bluuebunny/crossref_metadata_2025 huggingface dataset:
A Quantitative Proteomic Approach Explores the Possible Mechanisms by Which the Small Molecule Stemazole Promotes the Survival of Human Neural Stem Cells
Authors: Chen Mingzhu , Zhu Yizi , Li Huajun , Zhang Yubo , Han Mei
Published: May 2022

Neurodegenerative disorders have become a serious healthcare problem worldwide and there is no efficacious cure. However, regulating the fate of stem cells is an effective way to treat these neurological diseases. In previous work, stemazole was reported to maintain the survival of human neural stem cells in the absence of growth factors and to have therapeutic effects on neurodegenerative diseases. However, although it is a promising small molecule, the molecular mechanisms against apoptosis are ambiguous. In this study, tandem mass tag (TMT)-based proteomics were performed to obtain whole protein expression profiles of human neural stem cells in different groups under extreme conditions. Bioinformatics analysis based on protein–protein interaction (PPI) network construction, gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were adopted to explore crucial proteins and possible pharmacological mechanisms. A total of 77 differentially expressed proteins were identified, comprising 38 upregulated proteins and 39 downregulated proteins. Combined with a diseases database of Alzheimer’s disease (AD), caspase-2 (CASP2), PKA C-alpha (PRKACA), fibronectin (FN1), large neutral amino acid transporter small subunit 1 (SLC7A5), which are involved in cell proliferation and apoptosis, this was further validated by enzyme activity assay and molecular docking, and regarded as putative targets regulated by stemazole. The present results give an insight into this small molecule and a better understanding for further elucidating the underlying mechanisms in the treatment of stem cells and neurodegenerative diseases.
Full-Scale Prefabrication and Non-Destructive Quality Monitoring of Novel Bridge Substructure for “Pile-Column Integration”
Authors: Wang Longlin , Wang Hua , Yang Kailv , Xie Shuzhi , Wei Gangrong , Li Ruijiao , Wang Wensheng
Published: May 2022

The assembly process of “pile-column integration” is proposed in this study and applied in the engineering with the characteristics that most of the pile foundations are end-bearing piles, which is conducive to returning to the normal operation of transportation infrastructure in a timely manner. From the perspective of practical application, the bridge structure components, including pile column and cap beam, are reasonably designed and prefabricated according to the requirements of the reconstruction and expansion project of the old bridge. Through non-destructive testing technologies, the concrete strength, cover thickness of reinforcement, and component size of prefabricated components are monitored and tested to evaluate the quality of full-scale prefabricated bridge substructure for “pile-column integration”. The monitoring results showed that the concrete strength monitoring results of prefabricated components by the rebound method are relatively stable. The concrete strength of the prefabricated components was higher than the design concrete strength and their qualified rate was 100%. According to the monitoring of cover thickness of reinforcement, the measured cover thickness of reinforcement in prefabricated components by electromagnetic induction method fell within the allowable range, and their qualified rates were around 90%. The concrete strength and cover thickness of reinforcement for prefabricated components could meet the design requirements. Although the component size of the prefabricated components could be tested by a 3-D point cloud scanning system, the monitoring effect of a relatively smaller component size still needs to be improved. The quality monitoring of full-scale bridge substructures for “pile-column integration” proved the rationality of prefabrication and the feasibility of non-destructive testing technologies, providing references for the application of “pile-column integration”.
Effects of Carbon Thin Film on Low-Heat Cement Hydration, Temperature and Strength of the Wudongde Dam Concrete
Authors: Peng Haoyang , Lin Peng , Xiang Yunfei , Hu Jinwu , Yang Zongli
Published: May 2022

Research on the mechanism of carbon thin film (CTF) is a hot issue in the field of concrete materials and is of great significance to the temperature control and crack prevention of concrete structures, but little research has been conducted regarding this issue. In this paper, the composition of CTF and its influence on cement hydration, concrete temperature and strength are studied in the context of the Wudongde (WDD) dam project. Through observations of hand specimens, rock slice identification and X-Ray Fluorescence (XRF) analysis, it was shown that the CTF has the same chemical composition as the limestone component, except for the presence of low-crystalline graphite. Based on hydration testing using TAM Air, it was found that CTF promotes the dissolution of cement and the hydration of C3A in the very early stage but exerts a lowering effect on the second exothermic peak of cement hydration. In addition, the greater the CTF content, the greater the hydration heat release. According to temperature measurements of the Wudongde (WDD) dam, CTF could promote an increase in the maximum temperature of concrete blocks. Finally, compressive strength analysis revealed that the content of CTF was proportional to the compressive strength of concrete specimens and provides a reference for the effect of CTF on the performance of low-heat cement concrete.
Real Time Building Evacuation Modeling with an Improved Cellular Automata Method and Corresponding IoT System Implementation
Authors: Ji Yanping , Wang Wensi , Zheng Mengyi , Chen Shuo
Published: May 2022

