bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Biodiesel Influence on Unregulated Gaseous Emissions of Diesel Motor Vehicles
Authors: Puškár Michal , Živčák Jozef , Král Štefan , Kopas Melichar , Lavčák Matúš
Published: May 2021

This scientific study is focused on the analysis of an influence of the experimental diesel fuel mixtures containing various portions of the biocomponent on the unregulated gaseous emissions generated by a diesel motor vehicle, which is equipped with the diesel engine utilizing the direct fuel injection system “common rail”. The main reason for the choice of this engine type was its wide usage in the current vehicles. The experimental diesel fuel mixtures were created as a mixture of the standard low-sulfur diesel fuel with the biodiesel, using various mixing ratios. The experiments were realized by means of a special 13-regime engine test cycle, which was intentionally developed for the diesel combustion engines. All the individual experiments were performed on the base of the given test cycle with 13 different operational modes. The obtained results offer a complex view on the generation of the unregulated emissions with regard to the operational conditions and taking into consideration operational loading of the given experimental engine.
Insulator Faults Detection in Aerial Images from High-Voltage Transmission Lines Based on Deep Learning Model
Authors: Liu Chuanyang , Wu Yiquan , Liu Jingjing , Sun Zuo , Xu Huajie
Published: May 2021

Insulator fault detection is one of the essential tasks for high-voltage transmission lines’ intelligent inspection. In this study, a modified model based on You Only Look Once (YOLO) is proposed for detecting insulator faults in aerial images with a complex background. Firstly, aerial images with one fault or multiple faults are collected in diverse scenes, and then a novel dataset is established. Secondly, to increase feature reuse and propagation in the low-resolution feature layers, a Cross Stage Partial Dense YOLO (CSPD-YOLO) model is proposed based on YOLO-v3 and the Cross Stage Partial Network. The feature pyramid network and improved loss function are adopted to the CSPD-YOLO model, improving the accuracy of insulator fault detection. Finally, the proposed CSPD-YOLO model and compared models are trained and tested on the established dataset. The average precision of CSPD-YOLO model is 4.9% and 1.8% higher than that of YOLO-v3 and YOLO-v4, and the running time of CSPD-YOLO (0.011 s) model is slightly longer than that of YOLO-v3 (0.01 s) and YOLO-v4 (0.01 s). Compared with the excellent object detection models YOLO-v3 and YOLO-v4, the experimental results and analysis demonstrate that the proposed CSPD-YOLO model performs better in insulator fault detection from high-voltage transmission lines with a complex background.
Extracellular Matrix Behaviour in Masseter Muscle of Patients Affected by Unilateral Posterior Crossbite: An Immunofluorescence Study
Authors: Vermiglio Giovanna , Centofanti Antonio , Piancino Maria Grazia , Malandrino Maria Chiara , Runci Anastasi Michele , Picciolo Giacomo , Cutroneo Giuseppina
Published: May 2021

Unilateral posterior crossbite is a malocclusion disease that involves morpho-functional characteristics of masseter muscle; a normal or increased activity of contralateral muscle and a reduced activity of the ipsilateral muscle during unilateral crossbite have been shown. Since the extracellular matrix plays a key role in in mechano-transduction of transmitting forces during muscle contraction, the aim of the present study was to analyse the behaviour of extracellular matrix in this type of malocclusion through immunofluorescence reactions against laminin, collagen IV, MMP-2 and MMP-9. Our results show an increased expression of Laminin, Collagen IV, and MMP-9 in the contralateral side if compared to the ipsilateral side. No differences have been found in MMP-2 expression between contralateral and ipsilateral muscles. Since the increased expression of Laminin, Collagen IV and MMP-9 is associated with muscle hypertrophy and MMP-2 is associated with muscle atrophy, our results support the existence of a hypertrophic response of contralateral muscle during unilateral posterior crossbite that probably aims to compensate the altered function of the ipsilateral one.
Generation of Monoclonal Antibodies for Sensitive Detection of Pro-Inflammatory Protein S100A9
Authors: Kim Eun-Jung , Im Gyu-Min , Lee Chang-Soo , Kim Yun-Gon , Ko Byoung Joon , Jeong Hee-Jin , Kim Byung-Gee
Published: May 2021

