across cellular membranes recently implicated in the homeostasis of the cardiovascular system. Apolipoprotein-E deficient (apoE−/−) mice are a common model to study the progression of atherosclerosis. Nevertheless, the pattern of expression of AQPs in this atheroprone model is poorly characterized. In this study, apoE−/− mice were fed an atherogenic high-fat (HF) or a control diet. Plasma was collected at multiple time points to assess metabolic disturbances. At the endpoint, the aortic atherosclerotic burden was quantified using high field magnetic resonance imaging. Moreover, the transcriptional levels of several AQP isoforms were evaluated in the liver, white adipocyte tissue (WAT), and brown adipocyte tissue (BAT). The results revealed that HF-fed mice, when compared to controls, presented an exacerbated systemic inflammation and atherosclerotic phenotype, with no major differences in systemic methylation status, circulating amino acids, or plasma total glutathione. Moreover, an overexpression of the isoform AQP5 was detected in all studied tissues from HF-fed mice when compared to controls. These results suggest a novel role for AQP5 on diet-induced atherosclerosis that warrants further investigation.
Bacterial Genotoxin-Coated Nanoparticles for Radiotherapy Sensitization in Prostate Cancer
Authors: Chen Yu-An , Lai Yi-Ru , Wu Hui-Yu , Lo Yen-Ju , Chang Yu-Fang , Hung Chiu-Lien , Lin Chun-Jung , Lo U-Ging , Lin Ho , Hsieh Jer-Tsong , Chiu Cheng-Hsun , Lin Yu-Hsin , Lai Chih-Ho
Published: February 2021

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and usually becomes refractory because of recurrence and metastasis. CD44, a transmembrane glycoprotein, serves as a receptor for hyaluronic acid (HA). It has been found to be abundantly expressed in cancer stem cells (CSCs) that often exhibit a radioresistant phenotype. Cytolethal distending toxin (CDT), produced by Campylobacter jejuni, is a tripartite genotoxin composed of CdtA, CdtB, and CdtC subunits. Among the three, CdtB acts as a type I deoxyribonuclease (DNase I), which creates DNA double-strand breaks (DSBs). Nanoparticles loaded with antitumor drugs and specific ligands that recognize cancerous cell receptors are promising methods to overcome the therapeutic challenges. In this study, HA-decorated nanoparticle-encapsulated CdtB (HA-CdtB-NPs) were prepared and their targeted therapeutic activity in radioresistant PCa cells was evaluated. Our results showed that HA-CdtB-NPs sensitized radioresistant PCa cells by enhancing DSB and causing G2/M cell-cycle arrest, without affecting the normal prostate epithelial cells. HA-CdtB-NPs possess maximum target specificity and delivery efficiency of CdtB into the nucleus and enhance the effect of radiation in radioresistant PCa cells. These findings demonstrate that HA-CdtB-NPs exert target specificity accompanied with radiomimetic activity and can be developed as an effective strategy against radioresistant PCa.
Molecular Imaging of Inflammatory Disease
Authors: Jones Meredith A. , MacCuaig William M. , Frickenstein Alex N. , Camalan Seda , Gurcan Metin N. , Holter-Chakrabarty Jennifer , Morris Katherine T. , McNally Molly W. , Booth Kristina K. , Carter Steven , Grizzle William E. , McNally Lacey R.
Published: February 2021

Inflammatory diseases include a wide variety of highly prevalent conditions with high mortality rates in severe cases ranging from cardiovascular disease, to rheumatoid arthritis, to chronic obstructive pulmonary disease, to graft vs. host disease, to a number of gastrointestinal disorders. Many diseases that are not considered inflammatory per se are associated with varying levels of inflammation. Imaging of the immune system and inflammatory response is of interest as it can give insight into disease progression and severity. Clinical imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) are traditionally limited to the visualization of anatomical information; then, the presence or absence of an inflammatory state must be inferred from the structural abnormalities. Improvement in available contrast agents has made it possible to obtain functional information as well as anatomical. In vivo imaging of inflammation ultimately facilitates an improved accuracy of diagnostics and monitoring of patients to allow for better patient care. Highly specific molecular imaging of inflammatory biomarkers allows for earlier diagnosis to prevent irreversible damage. Advancements in imaging instruments, targeted tracers, and contrast agents represent a rapidly growing area of preclinical research with the hopes of quick translation to the clinic.
Ethanol-Related Behaviors in Mouse Lines Selectively Bred for Drinking to Intoxication
Authors: Jensen Bryan E. , Townsley Kayla G. , Grigsby Kolter B. , Metten Pamela , Chand Meher , Uzoekwe Miracle , Tran Alex , Firsick Evan , LeBlanc Katherine , Crabbe John C. , Ozburn Angela R.
Published: February 2021

Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line.
Epigenetics in Families: Covariance between Mother and Child Methylation Patterns
Authors: Van Aswegen Tanya , Bosmans Guy , Goossens Luc , Van Leeuwen Karla , Claes Stephan , Van Den Noortgate Wim , Hankin Benjamin L.
Published: February 2021

Theory and research both point at epigenetic processes affecting both parenting behavior and child functioning. However, little is known about the convergence of mother and child’s epigenetic patterns in families. Therefore, the current study investigated epigenetic covariance in mother–child dyads’ methylation levels regarding four stress-regulation related genes (5HTT, NR3C1, FKBP5, and BDNF). Covariance was tested in a general population sample, consisting of early adolescents (Mage = 11.63, SDage = 2.3) and mothers (N = 160 dyads). Results showed that mother and offspring 5HTT and NR3C1 methylation patterns correlated. Furthermore, when averaged across genes, methylation levels strongly correlated. These findings partially supported that child and parent methylation levels covary. It might be important to consider this covariance to understand maladaptive parent–child relationships.
Making the Most of Complexity to Create Opportunities: Comprehensive Genomic Profiling and Molecular Tumor Board for Patients with Non-Small Cell Lung Cancer (NSCLC)
Authors: Fumagalli Caterina , Guerini-Rocco Elena , Barberis Massimo
Published: February 2021

Personalized cancer therapy matches the plan of treatment with specific molecular alterations [...]
Comprehensive Epstein-Barr Virus Transcriptome by RNA-Sequencing in Angioimmunoblastic T Cell Lymphoma (AITL) and Other Lymphomas
Authors: Bayda Nader , Tilloy Valentin , Chaunavel Alain , Bahri Racha , Halabi Mohamad Adnan , Feuillard Jean , Jaccard Arnaud , Ranger-Rogez Sylvie
Published: February 2021

The Epstein–Barr virus (EBV) is associated with angioimmunoblastic T cell lymphoma (AITL) in more than 80% of cases. Few studies have focused on this association and it is not clear now what role the virus plays in this pathology. We used next-generation sequencing (NGS) to study EBV transcriptome in 14 AITLs compared to 21 other lymphoma samples and 11 cell lines including 4 lymphoblastoid cell lines (LCLs). Viral transcripts were recovered using capture probes and sequencing was performed on Illumina. Bam-HI A rightward transcripts (BARTs) were the most latency transcripts expressed in AITLs, suggesting they may play a role in this pathology. Thus, BARTs, already described as highly expressed in carcinoma cells, are also very present in AITLs and other lymphomas. They were poorly expressed in cell lines other than LCLs. AITLs showed a latency IIc, with BNLF2a gene expression. For most AITLs, BCRF1, which encodes a homologous protein of human interleukin 10, vIL-10, was in addition expressed. This co-expression can contribute to immune escape and survival of infected cells. Considering these results, it can be assumed that EBV plays a pathogenic role in AITLs.
Targeting the Hippo Pathway in Prostate Cancer: What’s New?
Authors: Coffey Kelly
Published: February 2021

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.
Personalizing Oncolytic Virotherapy for Glioblastoma: In Search of Biomarkers for Response
Authors: Stavrakaki Eftychia , Dirven Clemens M. F. , Lamfers Martine L. M.
Published: February 2021

Oncolytic virus (OV) treatment may offer a new treatment option for the aggressive brain tumor glioblastoma. Clinical trials testing oncolytic viruses in this patient group have shown promising results, with patients achieving impressive long-term clinical responses. However, the number of responders to each OV remains low. This is thought to arise from the large heterogeneity of these tumors, both in terms of molecular make-up and their immune-suppressive microenvironment, leading to variability in responses. An approach that may improve response rates is the personalized utilization of oncolytic viruses against Glioblastoma (GBM), based on specific tumor- or patient-related characteristics. In this review, we discuss potential biomarkers for response to different OVs as well as emerging ex vivo assays that in the future may enable selection of optimal OV for a specific patient and design of stratified clinical OV trials for GBM.
Role of Short- and Long-Lived Reactive Species on the Selectivity and Anti-Cancer Action of Plasma Treatment In Vitro
Authors: Sklias Kyriakos , Santos Sousa João , Girard Pierre-Marie
Published: February 2021