Facility emergence evacuation is often a complicated process under extreme conditions. Most of the buildings today use pre-installed signages to guide the emergence evacuation. However, these guidances are sometimes insufficient or misleading, particularly for evacuating from high-rise buildings or complex buildings, such as schools, hospitals, and stadiums. Following a planned route may lead the crowd to move towards dangers, such as smoke and fire. The future emergency guidance system should be more intelligent and be able to guide people to evacuate with a higher survival possibility. This study proposes a real-time building evacuation model with an improved cellular automata (CA) method. This algorithm combines cellular automata with the potential energy field (PEF) model in fluid dynamic theory (FDT) to choose safe paths for the crowd and reduce the possibility of stampedes. Custom-designed wireless sensors, artificial intelligence (A.I.) enhanced surveillance cameras, intelligent emergency signage systems, and edge computing servers are used to sample fire and crowd data, operate the intelligent evacuation algorithm, and guide the crowd with the signage system in real-time conditions. In addition, we performed the algorithm simulation on a two-dimensional plane generated based on the building structure of the Beijing Capital Airport Hospital. The evacuation drill simulations show that the average escape time is significantly shortened with optimal real-time guidance. In one case, a 72% reduction in evacuation time is achieved compared with evacuation using pre-installed signages. The results also demonstrated that the proposed model and system’s evacuation time reduction performance is particularly good in crowded buildings, such as schools or stadiums.
Developing a Conceptual Partner Selection Framework: Digital Green Innovation Management of Prefabricated Construction Enterprises for Sustainable Urban Development
Authors: Yin Shi , Dong Tong , Li Baizhou , Gao Shuo
Published: May 2022

Digital green innovation management activities are the core of low-carbon intelligent development of prefabricated construction enterprises (PCEs) for sustainable urban development. PCEs have to seek joint venture partners to avoid the financial risk of digital green innovation projects. The purpose of this study is to develop a conceptual partner selection framework for the digital green innovation management of prefabricated construction towards urban building 5.0. In this study, first, symbiosis theory and six analysis methods were integrated to innovatively build a 3W1H-P framework system for the joint venture capital partner selection of digital green innovation projects. Second, the dual combination weighting method was innovatively proposed to avoid subjective and objective deviation in attribute weight and time weight. Finally, empirical research was carried out to verify the scientific nature, reliability, and practicability of the framework system and selection model. The results of this study show that the framework system and selection model proposed can be used to assist PCEs to select joint investment partners of digital green and innovative projects for sustainable urban development.
Reliability Analysis of Serviceability Limit State for Braced Excavation Considering Multiple Failure Modes in Spatially Variable Soil
Authors: Hong Li , Chen Longlong , Wang Xiangyu
Published: May 2022

High uncertainty is an inherent behavior of geotechnical materials. Nowadays, random field theory is an advanced method to quantify the effect of high uncertainty on geotechnical engineering. This study investigates the effect of spatial variable soil layers on deformations of deep excavation via the random finite element method. A procedure based on PLAXIS 2D software was developed to generate two-dimension random finite element models including multiple variables. Via the K-S test and S-W test, the excavation deformations basically followed lognormal distribution. With the growth of standard deviation of soil properties parameters, the distribution of excavation deformations becomes wider, and the failure probability increases. When the vertical scale of fluctuation ranges from 1 m to 25 m, the distribution of excavation deformations becomes wider. To analyze system reliability, this study proposed a fitted multiple lognormal distribution methods, which was a method with higher efficiency. The results indicated that system reliability was lower than single failure probability and sensitive to design level. The system failure probability will be over-evaluated or under-evaluated if the correlation between excavation responses is ignored. This study provided a novel method to quantify the effect of high uncertainty of soil layer on excavation responses and proposed an efficient method for system reliability analysis, which is meaningful for excavation reliability design.
Effect of Municipal Solid Waste Incineration Ash on Microstructure and Hydration Mechanism of Geopolymer Composites
Authors: Wang Chuantong , Zhang Peng , Guo Jinjun , Zhang Hongsen , Wang Tingya
Published: May 2022