The calcium-binding protein S100A9 regulates inflammatory processes and the immune response. It is overexpressed in a variety of inflammatory and oncologic conditions. In this study, we produced a recombinant human S100A9 (hS100A9) antigen with high yield and purity and used it to generate a hybridoma cell culture-based monoclonal anti-hS100A9 antibody. We selected five anti-hS100A9 antibodies from cell supernatants that showed high antigen binding efficiency and identified the nucleotide sequences of three antibodies: two with high effective concentration values and one with the lowest value. The antigen and antibody development procedures described herein are useful for producing large amounts of monoclonal antibodies against hS100A9 and other antigens of interest. The nucleotide sequences of the anti-hS100A9 monoclonal antibody revealed herein will be helpful in the generation of recombinant antibodies or antibody fragments against hS100A9.
Image Quality Assessment without Reference by Combining Deep Learning-Based Features and Viewing Distance
Authors: Chetouani Aladine , Pedersen Marius
Published: May 2021

An abundance of objective image quality metrics have been introduced in the literature. One important essential aspect that perceived image quality is dependent on is the viewing distance from the observer to the image. We introduce in this study a novel image quality metric able to estimate the quality of a given image without reference for different viewing distances between the image and the observer. We first select relevant patches from the image using saliency information. For each patch, a feature vector is extracted from a convolutional neural network model and concatenated at the viewing distance, for which the quality is predicted. The resulting vector is fed to fully connected layers to predict subjective scores for the considered viewing distance. The proposed method was evaluated using the Colourlab Image Database: Image Quality and Viewing Distance-changed Image Database. Both databases provide subjective scores at two different viewing distances. In the Colourlab Image Database: Image Quality we obtain a Pearson correlation of 0.87 at both 50 cm and 100 cm viewing distances, while in the Viewing Distance-changed Image Database we obtained a Pearson correlation of 0.93 and 0.94 at viewing distance of four and six times the image height. The results show the efficiency of our method and its generalization ability.
Involvement of Antioxidant Defenses and NF-κB/ERK Signaling in Anti-Inflammatory Effects of Pterostilbene, a Natural Analogue of Resveratrol
Authors: Jayakumar Thanasekaran , Wu Ming-Ping , Sheu Joen-Rong , Hsia Chih-Wei , Bhavan Periyakali Saravana , Manubolu Manjunath , Chung Chi-Li , Hsia Chih-Hsuan
Published: May 2021

Pterostilbene (PTE), a natural stilbenoid occurring in grapes and berries, is recognized as a dimethylated analogue of resveratrol. This compound shows numerous notable pharmacological activities, including antiaging, anticancer, antidiabetes, antioxidant, and neuroprotection. This study investigates the anti-inflammatory properties of PTE in macrophage cells (RAW 264.7) against the lipoteichoic acid (LTA) stimulation. The expression of inflammatory tumor necrosis factor (TNF-α), interleukin-1β (IL-1 β), and inducible nitric oxide synthase (iNOS) and the content of nitric oxide (NO) were detected in LTA-induced cells. In addition, a Western blot assay was used to detect mitogen-activated protein kinases: extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and c-Jun N-terminal kinase (JNK). The phosphorylation of IκB and p65 and translocation of nuclear factor kappa B (NF-κB) were assessed by Western blot and immuno-fluorescence staining. The results showed that PTE significantly attenuated NO production and TNF-α, IL-1 β, and iNOS expression in LTA stimulated cells. Among the activation of ERK, JNK, and p38 in cells treated with LTA, PTE at higher concentration had only inhibited ERK activation. However, PTE blocked IκB phosphorylation, phosphorylation and nuclear translocation of p65NF-κB. Fascinatingly, PTE enhanced antioxidant defense molecules as verified by the enhanced heme oxygenase-1 (HO-1) expression, catalase (CAT) antioxidant enzyme, and non-enzymatic antioxidant, and reduced glutathione (GSH) in LTA-induced RAW 264.7 cells. These results suggest that PTE exerts an anti-inflammatory property via attenuating NF-κB/ERK signaling pathways as well as enriching antioxidant defense mechanisms.
An ISM-Based Methodology for Interrelationships of Critical Success Factors for Construction Projects in Ecologically Fragile Regions: Take Korla, China as an Example
Authors: He Zheng , Chen Huihua
Published: May 2021