(1) Plasma-activated liquids (PAL) have been extensively studied for their anti-cancer properties. Two treatment modalities can be applied to the cells, direct and indirect plasma treatments, which differ by the environment to which the cells are exposed. For direct plasma treatment, the cells covered by a liquid are present during the plasma treatment time (phase I, plasma ON) and the incubation time (phase II, plasma OFF), while for indirect plasma treatment, phase I is cell-free and cells are only exposed to PAL during phase II. The scope of this work was to study these two treatment modalities to bring new insights into the potential use of PAL for cancer treatment. (2) We used two models of head and neck cancer cells, CAL27 and FaDu, and three models of normal cells (1Br3, NHK, and RPE-hTERT). PBS was used as the liquid of interest, and the concentration of plasma-induced H2O2, NO2− and NO3−, as well as pH change, were measured. Cells were exposed to direct plasma treatment, indirect plasma treatment or reconstituted buffer (PBS adjusted with plasma-induced concentrations of H2O2, NO2−, NO3− and pH). Metabolic cell activity, cell viability, lipid peroxidation, intracellular ROS production and caspase 3/7 induction were quantified. (3) If we showed that direct plasma treatment is slightly more efficient than indirect plasma treatment and reconstituted buffer at inducing lipid peroxidation, intracellular increase of ROS and cancer cell death in tumor cells, our data also revealed that reconstituted buffer is equivalent to indirect plasma treatment. In contrast, normal cells are quite insensitive to these two last treatment modalities. However, they are extremely sensitive to direct plasma treatment. Indeed, we found that phase I and phase II act in synergy to trigger cell death in normal cells and are additive concerning tumor cell death. Our data also highlight the presence in plasma-treated PBS of yet unidentified short-lived reactive species that contribute to cell death. (4) In this study, we provide strong evidence that, in vitro, the concentration of RONS (H2O2, NO2− and NO3−) in combination with the acidic pH are the main drivers of plasma-induced PBS toxicity in tumor cells but not in normal cells, which makes ad hoc reconstituted solutions powerful anti-tumor treatments. In marked contrast, direct plasma treatment is deleterious for normal cells in vitro and should be avoided. Based on our results, we discuss the limitations to the use of PAL for cancer treatments.
PathoFusion: An Open-Source AI Framework for Recognition of Pathomorphological Features and Mapping of Immunohistochemical Data
Authors: Bao Guoqing , Wang Xiuying , Xu Ran , Loh Christina , Adeyinka Oreoluwa Daniel , Pieris Dula Asheka , Cherepanoff Svetlana , Gracie Gary , Lee Maggie , McDonald Kerrie L. , Nowak Anna K. , Banati Richard , Buckland Michael E. , Graeber Manuel B.
Published: February 2021

We have developed a platform, termed PathoFusion, which is an integrated system for marking, training, and recognition of pathological features in whole-slide tissue sections. The platform uses a bifocal convolutional neural network (BCNN) which is designed to simultaneously capture both index and contextual feature information from shorter and longer image tiles, respectively. This is analogous to how a microscopist in pathology works, identifying a cancerous morphological feature in the tissue context using first a narrow and then a wider focus, hence bifocal. Adjacent tissue sections obtained from glioblastoma cases were processed for hematoxylin and eosin (H&E) and immunohistochemical (CD276) staining. Image tiles cropped from the digitized images based on markings made by a consultant neuropathologist were used to train the BCNN. PathoFusion demonstrated its ability to recognize malignant neuropathological features autonomously and map immunohistochemical data simultaneously. Our experiments show that PathoFusion achieved areas under the curve (AUCs) of 0.985 ± 0.011 and 0.988 ± 0.001 in patch-level recognition of six typical pathomorphological features and detection of associated immunoreactivity, respectively. On this basis, the system further correlated CD276 immunoreactivity to abnormal tumor vasculature. Corresponding feature distributions and overlaps were visualized by heatmaps, permitting high-resolution qualitative as well as quantitative morphological analyses for entire histological slides. Recognition of more user-defined pathomorphological features can be added to the system and included in future tissue analyses. Integration of PathoFusion with the day-to-day service workflow of a (neuro)pathology department is a goal. The software code for PathoFusion is made publicly available.
miR-224-5p Contained in Urinary Extracellular Vesicles Regulates PD-L1 Expression by Inhibiting Cyclin D1 in Renal Cell Carcinoma Cells
Authors: Qin Zhiyuan , Hu Haihong , Sun Wen , Chen Lu , Jin Shengnan , Xu Qingwen , Liu Yuxi , Yu Lushan , Zeng Su
Published: February 2021