The geopolymerization process is an appropriate way of disposing of municipal solid waste incineration fly ash (MSWIFA), and possesses the advantages of immobilizing the heavy metals and making full use of its pozzolanic properties in manufacturing green, cementitious materials. In this study, coal fly ash (FA) and metakaolin (MK) were used to prepare a geopolymer composite, with MK partially replaced by different proportions of MSWIFA through the alkali-activation method. The microstructure and hydration mechanism of the geopolymer composites containing MSWIFA were investigated through mercury intrusion porosimetry (MIP), scanning electron microscopy (SEM), and Fourier transform-infrared spectroscopy (FT-IR) tests; and the immobilization effect of the geopolymer paste on heavy metal ions was explored through inductively coupled plasma-atomic emission spectrometry (ICP-AES). The MIP analysis showed that the addition of MFARR had an overall degrading effect on the pore structure of the matrix. When the content of MSWIFA reached the maximum of 35%, the porosity and average pore diameter increased by 25% and 16%, respectively, corresponding to the case without MSWIFA. However, the pore size distribution exhibited an improving trend when the MFARR was increased from 15% to 25%. The SEM images revealed that the integrity of the micromorphology of the geopolymer mortar became weaker after adding MSWIFA. When the MSWIFA content was increased to 35%, the microstructural compactness decreased and more pores and microcracks appeared in the matrix. The FT-IR pattern study suggested that all the geopolymer composites had a similar internal structure, consisting of O-H, C-O, Si-O-Si, and Si-O-Al. The main component of the geopolymer paste hydrated at 28 d remained dominated by calcium silica-aluminate (C-A-S-H), when the MSWIFA ranged from 0% to 35%. Finally, the ICP-AES results showed that the leaching concentrations of the geopolymer paste of J-40 at 28 d for Cd, Cr, Cu, Pb, and Zn met the requirements of Chinese standards.
The Impact of Building Orientation and Window-to-Wall Ratio on the Performance of Electrochromic Glazing in Hot Arid Climates: A Parametric Assessment
Authors: Lahmar Imene , Cannavale Alessandro , Martellotta Francesco , Zemmouri Noureddine
Published: May 2022

The significant increase in construction industry demand with its negative effects on energy consumption is particularly evident in areas with severe climatic factors. Here, the designers aim at providing comfort with the least amount of energy, and consequently have resorted to using different software tools to choose the optimal solution in the early phase of design to avoid time and cost losses. The use of smart innovative technologies such as electrochromic (EC) glazing may provide an important contribution in reducing consumptions while providing good thermal and visual comfort conditions. Nonetheless, as shown in the literature, such glazing should be used and managed carefully to avoid any adverse effects or low performance. Thus, a parametric simulation was carried out using Rhinoceros and Grasshopper to assess the advantages in terms of energy use resulting from use of EC glazing in residential buildings as a function of façade orientation and window-to-wall ratio (WWR) with reference to the city of Biskra, located in the northeastern region of Algeria. Eight main orientations and ten WWR scenarios were investigated in order to evaluate the benefit of using this technology in the selected climatic region. The research results proved the benefit of using EC glazing in all orientations, with energy savings ranging from 35.88% in the northern façade to 60.47% in the southwestern façade.
Data-Driven Rock Strength Parameter Identification Using Artificial Bee Colony Algorithm
Authors: Wang Meng , Chen Bingrui , Zhao Hongbo
Published: May 2022

Rock strength parameters are essential to understanding the rock failure mechanism and safely constructing rock excavation. It is a challenging problem for determining the rock failure criterion and its parameters due to the complexity of rock media. This study adopts an artificial bee colony (ABC) algorithm to determine the Hoek-Brown failure criterion, widely used in rock engineering practice, based on experimental data. The ABC-based approach is presented in detail and applied to a collection of experimental data collected from the literature. The ABC-based approach successfully determines the Hoek-Brown failure criterion, and the determined failure envelope is in excellent agreement with the measured curve. The maximum relative error obtained by ABC is only 2.15% and is far less than the 12.24% obtained by the traditional method. Then, the developed approach is applied to the Goupitan Hydropower Station, China, and determines the rheological parameters of soft rock based on the Burgers model. The deformation of an experiment located in the Goupitan Hydropower Station is evaluated based on obtained parameters by the developed approach. The predicted deformation matches the monitored displacement in the field. The obtained parameters of the failure criterion characterize the mechanical behavior of rock mass well. Thus, the method used provides a reliable and robust approach to determining the mechanical parameters of the failure criterion.
Detection and Characterization of Estrogen Receptor α Expression of Circulating Tumor Cells as a Prognostic Marker
Authors: Ningsi Retno , Elazezy Maha , Stegat Luisa , Laakmann Elena , Peine Sven , Riethdorf Sabine , Müller Volkmar , Pantel Klaus , Joosse Simon A.
Published: May 2022