Construction activities taken place in ecologically fragile regions (EFRs) of China are facing a series of environmental obstacles. Studying critical success factors (CSFs) to arrive at the sustainable objectives for construction project in EFRs is needed. Understanding the interrelationships of these CSFs is one of the vital ways to achieve this. This paper identifies and analyzes 18 CSFs for construction projects in EFRs through a literature review from a multi-perspective and a case study of Korla City in China. The causal relationship between each CSF is obtained by pairwise comparisons and thereafter, an ISM (Interpretative Structural Modeling) method is employed to study the hierarchical structuring of the CSFs. As a result, we established a five-level ISM. Subsequently, an MICMAC (cross-impact matrix multiplication applied to classification) approach is implemented to partition and classify each CSF into four quadrants (independent, linkage, autonomous, and dependent) according to their driver and dependence powers. Through the implementation of an MICMAC approach, the degrees of relationship between each CSF is gained. The findings reveal that the studied 18 CSFs have a strong hierarchy and interrelationship. The project manager’s leadership style and economic viability are the root source of project success and has the highest influence, which is supported by the result of MICMAC analysis. CSF planning and implementation of sustainable strategies are more dependent and are influenced by others. The CSFs on the top level of ISM: conflict resolution, planning and implementation of sustainable strategies and resources of water play a significant role in arriving at the project success, and has a great potential for future study. The approaches implemented in this paper can be helpful for decision-makers and managers of construction projects in comprehending the interrelationships and the degrees of CSFs for construction projects in EFRs and for efficiently achieving the project success.
Injuries and Pain Associated with Goalkeeping in Football—Review of the Literature
Authors: Muracki Jarosław , Klich Sebastian , Kawczyński Adam , Boudreau Shellie Ann
Published: May 2021

Knowledge and research about football goalkeeper (GK) injuries are scarce, which prevents the development of evidence-based injury prevention programs. Fortunately, progress is evident in injury prevention strategies in outfield football players. However, a GK fulfills a unique role, and an injured GK can substantially impact a team. Thus, there is a need to clarify and summarize current knowledge concerning football goalkeeper pain and injuries. This narrative review aims to present the best-evidence synthesis of knowledge about football GK injuries and pain, their type, location, and incidence. A secondary aim is to contrast these findings with outfield players and identify knowledge gaps. Scientific databases were searched for the following indexed terms: goalkeeper, injury, soccer, and football. Original papers, including case studies and systematic reviews published from August 1994 to March 2021, were screened for relevance using a priori criteria and reviewed. Commonly described injuries are fractures, luxation and dislocations in the fingers, hand and wrist. The quadriceps femoris and forearms muscles are the most frequently described muscle and tendon injuries. Further, football GK injuries differ in type, location, and incidence compared to outfield players. Whether GKs suffer fewer injuries than players in other positions, whether GK suffer more injuries in training than matches, and whether they sustain more upper limb injuries comparing to field players is still unclear and controversial. Few studies assess pain, and current data point to the development of hip and groin, thigh, knee, arm and forearm pain resulting from training and match play. Due to the crucial role of GK in the football team, it is recommended to use the injury burden as a parameter considering the number and time-loss of injuries in future studies.
Electric Field Multifractal Features in the High-Latitude Ionosphere: CSES-01 Observations
Authors: Consolini Giuseppe , Quattrociocchi Virgilio , D’Angelo Giulia , Alberti Tommaso , Piersanti Mirko , Marcucci Maria Federica , De Michelis Paola
Published: May 2021

In the polar ionosphere, the electric field is characterized by broadband and power law spectral densities at small/short spatio-temporal scales, which support a possible turbulent nature of the electric field fluctuations. Here, we investigate the multifractal character of the full three-dimensional electric field in the polar ionosphere as recorded on board the first Chinese Seismo-Electromagnetic Satellite (CSES-01). The results of our analysis prove a clear different degree of multifractality of the electric field fluctuations approaching either the polar cap trailing edge or the auroral region. The observed differences in the multifractal character are interpreted in terms of the different natures of the particle precipitation in the polar cap and in the auroral region. A possible link between the multifractal nature of electric field fluctuations, parallel to the geomagnetic field, and filamentation of field aligned currents (FACs) is established.
Recent Advances in Our Understanding of Tropical Cyclone Intensity Change Processes from Airborne Observations
Authors: Rogers Robert F.
Published: May 2021