The abundant miRNAs in urinary extracellular vesicles (EVs) represent ideal reservoirs for biomarker discovery, especially in renal cell carcinoma (RCC). However, the content and biological functions of microRNAs contained in urinary EVs in RCC remain ambiguous. In this study, urinary EVs were isolated and characterized from RCC patients and healthy volunteers. Differentially expressed microRNAs in urinary EVs were screened by small RNA sequencing. The target gene and biological functions of selected microRNAs were investigated through multifaceted methods. Results indicated that miR-224-5p was significantly upregulated in urinary EVs of RCC patients compared to healthy volunteers. The overexpression of miR-224-5p inhibited RCC cell proliferation and induced cell cycle arrest. The gene CCND1 encoding cyclin D1 was identified as a direct target of miR-224-5p via prediction and validation. Moreover, the invasive and metastatic abilities of RCC cells were enhanced by miR-224-5p. Interestingly, miR-224-5p also increased the stability of PD-L1 protein by inhibiting CCND1. This effect could be transmitted via EVs and further promoted the resistance of RCC cells to T cell-dependent toxicity. In summary, urinary EVs containing miR-224-5p were identified as a potential biomarker in RCC. Regulation of PD-L1 protein expression by miR-224-5p through suppressing CCND1 elucidates new roles of miR-224-5p in RCC progression.
Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma
Authors: Wickenhauser Claudia , Bethmann Daniel , Kappler Matthias , Eckert Alexander Walter , Steven André , Bukur Jürgen , Fox Bernard Aloysius , Beer Jana , Seliger Barbara
Published: February 2021

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient’s outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells were found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN-γ signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.
Redundancy-Free Models for Mathematical Descriptions of Three-Phase Catalytic Hydrogenation of Cinnamaldehyde
Authors: Borovinskaya Ekaterina
Published: February 2021

A new approach on how to formulate redundancy-free models for mathematical descriptions of three-phase catalytic hydrogenation of cinnamaldehyde is presented. An automatically created redundant (generalized) model is formulated according to the complete reaction network. Models based on formal kinetics and kinetics concerning the Langmuir-Hinshelwood theory for three-phase catalytic hydrogenation of cinnamaldehyde were investigated. Redundancy-free models were obtained as a result of a step-by-step elimination of model parameters using sensitivity and interval analysis. Starting with 24 parameters in the redundant model, the redundancy-free model based on the Langmuir-Hinshelwood mechanism contains 6 parameters, while the model based on formal kinetics includes only 4 parameters. Due to less degrees of freedom of molecular rotation in the adsorbed state, the probability of a direct conversion of cinnamaldehyde to 3-phenylpropanol according to the redundancy-free model based on Langmuir-Hinshelwood approach is practically negligible compared to the model based on formal kinetics.
Dynamic and Static Splinting for Treatment of Developmental Dysplasia of the Hip: A Systematic Review
Authors: Pavone Vito , de Cristo Claudia , Vescio Andrea , Lucenti Ludovico , Sapienza Marco , Sessa Giuseppe , Pavone Piero , Testa Gianluca
Published: February 2021