CTCs have increasingly been used as a liquid biopsy analyte to obtain real-time information on the tumor through minimally invasive blood analyses. CTCs allow for the identification of proteins relevant for targeted therapies. Here, we evaluated the expression of estrogen receptors (ER) in CTCs of patients with metastatic breast cancer. From sixty metastatic breast cancer patients who had ER-positive primary tumors (range of 1–70% immunostaining) at initial cancer diagnosis, 109 longitudinal blood samples were prospectively collected and analyzed using the CellSearch System in combination with the ERα monoclonal murine ER-119.3 antibody. Prolonged cell permeabilization was found to be required for proper staining of nuclear ER in vitro. Thirty-one cases were found to be CTC-positive; an increased number of CTCs during endocrine and chemotherapy was correlated with disease progression, whereas a decrease or stable amount of CTC number (<5) during treatment was correlated with a better clinical outcome. Survival analyses further indicate a positive association of CTC-status with progression-free survival (HR, 66.17; 95%CI, 3.66–195.96; p = 0.0045) and overall survival (HR, 6.21; 95%CI, 2.66–14.47; p < 0.0001). Only one-third of CTC-positive breast cancer patients, who were initially diagnosed with ER-positive primary tumors, harbored ER-positive CTCs at the time of metastasis, and even in those patients, both ER-positive and ER-negative CTCs were found. CTC-positivity was correlated with a shorter relapse-free survival. Remarkably, ER-negative CTCs were frequent despite initial ER-positive status of the primary tumor, suggesting a switch of ER phenotype or selection of minor ER-negative clones as a potential mechanism of escape from ER-targeting therapy.
Pilot Investigation on p75ICD Expression in Laryngeal Squamous Cell Carcinoma
Authors: Triaca Viviana , Fico Elena , Rosso Pamela , Ralli Massimo , Corsi Alessandro , Severini Cinzia , Crevenna Alvaro , Agostinelli Enzo , Rullo Emma , Riminucci Mara , Colizza Andrea , Polimeni Antonella , Greco Antonio , Tirassa Paola
Published: May 2022

We investigated the p75 Neurotrophin Receptor (p75NTR) expression and cleavage product p75NTR Intracellular Domain (p75ICD) as potential oncogenic and metastatic markers in human Laryngeal Squamous Cell Carcinoma (LSCC). p75NTR is highly expressed in Cancer Stem Cells (CSCs) of the laryngeal epithelia and it has been proposed as a marker for stemness, cell migration, and chemo-resistance in different squamous carcinomas. To investigate the clinical significance of p75NTR cleavage products in solid tumors, full-length and cleaved p75NTR expression was analyzed in laryngeal primary tumors from different-stage LSCC patients, diagnosed at the Policlinico Umberto I Hospital. Molecular and histological techniques were used to detect the expressions of p75NTR and p75ICD, and ATP Binding Cassette Subfamily G Member 2 (ABCG2), a CSC marker. We found regulated p75NTR cleavage during squamous epithelial tumor progression and tissue invasion. Our preliminary investigation suggests p75ICD expression and localization as possible features of tumorigenesis and metastaticity. Its co-localization with ABCG2 in squamous cells in the parenchyma invaded by the tumor formation allows us to hypothesize p75NTR and p75ICD roles in tumor invasion and CSC spreading in LSCC patients. These data might represent a starting point for a comprehensive analysis of p75NTR cleavage and of its clinical relevance as a potential molecular LSCC signature, possibly helping diagnosis, and improving prognosis and personalized therapy.
Machine Learning Tools for Image-Based Glioma Grading and the Quality of Their Reporting: Challenges and Opportunities
Authors: Merkaj Sara , Bahar Ryan C. , Zeevi Tal , Lin MingDe , Ikuta Ichiro , Bousabarah Khaled , Cassinelli Petersen Gabriel I. , Staib Lawrence , Payabvash Seyedmehdi , Mongan John T. , Cha Soonmee , Aboian Mariam S.
Published: May 2022

Technological innovation has enabled the development of machine learning (ML) tools that aim to improve the practice of radiologists. In the last decade, ML applications to neuro-oncology have expanded significantly, with the pre-operative prediction of glioma grade using medical imaging as a specific area of interest. We introduce the subject of ML models for glioma grade prediction by remarking upon the models reported in the literature as well as by describing their characteristic developmental workflow and widely used classifier algorithms. The challenges facing these models—including data sources, external validation, and glioma grade classification methods —are highlighted. We also discuss the quality of how these models are reported, explore the present and future of reporting guidelines and risk of bias tools, and provide suggestions for the reporting of prospective works. Finally, this review offers insights into next steps that the field of ML glioma grade prediction can take to facilitate clinical implementation.
Validation of Pretreatment Prognostic Factors and Prognostic Staging Systems for Small Cell Lung Cancer in a Real-World Data Set
Authors: Hagmann Raphael , Zippelius Alfred , Rothschild Sacha I.
Published: May 2022