Recent (past ~15 years) advances in our understanding of tropical cyclone (TC) intensity change processes using aircraft data are summarized here. The focus covers a variety of spatiotemporal scales, regions of the TC inner core, and stages of the TC lifecycle, from preformation to major hurricane status. Topics covered include (1) characterizing TC structure and its relationship to intensity change; (2) TC intensification in vertical shear; (3) planetary boundary layer (PBL) processes and air–sea interaction; (4) upper-level warm core structure and evolution; (5) genesis and development of weak TCs; and (6) secondary eyewall formation/eyewall replacement cycles (SEF/ERC). Gaps in our airborne observational capabilities are discussed, as are new observing technologies to address these gaps and future directions for airborne TC intensity change research.
Plant-Pathogen Interaction
Authors: Campos Maria Doroteia , Patanita Mariana , Varanda Carla , Materatski Patrick , Félix Maria do Rosário
Published: May 2021

Plant diseases result in severe losses to natural plant systems, and also cause problems for economics and production in agricultural systems [...]
Potent Antimicrobial and Antibiofilm Activities of Feleucin-K3 Analogs Modified by α-(4-Pentenyl)-Ala against Multidrug-Resistant Bacteria
Authors: Guo Xiaomin , Yan Tiantian , Rao Jing , Yue Xin , Pei Xiong , Deng Jiahui , Sun Wangsheng , Yang Wenle , Zhang Bangzhi , Xie Junqiu
Published: May 2021

The dramatic increase in antimicrobial resistance (AMR) highlights an urgent need to develop new antimicrobial therapies. Thus, antimicrobial peptides (AMPs) have emerged as promising novel antibiotic alternatives. Feleucin-K3 is an amphiphilic α-helical nonapeptide that has powerful antimicrobial activity. In our previous study, it was found that the fourth residue of Feleucin-K3 is important for antimicrobial activity. After α-(4-pentenyl)-Ala was introduced into this position, both the antimicrobial activity and stability were greatly improved. Herein, to improve the limitations of Feleucin-K3, this unnatural amino acid was further introduced into different positions of Feleucin-K3. Among these synthetic Feleucin-K3 analogs, the N-terminal-substituted analog Feleucin-K65 (K65) and C-terminal-substituted analog Feleucin-K70 (K70) had preferable antimicrobial activity. In particular, their antimicrobial activities against multidrug-resistant bacteria were more potent than that of antibiotics. The stabilities of these peptides in salt and serum environments were improved compared with those of Feleucin-K3. In addition, these analogs had low hemolytic activity and AMR. More importantly, they effectively inhibited biofilm formation and exhibited considerable efficacy compared with traditional antibiotics against biofilm infection caused by methicillin-resistant Staphylococcus aureus (MRSA). In antimicrobial mechanism studies, K65 and K70 mainly permeated the outer membrane and depolarized the cytoplasmic membrane, resulting in cellular component leakage and cell death. In summary, analogs K65 and K70 are potential antimicrobial alternatives to solve the antibiotic crisis.
A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia?
Authors: Jozic Ivan , Chéret Jérémy , Abujamra Beatriz Abdo , Miteva Mariya , Gherardini Jennifer , Paus Ralf
Published: May 2021

Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-β and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies.
Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer’s Disease and Diabetes
Authors: Stanciu Gabriela Dumitrita , Rusu Razvan Nicolae , Bild Veronica , Filipiuc Leontina Elena , Tamba Bogdan-Ionel , Ababei Daniela Carmen
Published: May 2021