Background: Developmental dysplasia of the hip (DDH) is one of the most common pediatric conditions. The current gold-standard treatment for children under six months of age with a reducible hip is bracing, but the orthopedic literature features several splint options, and each one has many advantages and disadvantages. The aim of this review is to analyze the available literature to document the up-to-date evidence on DDH conservative treatment. Methods: A systematic review of PubMed and Science Direct databases was performed by two independent authors (C.d.C. and A.V.) using the keywords “developmental dysplasia hip”, “brace”, “harness”, “splint”, “abduction brace” to evaluate studies of any level of evidence that reported clinical or preclinical results and dealt with conservative DDH treatment. The result of every stage was reviewed and approved by the senior investigators (V.P. and G.T.). Results: A total of 1411 articles were found. After the exclusion of duplicates, 367 articles were selected. At the end of the first screening, following the previously described selection criteria, we selected 29 articles eligible for full text reading. The included articles mainly focus on the Pavlik harness, Frejka, and Tubingen among the dynamic splint applications as well as the rhino-style brace, Ilfeld and generic abduction brace among the static splint applications. The main findings of the included articles were summarized. Conclusions: Dynamic splinting for DDH represents a valid therapeutic option in cases of instability and dislocation, especially if applied within 4–5 months of life. Dynamic splinting has a low contraindication. Static bracing is an effective option too, but only for stable hips or residual acetabular dysplasia.
The Prevalence of Metabolic Syndrome According to Grip Strength in Teenagers
Authors: Ko Duk Han , Kim Young Kyun
Published: February 2021

The prevalence of metabolic syndrome in adolescents is increasing. Recently, the relevance of grip strength as a factor of metabolic syndrome in this population has raised questions. This study investigated the prevalence of metabolic syndrome according to grip strength in children and adolescents using large-scale data from the Korean National Health and Nutrition Survey (KNHNS). From 2014 to 2018, 1527 boys and 1292 girls participated in the KNHNS. The participants were classified into three groups according to age: 10–12 years (early teenager, ET), 13–15 years (middle teenager, MT), and 16–18 years (late teenager, LT). The participants were classified as having metabolic syndrome if they fulfilled three of the adolescent metabolic syndrome criteria. The grip strength was divided into groups with high and low grip strength, respectively, and the cutoff value for the prevalence was calculated using receiver operating characteristic curve analysis. There were significant differences in waist circumference, high-density lipoprotein cholesterol, and triglyceride levels based on grip strength in the ET, MT, and LT groups. Therefore, the prevalence of metabolic syndrome was lower when grip strength was higher. The cut-off values of the relative grip strength (kg/body weight) to predict metabolic syndrome among boys were 0.349, 0.466, and 0.485 for the ET, MT, and LT groups, respectively. The corresponding cut-off values for girls were 0.373, 0.383, and 0.382, respectively. In conclusion, there is a non-linear relationship between grip strength and metabolic syndrome in adolescents.
Interfacial Tension Sensor for Low Dosage Surfactant Detection
Authors: Pawliszak Piotr , Bradshaw-Hajek Bronwyn H. , Greet Christopher , Skinner William , Beattie David A. , Krasowska Marta
Published: February 2021

Currently there are no available methods for in-line measurement of gas-liquid interfacial tension during the flotation process. Microfluidic devices have the potential to be deployed in such settings to allow for a rapid in-line determination of the interfacial tension, and hence provide information on frother concentration. This paper presents the development of a simple method for interfacial tension determination based on a microfluidic device with a flow-focusing geometry. The bubble generation frequency in such a microfluidic device is correlated with the concentration of two flotation frothers (characterized by very different adsorption kinetic behavior). The results are compared with the equilibrium interfacial tension values determined using classical profile analysis tensiometry.
Reducing the Extinction Risk of Populations Threatened by Infectious Diseases
Authors: Glassock Gael L. , Grueber Catherine E. , Belov Katherine , Hogg Carolyn J.
Published: February 2021

Extinction risk is increasing for a range of species due to a variety of threats, including disease. Emerging infectious diseases can cause severe declines in wild animal populations, increasing population fragmentation and reducing gene flow. Small, isolated, host populations may lose adaptive potential and become more susceptible to extinction due to other threats. Management of the genetic consequences of disease-induced population decline is often necessary. Whilst disease threats need to be addressed, they can be difficult to mitigate. Actions implemented to conserve the Tasmanian devil (Sarcophilus harrisii), which has suffered decline to the deadly devil facial tumour disease (DFTD), exemplify how genetic management can be used to reduce extinction risk in populations threatened by disease. Supplementation is an emerging conservation technique that may benefit populations threatened by disease by enabling gene flow and conserving their adaptive potential through genetic restoration. Other candidate species may benefit from genetic management via supplementation but concerns regarding outbreeding depression may prevent widespread incorporation of this technique into wildlife disease management. However, existing knowledge can be used to identify populations that would benefit from supplementation where risk of outbreeding depression is low. For populations threatened by disease and, in situations where disease eradication is not an option, wildlife managers should consider genetic management to buffer the host species against inbreeding and loss of genetic diversity.