Treatment decisions in patients with small cell lung cancer (SCLC) are made based on the extent of the disease. However, the outcome varies among patients at the same stage. A simple tool to predict outcomes in SCLC patients would be helpful for clinical decision-making. In recent years, several prognostic scores have been proposed. In this study, we evaluated the different prognostic factors in an unselected real-world cohort of patients. We retrospectively collected clinical, radiological and laboratory data from 92 patients diagnosed with SCLC. Univariate and multivariate cox regression analyses of survival were performed to assess the prognostic value of relevant clinical and laboratory factors for SCLC. Furthermore, we examined the association between eight published prognostic scores for SCLC and overall survival (OS). In the overall cohort, the median OS was 10.3 months (20.9 months and 9.2 months for limited disease (LD) SCLC and extensive disease (ED) SCLC, respectively). In univariate analysis, initial staging, number of metastatic sites and presence of liver, bone and adrenal gland metastases were significantly associated with worse OS. Of the established laboratory markers, albumin, alkaline phosphatase and hyponatremia but not lactate dehydrogenase (LDH) significantly predicted OS. All published prognostic scores, with the exception of the Glasgow Prognostic Score, did not significantly predict OS. In multivariate analysis, age, staging and alkaline phosphatase serum levels showed significant association with OS. We could not confirm the prognostic significance of most of the published complex prognostic scores. We therefore recommend using simple clinical and laboratory factors instead of complex scores to estimate the prognosis of SCLC patients in clinical practice.
Emerging Blood-Based Biomarkers for Predicting Immunotherapy Response in NSCLC
Authors: Oitabén Ana , Fonseca Pablo , Villanueva María J. , García-Benito Carme , López-López Aida , Garrido-Fernández Alberto , González-Ojea Clara , Juaneda-Magdalena Laura , Lázaro Martín E. , Martínez-Fernández Mónica
Published: May 2022

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has demonstrated a profitable performance for Non-Small Cell Lung Cancer (NSCLC) cancer treatment in some patients; however, there is still a percentage of patients in whom immunotherapy does not provide the desired results regarding beneficial outcomes. Therefore, obtaining predictive biomarkers for ICI response will improve the treatment management in clinical practice. In this sense, liquid biopsy appears as a promising method to obtain samples in a minimally invasive and non-biased way. In spite of its evident potential, the use of these circulating biomarkers is still very limited in the real clinical practice, mainly due to the huge heterogeneity among the techniques, the lack of consensus, and the limited number of patients included in these previous studies. In this work, we review the pros and cons of the different proposed biomarkers, such as soluble PD-L1, circulating non-coding RNA, circulating immune cells, peripheral blood cytokines, and ctDNA, obtained from liquid biopsy to predict response to ICI treatment at baseline and to monitor changes in tumor and tumor microenvironment during the course of the treatment in NSCLC patients.
Extracellular Vesicle-Based Method for Detecting MYCN Amplification Status of Pediatric Neuroblastoma
Authors: Panachan Jirawan , Rojsirikulchai Napat , Pongsakul Nutkridta , Khowawisetsut Ladawan , Pongphitcha Pongpak , Siriboonpiputtana Teerapong , Chareonsirisuthigul Takol , Phornsarayuth Pitichai , Klinkulab Nisakorn , Jinawath Natini , Chiangjong Wararat , Anurathapan Usanarat , Pattanapanyasat Kovit , Hongeng Suradej , Chutipongtanate Somchai
Published: May 2022

MYCN amplification is the strongest predictor of high-risk neuroblastoma (NB). The standard procedure to detect MYCN status requires invasive procedures. Extracellular vesicles (EVs) contain molecular signatures of originated cells, present in biofluids, and serve as an invaluable source for cancer liquid biopsies. This study aimed to establish an EV-based method to detect the MYCN status of NB. Two EV subtypes, i.e., microvesicles (MVs) and exosomes, were sequentially isolated from the culture supernatant by step-wise centrifugation, ultrafiltration, and size-exclusion chromatography. Quantitative RT-PCR was performed to detect MYCN mRNA. As a result, MYCN mRNA was detectable in the MVs, but not exosomes, of MYCN-amplified NB cells. MYCN mRNA-containing MVs (MYCN-MV) were successfully detected in three distinct MYCN-amplified NB cell lines but absent in three MYCN non-amplification cells. The simulated samples were prepared by pulsing MVs into human serum. MYCN–MV detection in the simulated samples showed a less interfering effect from the human blood matrix. Validation using clinical specimens (2 mL bone marrow plasma) obtained from patients at various disease stages showed a promising result. Five out of six specimens of MYCN-amplified patients showed positive results, while there were no false positives in four plasma samples of the MYCN non-amplification group. This study communicated a novel EV-based method for detecting the MYCN status of pediatric NB based on MYCN mRNA contents in MVs. Future studies should be pursued in a prospective cohort to determine its true diagnostic performance.
Dialogue among Lymphocytes and Microglia in Glioblastoma Microenvironment
Authors: Mormino Alessandro , Garofalo Stefano
Published: May 2022