Alzheimer’s disease (AD) affects tens of millions of people worldwide. Despite the advances in understanding the disease, there is an increased urgency for pharmacological approaches able of impacting its onset and progression. With a multifactorial nature, high incidence and prevalence in later years of life, there is growing evidence highlighting a relationship between metabolic dysfunction related to diabetes and subject’s susceptibility to develop AD. The link seems so solid that sometimes AD and type 3 diabetes are used interchangeably. A candidate for a shared pathogenic mechanism linking these conditions is chronically-activated mechanistic target of rapamycin (mTOR). Chronic activation of unrestrained mTOR could be responsible for sustaining metabolic dysfunction that causes the breakdown of the blood-brain barrier, tau hyperphosphorylation and senile plaques formation in AD. It has been suggested that inhibition of sodium glucose cotransporter 2 (SGLT2) mediated by constant glucose loss, may restore mTOR cycle via nutrient-driven, preventing or even decreasing the AD progression. Currently, there is an unmet need for further research insight into molecular mechanisms that drive the onset and AD advancement as well as an increase in efforts to expand the testing of potential therapeutic strategies aimed to counteract disease progression in order to structure effective therapies.
Design and Fabrication of the Vertical-Flow Bioreactor for Compaction Hepatocyte Culture in Drug Testing Application
Authors: Zhu Liang , Wang Zhenfeng , Xia Huanming , Yu Hanry
Published: May 2021

The perfusion culture of primary hepatocytes has been widely adopted to build bioreactors for various applications. As a drug testing platform, a unique vertical-flow bioreactor (VfB) array was found to create the compaction culture of hepatocytes which mimicked the mechanic microenvironment in vivo while maintaining the 3D cell morphology in a 2D culture setup and enhancing the hepatic functions for a sustained culture. Here, we report the methodology in designing and fabricating the VfB to reach ideal bioreactor requirements, optimizing the VfB as a prototype for drug testing, and to demonstrate the enhanced hepatic function so as to demonstrate the performance of the bioreactor. This device enables the modular, scalable, and manufacturable construction of a functional drug testing platform through the sustained maintenance of model cells.
Thermoplastic Elastomer (TPE)–Poly(Methyl Methacrylate) (PMMA) Hybrid Devices for Active Pumping PDMS-Free Organ-on-a-Chip Systems
Authors: Busek Mathias , Nøvik Steffen , Aizenshtadt Aleksandra , Amirola-Martinez Mikel , Combriat Thomas , Grünzner Stefan , Krauss Stefan
Published: May 2021

Polydimethylsiloxane (PDMS) has been used in microfluidic systems for years, as it can be easily structured and its flexibility makes it easy to integrate actuators including pneumatic pumps. In addition, the good optical properties of the material are well suited for analytical systems. In addition to its positive aspects, PDMS is well known to adsorb small molecules, which limits its usability when it comes to drug testing, e.g., in organ-on-a-chip (OoC) systems. Therefore, alternatives to PDMS are in high demand. In this study, we use thermoplastic elastomer (TPE) films thermally bonded to laser-cut poly(methyl methacrylate) (PMMA) sheets to build up multilayered microfluidic devices with integrated pneumatic micro-pumps. We present a low-cost manufacturing technology based on a conventional CO2 laser cutter for structuring, a spin-coating process for TPE film fabrication, and a thermal bonding process using a pneumatic hot-press. UV treatment with an Excimer lamp prior to bonding drastically improves the bonding process. Optimized bonding parameters were characterized by measuring the burst load upon applying pressure and via profilometer-based measurement of channel deformation. Next, flow and long-term stability of the chip layout were measured using microparticle Image Velocimetry (uPIV). Finally, human endothelial cells were seeded in the microchannels to check biocompatibility and flow-directed cell alignment. The presented device is compatible with a real-time live-cell analysis system.
Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review
Authors: Bazhanova Elena D. , Kozlov Alexander A. , Litovchenko Anastasia V.
Published: May 2021

Epilepsy is a chronic neurological disorder characterized by recurring spontaneous seizures. Drug resistance appears in 30% of patients and it can lead to premature death, brain damage or a reduced quality of life. The purpose of the study was to analyze the drug resistance mechanisms, especially neuroinflammation, in the epileptogenesis. The information bases of biomedical literature Scopus, PubMed, Google Scholar and SciVerse were used. To obtain full-text documents, electronic resources of PubMed Central and Research Gate were used. The article examines the recent research of the mechanisms of drug resistance in epilepsy and discusses the hypotheses of drug resistance development (genetic, epigenetic, target hypothesis, etc.). Drug-resistant epilepsy is associated with neuroinflammatory, autoimmune and neurodegenerative processes. Neuroinflammation causes immune, pathophysiological, biochemical and psychological consequences. Focal or systemic unregulated inflammatory processes lead to the formation of aberrant neural connections and hyperexcitable neural networks. Inflammatory mediators affect the endothelium of cerebral vessels, destroy contacts between endothelial cells and induce abnormal angiogenesis (the formation of “leaky” vessels), thereby affecting the blood–brain barrier permeability. Thus, the analysis of pro-inflammatory and other components of epileptogenesis can contribute to the further development of the therapeutic treatment of drug-resistant epilepsy.
Bone Marrow Environment in Metastatic Neuroblastoma
Authors: Brignole Chiara , Pastorino Fabio , Perri Patrizia , Amoroso Loredana , Bensa Veronica , Calarco Enzo , Ponzoni Mirco , Corrias Maria Valeria
Published: May 2021

The study of the interactions occurring in the BM environment has been facilitated by the peculiar nature of metastatic NB. In fact: (i) metastases are present at diagnosis; (ii) metastases are confined in a very specific tissue, the BM, suggestive of a strong attraction and possibility of survival; (iii) differently from adult cancers, NB metastases are available because the diagnostic procedures require morphological examination of BM; (iv) NB metastatic cells express surface antigens that allow enrichment of NB metastatic cells by immune–magnetic separation; and (v) patients with localized disease represent an internal control to discriminate specific alterations occurring in the metastatic niche from generic alterations determined by the neoplastic growth at the primary site. Here, we first review the information regarding the features of BM-infiltrating NB cells. Then, we focus on the alterations found in the BM of children with metastatic NB as compared to healthy children and children with localized NB. Specifically, information regarding all the BM cell populations and their sub-sets will be first examined in the context of BM microenvironment in metastatic NB. In the last part, the information regarding the soluble factors will be presented.
Machine Learning and Radiomics Applications in Esophageal Cancers Using Non-Invasive Imaging Methods—A Critical Review of Literature
Authors: Xie Chen-Yi , Pang Chun-Lap , Chan Benjamin , Wong Emily Yuen-Yuen , Dou Qi , Vardhanabhuti Varut
Published: May 2021

Esophageal cancer (EC) is of public health significance as one of the leading causes of cancer death worldwide. Accurate staging, treatment planning and prognostication in EC patients are of vital importance. Recent advances in machine learning (ML) techniques demonstrate their potential to provide novel quantitative imaging markers in medical imaging. Radiomics approaches that could quantify medical images into high-dimensional data have been shown to improve the imaging-based classification system in characterizing the heterogeneity of primary tumors and lymph nodes in EC patients. In this review, we aim to provide a comprehensive summary of the evidence of the most recent developments in ML application in imaging pertinent to EC patient care. According to the published results, ML models evaluating treatment response and lymph node metastasis achieve reliable predictions, ranging from acceptable to outstanding in their validation groups. Patients stratified by ML models in different risk groups have a significant or borderline significant difference in survival outcomes. Prospective large multi-center studies are suggested to improve the generalizability of ML techniques with standardized imaging protocols and harmonization between different centers.
Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models
Authors: Hoare Owen , Fraunhoffer Nicolas , Elkaoutari Abdessamad , Gayet Odile , Bigonnet Martin , Roques Julie , Nicolle Rémy , McGuckin Colin , Forraz Nico , Sohier Emilie , Tonon Laurie , Wajda Pauline , Boyault Sandrine , Attignon Valéry , Tabone-Eglinger Séverine , Barbier Sandrine , Mignard Caroline , Duchamp Olivier , Iovanna Juan , Dusetti Nelson J.
Published: May 2021

Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design: Three paired PDAC preclinical models—patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)—were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions: Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.
A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors
Authors: Khurshed Mohammed , Molenaar Remco J. , van Linde Myra E. , Mathôt Ron A. , Struys Eduard A. , van Wezel Tom , van Noorden Cornelis J. F. , Klümpen Heinz-Josef , Bovée Judith V. M. G. , Wilmink Johanna W.
Published: May 2021

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.
The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy
Authors: Sheridan Megan , Ogretmen Besim
Published: May 2021

Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.
Impact of Previous Irradiation on Wound Healing after Negative Pressure Wound Therapy in Head and Neck Cancer Patients—A Systematic Review
Authors: Faisal Muhammad , Berend Peter D. , Seemann Rudolf , Janik Stefan , Grasl Stefan , Ritzengruber Andrea , Mendel Herbert , Jamshed Arif , Hussain Raza , Erovic Boban M.
Published: May 2021