Microglia and lymphocytes are fundamental constituents of the glioblastoma microenvironment. In this review, we summarize the current state-of-the-art knowledge of the microglial role played in promoting the development and aggressive hallmarks of this deadly brain tumor. Particularly, we report in vitro and in vivo studies related to glioblastoma models and human patients to outline the symbiotic bidirectional interaction between microglia, lymphocytes, and tumor cells that develops during tumor progression. Furthermore, we highlight the current experimental therapeutic approaches that aim to shape these interplays, such as adeno-associated virus (AAV) delivery and CAR-T and -NK cell infusion, and to modulate the tumor microenvironment in an anti-tumoral way, thus counteracting glioblastoma growth.
Intra- and Interobserver Variability of Shear Wave Elastography in Rectal Cancer
Authors: Loft Martina Kastrup , Pedersen Malene Roland Vils , Grimm Peter , Lauritzen Andreas Hoffmann , Dam Claus , Rafaelsen Søren Rafael
Published: May 2022

Background: Endorectal ultrasound (ERUS) is an important tool when evaluating complex rectal adenomas and rectal cancer, and the accuracy is improved by adding elastography measurements. A high interobserver agreement is imperative in clinical practice. Therefore, the aim of this study was to evaluate interobserver agreement assessed on real-time images. Additionally, we investigated the intra- and interobserver agreement between experienced and inexperienced observers. Materials and methods: We prospectively included patients referred to an ERUS at the Department of Radiology with a complex rectal polyp or suspected rectal malignancy. Two operators independently scanned each patient in turn. Furthermore, four observers assessed previously obtained images using three different methods for placing the region of interest (ROI). Three months later, the four observers reassessed the images to assess intraobserver variability. Results: A total of 19 patients were included for live assessment. Agreement of tumor classification was substantial for T stage (kappa: 0.86) and fair for N stage (kappa: 0.73), with an absolute agreement for T and N stages of 84% and 89%, respectively. Agreement of SWE was good for Emean (ICC 0.94, 95% CI 0.86–0.98) and fair for Emax (ICC 0.85, 95% CI 0.66–0.94). Intra- and interobserver agreement between inexperienced and experienced observers showed good to excellent agreement with all ROI methods. Conclusion: Interobserver agreement is high in SWE when performed in a clinical setting. We found the best agreement using the mean value of several ROIs. Intra- and interobserver agreement was high regardless of operator experience.
Fusogenic Hybrid Extracellular Vesicles with PD-1 Membrane Proteins for the Cytosolic Delivery of Cargos
Authors: Ishikawa Raga , Yoshida Shosuke , Sawada Shin-ichi , Sasaki Yoshihiro , Akiyoshi Kazunari
Published: May 2022

Extracellular vesicles (EVs) are cell-derived lipid membrane capsules that can deliver functional molecules, such as nucleic acids, to target cells. Currently, the application of EVs is limited because of the difficulty of loading cargo into EVs. We constructed hybrid EVs by the fusion of liposomes and insect cell-derived EVs expressing recombinant programmed cell death 1 (PD-1) protein and baculoviral fusogenic glycoprotein gp64, and evaluated delivery of the model cargo molecule, Texas Red-labeled dextran (TR-Dex), into the cytosol. When PD-1 hybrid EVs were added to HeLa cells, the intracellular uptake of the hybrid EVs was increased compared with hybrid EVs without PD-1. After cellular uptake, the PD-1 hybrid EVs were shown to be localized to late endosomes or lysosomes. The results of fluorescence resonance energy transfer (FRET) indicated that membrane fusion between the hybrid EVs and organelles had occurred in the acidic environment of the organelles. When TR-Dex-loaded liposomes were fused with the PD-1 EVs, confocal laser scanning microscopy indicated that TR-Dex was distributed throughout the cells, which suggested that endosomal escape of TR-Dex, through membrane fusion between the hybrid EVs and acidic organelles, had occurred. These engineered PD-1 hybrid EVs have potential as delivery carriers for biopharmaceuticals.
Extracellular Prostaglandins E1 and E2 and Inflammatory Cytokines Are Regulated by the Senescence Program in Potentially Premalignant Oral Keratinocytes
Authors: Karen-Ng Lee Peng , Ahmad Usama Sharif , Gomes Luis , Hunter Keith David , Wan Hong , Hagi-Pavli Eleni , Parkinson Eric Kenneth
Published: May 2022

Potentially pre-malignant oral lesions (PPOLs) are composed of keratinocytes that are either mortal (MPPOL) or immortal (IPPOL) in vitro. We report here that MPPOL, but not generally IPPOL, keratinocytes upregulate various extracellular tumor-promoting cytokines (interleukins 6 and 8) and prostaglandins E1 (ePGE1) and E2 (ePGE2) relative to normal oral keratinocytes (NOKs). ePGE upregulation in MPPOL was independent of PGE receptor status and was associated with some but not all markers of cellular senescence. Nevertheless, ePGE upregulation was dependent on the senescence program, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase and was partially regulated by hydrocortisone. Following senescence in the absence of p16INK4A, ePGEs accumulated in parallel with a subset of tumor promoting cytokine and metalloproteinase (MMP) transcripts, all of which were ablated by ectopic telomerase. Surprisingly, ataxia telangiectasia mutated (ATM) function was not required for ePGE upregulation and was increased in expression in IPPOL keratinocytes in line with its recently reported role in telomerase function. Only ePGE1 was dependent on p53 function, suggesting that ePGEs 1 and 2 are regulated differently in oral keratinocytes. We show here that ePGE2 stimulates IPPOL keratinocyte proliferation in vitro. Therefore, we propose that MPPOL keratinocytes promote the progression of IPPOL to oral SCC in a pre-cancerous field by supplying PGEs, interleukins and MMPs in a paracrine manner. Our results suggest that the therapeutic targeting of COX-2 might be enhanced by strategies that target keratinocyte senescence.
The Role of Cancer-Associated Fibroblasts in Ovarian Cancer
Authors: Zhang Mo , Chen Zhixian , Wang Yan , Zhao Hongbo , Du Yan
Published: May 2022

Ovarian cancer is a lethal gynecologic tumor and is generally resistant to conventional treatments. Stable cancer-associated fibroblasts (CAFs) are important cellular components in the ovarian cancer tumor microenvironment and may provide novel resources for future treatment strategies. Different subtypes of CAFs display specific functions in tumor pathogenesis and various CAF markers suggest potential treatment targets, such as FAP and GPR77. Both autocrine and paracrine cytokines play important roles in the CAF activation process and regulate tumor progression. Downstream mediators and pathways, including IL-6, TGF-β, NF-κB, mitogen-activated protein kinase (MAPK), and AKT/mTOR/(p70S6K), play important roles in the initiation, proliferation, invasiveness, and metastasis of ovarian cancer cells and also participate in angiogenesis, therapeutic resistance, and other biological processes. Several clinical or preclinical trials have targeted stromal fibroblasts and focused on the properties of CAFs to enhance ovarian cancer treatment outcomes. This review concentrates on the origins, subtypes, and activation of CAFs, as well as specific roles of CAFs in regulating tumor development and drug resistance, and aims to provide potential and prospective targets for improving the therapeutic efficacy of ovarian cancer treatment.
Pharmacologic Induction of BRCAness in BRCA-Proficient Cancers: Expanding PARP Inhibitor Use
Authors: Abbotts Rachel , Dellomo Anna J. , Rassool Feyruz V.
Published: May 2022

The poly(ADP-ribose) polymerase (PARP) family of proteins has been implicated in numerous cellular processes, including DNA repair, translation, transcription, telomere maintenance, and chromatin remodeling. Best characterized is PARP1, which plays a central role in the repair of single strand DNA damage, thus prompting the development of small molecule PARP inhibitors (PARPi) with the intent of potentiating the genotoxic effects of DNA damaging agents such as chemo- and radiotherapy. However, preclinical studies rapidly uncovered tumor-specific cytotoxicity of PARPi in a subset of cancers carrying mutations in the BReast CAncer 1 and 2 genes (BRCA1/2), which are defective in the homologous recombination (HR) DNA repair pathway, and several PARPi are now FDA-approved for single agent treatment in BRCA-mutated tumors. This phenomenon, termed synthetic lethality, has now been demonstrated in tumors harboring a number of repair gene mutations that produce a BRCA-like impairment of HR (also known as a ‘BRCAness’ phenotype). However, BRCA mutations or BRCAness is present in only a small subset of cancers, limiting PARPi therapeutic utility. Fortunately, it is now increasingly recognized that many small molecule agents, targeting a variety of molecular pathways, can induce therapeutic BRCAness as a downstream effect of activity. This review will discuss the potential for targeting a broad range of molecular pathways to therapeutically induce BRCAness and PARPi synthetic lethality.
Timeline of FDA-Approved Targeted Therapy for Cholangiocarcinoma
Authors: Cho Su Min , Esmail Abdullah , Raza Ali , Dacha Sunil , Abdelrahim Maen
Published: May 2022