(1) Background: Negative pressure wound therapy (NPWT) has been effectively used for wound management in comparison to traditional dressings. The purpose of this study was to provide an evidence-based review of NPWT in head and neck cancer patients, as well as the impact of previous irradiation and other risk factors on wound healing. (2) Material and Methods: We conducted a comprehensive search in PubMed, Medline, Embase, Web of Science, and Cochrane Library databases for relevant literature. (3) Results: 15 studies fulfilled the inclusion criteria. The most common etiologies requiring NPWT were defects post tumor resection and flap reconstruction and oro/pharyngo-cutaneous fistulas. The neck was found to be the most common site of involvement (47.3%). The overall wound healing response rate was 87.5%. The median negative pressure recorded was 125 mm of Hg, with a median dressing change time of three days. Previous irradiation (p = 0.01; OR = 4.07) and diabetes mellitus (DM) (p = 0.001; OR = 5.62) were found to be significantly associated with delayed wound healing after NPWT. (4) Conclusion: NPWT treats complex wounds in head and neck cancer patients and should represent a significant armamentarium in head and neck cancers. Previous irradiation and DM have detrimental effects on wound healing after NPWT.
Multimodal Imaging Techniques to Evaluate the Anticancer Effect of Cold Atmospheric Pressure Plasma
Authors: Kordt Marcel , Trautmann Isabell , Schlie Christin , Lindner Tobias , Stenzel Jan , Schildt Anna , Boeckmann Lars , Bekeschus Sander , Kurth Jens , Krause Bernd J. , Vollmar Brigitte , Grambow Eberhard
Published: May 2021

Background: Skin cancer is the most frequent cancer worldwide and is divided into non-melanoma skin cancer, including basal cell carcinoma, as well as squamous cell carcinoma (SCC) and malignant melanoma (MM). Methods: This study evaluates the effects of cold atmospheric pressure plasma (CAP) on SCC and MM in vivo, employing a comprehensive approach using multimodal imaging techniques. Longitudinal MR and PET/CT imaging were performed to determine the anatomic and metabolic tumour volume over three-weeks in vivo. Additionally, the formation of reactive species after CAP treatment was assessed by non-invasive chemiluminescence imaging of L-012. Histological analysis and immunohistochemical staining for Ki-67, ApopTag®, F4/80, CAE, and CD31, as well as protein expression of PCNA, caspase-3 and cleaved-caspase-3, were performed to study proliferation, apoptosis, inflammation, and angiogenesis in CAP-treated tumours. Results: As the main result, multimodal in vivo imaging revealed a substantial reduction in tumour growth and an increase in reactive species after CAP treatment, in comparison to untreated tumours. In contrast, neither the markers for apoptosis, nor the metabolic activity of both tumour entities was affected by CAP. Conclusions: These findings propose CAP as a potential adjuvant therapy option to established standard therapies of skin cancer.
HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development
Authors: Pascut Devis , Hoang Minh , Nguyen Nhu N. Q. , Pratama Muhammad Yogi , Tiribelli Claudio
Published: May 2021

Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.
Modified Layered Silicas as Catalysts for Conversion of Nitrogen Pollutants in Flue Gases—A Review
Authors: Chmielarz Lucjan , Dziembaj Roman
Published: May 2021

This paper is focused on the recent achievements in the studies of modified layered zeolites and cationic layered clay minerals. These materials are very promising catalysts in green chemistry processes, such as selective catalytic reduction of NOx with ammonia (NH3-SCR) and selective catalytic oxidation of ammonia to dinitrogen (NH3-SCO). Special attention is paid to the roles of the micro- and mesoporous structures of the catalytic materials, the type and location of deposited transition metals, as well as surface acidity in the design of effective catalysts for the NH3-SCR and NH3-SCO processes. The majority of the presented analysis is based on the authors’ research.
Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers
Authors: Kasper Philipp , Breuer Saida , Hoffmann Thorben , Vohlen Christina , Janoschek Ruth , Schmitz Lisa , Appel Sarah , Fink Gregor , Hünseler Christoph , Quaas Alexander , Demir Münevver , Lang Sonja , Steffen Hans-Michael , Martin Anna , Schramm Christoph , Bürger Martin , Mahabir Esther , Goeser Tobias , Dötsch Jörg , Hucklenbruch-Rother Eva , Bae-Gartz Inga
Published: May 2021

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.
Regulatory Effects of Cannabidiol on Mitochondrial Functions: A Review
Authors: Chan John Zewen , Duncan Robin Elaine
Published: May 2021

Cannabidiol (CBD) is part of a group of phytocannabinoids derived from Cannabissativa. Initial work on CBD presumed the compound was inactive, but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation. Despite these advances, current data demonstrate contradictory findings with regard to not only the magnitude of effects mediated by CBD, but also to the direction of effects. For example, there are data indicating that CBD treatment can increase, decrease, or have no significant effect on intrinsic apoptosis. Differences between studies in cell type, cell-specific response to CBD, and, in some cases, dose of CBD may help to explain differences in outcomes. Most studies on CBD and mitochondria have utilized treatment concentrations that exceed the highest recorded plasma concentrations in humans, suggesting that future studies should focus on CBD treatments within a range observed in pharmacokinetic studies. This review focuses on understanding the mechanisms of CBD-mediated regulation of mitochondrial functions, with an emphasis on findings in neural cells and tissues and therapeutic relevance based on human pharmacokinetics.
The Role of Trogocytosis in the Modulation of Immune Cell Functions
Authors: Miyake Kensuke , Karasuyama Hajime
Published: May 2021

Trogocytosis is an active process, in which one cell extracts the cell fragment from another cell, leading to the transfer of cell surface molecules, together with membrane fragments. Recent reports have revealed that trogocytosis can modulate various biological responses, including adaptive and innate immune responses and homeostatic responses. Trogocytosis is evolutionally conserved from protozoan parasites to eukaryotic cells. In some cases, trogocytosis results in cell death, which is utilized as a mechanism for antibody-dependent cytotoxicity (ADCC). In other cases, trogocytosis-mediated intercellular protein transfer leads to both the acquisition of novel functions in recipient cells and the loss of cellular functions in donor cells. Trogocytosis in immune cells is typically mediated by receptor–ligand interactions, including TCR–MHC interactions and Fcγ receptor-antibody-bound molecule interactions. Additionally, trogocytosis mediates the transfer of MHC molecules to various immune and non-immune cells, which confers antigen-presenting activity on non-professional antigen-presenting cells. In this review, we summarize the recent advances in our understanding of the role of trogocytosis in immune modulation.
Regional Differences in Heat Shock Protein 25 Expression in Brain and Spinal Cord Astrocytes of Wild-Type and SOD1 G93A Mice
Authors: San Gil Rebecca , Clarke Benjamin E. , Ecroyd Heath , Kalmar Bernadett , Greensmith Linda
Published: May 2021

Heterogeneity of glia in different CNS regions may contribute to the selective vulnerability of neuronal populations in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). Here, we explored regional variations in the expression of heat shock protein 25 in glia under conditions of acute and chronic stress. Hsp27 (Hsp27; murine orthologue: Hsp25) fulfils a number of cytoprotective functions and may therefore be a possible therapeutic target in ALS. We identified a subpopulation of astrocytes in primary murine mixed glial cultures that expressed Hsp25. Under basal conditions, the proportion of Hsp25-positive astrocytes was twice as high in spinal cord cultures than in cortical cultures. To explore the physiological role of the elevated Hsp25 expression in spinal cord astrocytes, we exposed cortical and spinal cord glia to acute stress, using heat stress and pro-inflammatory stimuli. Surprisingly, we observed no stress-induced increase in Hsp25 expression in either cortical or spinal cord astrocytes. Similarly, exposure to endogenous stress, as modelled in glial cultures from SOD1 G93A-ALS mice, did not increase Hsp25 expression above that observed in astrocytes from wild-type mice. In vivo, Hsp25 expression was greater under conditions of chronic stress present in the spinal cord of SOD1 G93A mice than in wild-type mice, although this increase in expression is likely to be due to the extensive gliosis that occurs in this model. Together, these results show that there are differences in the expression of Hsp25 in astrocytes in different regions of the central nervous system, but Hsp25 expression is not upregulated under acute or chronic stress conditions.