Cholangiocarcinoma (CCA) represents approximately 3% of gastrointestinal malignancies worldwide and constitutes around 10–15% of all primary liver cancers, being only second to hepatocellular carcinoma. Mortality from CCA has been on the rise in recent decades, and in the United States alone there has been a 36% increase in CCA from 1999 to 2014, with over 7000 CCA mortalities since 2013. Targeted therapies, which have been gaining interest due to their greater specificity toward cancer cells, have only recently started gaining FDA approval for the treatment of CCA. In this manuscript, we will go through the timeline of current FDA-approved targeted therapies as well as those that have gained FDA breakthrough therapy designation.
Growth Inhibition of Two Prenylated Chalcones on Prostate Cancer Cells through the Regulation of the Biological Activity and Protein Translation of Bloom Helicase
Authors: Sun Bao-Fei , Zhu Xu-Hui , Hou Jing , Li Lan-Lan , Qin Yuan-Kun , Yu Jia , Cheng Sha , Xu Bi-Xue , Song Fa-Jun , Luo Heng
Published: May 2022

Bloom (BLM) helicase is an important member of the RecQ family of DNA helicases that plays a vital role in the maintenance of genomic stability. The defect of BLM helicase leads to a human genetic disorder called Bloom syndrome, characterized by genomic instability, specific phenotypic features, and a predisposition to many types of cancer. The predisposition to cancer caused by BLM helicase is due to defects in important DNA metabolic pathways such as replication, recombination, and repair. Therefore, the aim of this work was to investigate the effects of two prenylated chalcones, WZH-10 and WZH-43, on the expression of BLM helicase in prostate cancer cells, as well as the biological activity of the purified BLM helicase from cancer cells. This might lead to a better understanding of the role of BLM helicase in the aforementioned DNA metabolic pathways that directly influence chromosomal integrity leading to cancer. The results indicated that the two prenylated chalcones inhibited the growth of prostate cancer cells PC3 by inducing apoptosis and arresting the cell cycle. However, they only inhibited the protein expression of BLM helicase without regulating its transcriptional expression. In addition, they did not significantly regulate the expression of the homologous family members WRN and RECQL1, although the DNA unwinding and ATPase activity of BLM helicase were inhibited by the two prenylated chalcones. Finally, a negligible effect was found on the DNA-binding activity of this enzyme. These results demonstrated that prenylated chalcones can be an effective intervention on the expression and function of the BLM helicase protein in cancer cells to inhibit their growth. Therefore, they might provide a novel strategy for developing new anti-cancer drugs targeting the genomic stability and DNA helicase.
Phase Separation in the Nucleus and at the Nuclear Periphery during Post-Mitotic Nuclear Envelope Reformation
Authors: Maccaroni Klizia , La Torre Mattia , Burla Romina , Saggio Isabella
Published: May 2022

Membrane-enclosed organelle compartmentalization is not the only way by which cell processes are spatially organized. Phase separation is emerging as a new driver in the organization of membrane-less compartments and biological processes. Liquid–liquid phase separation has been indicated as a new way to control the kinetics of molecular reactions and is based on weak multivalent interactions affecting the stoichiometry of the molecules involved. In the nucleus, liquid–liquid phase separation may represent an ancestral means of controlling genomic activity by forming discrete chromatin regions, regulating transcriptional activity, contributing to the assembly of DNA damage response foci, and controlling the organization of chromosomes. Liquid–liquid phase separation also contributes to chromatin function through its role in the reorganization of the nuclear periphery in the post-mitotic phase. Herein, we describe the basic principles regulating liquid–liquid phase separation, analyze examples of phase separation occurring in the nucleus, and dedicate attention to the implication of liquid–liquid phase separation in the reorganization of the nuclear periphery by the endosomal sorting complexes required for transport (ESCRT) machinery. Although some caution is warranted, current scientific knowledge allows for the hypothesis that many factors and processes in the cell are yet to be discovered which are functionally associated with phase separation.
The Association between ADHD and Celiac Disease in Children
Authors: Gaur Sonia
Published: May 2022

Controversy around the association between celiac disease (CeD) and attention deficit hyperactive disorder (ADHD) was addressed by a systematic review in 2015, ultimately showing no association. Since 2015, there have been several studies showing an association between celiac disease and attention deficit hyperactive disorder. This is an updated systematic review. Background: Most experts agree on the recommendation to not screen as part of the standard of care for ADHD in persons with CeD or vice versa. Simultaneously, they propose that untreated patients with CeD and neurological symptoms such as chronic fatigue, inattention, pain, and headache could be predisposed to ADHD-like behavior, namely inattention (which may be alleviated by following a gluten-free diet). The inattentive subtype of ADHD that encompasses the symptoms of inattention is phenotypically heterogeneous, as it includes the clinical construct of sluggish cognitive tempo (SCT). SCT symptoms overlap with the neurological manifestations of CeD. Methods: A systematic search (PRISMA) of PubMed, Google Scholar, EMBASE, Web of Science, Stanford Lane, SCOPUS, and Ovid was conducted for articles up to 21 February 2022. Of these, 23 studies met the criteria. Results: Out of the 23 studies, 13 showed a positive association between ADHD and CeD. Most studies that showed a positive association had been published in the last five years. Inconsistencies in the results remain due to the heterogeneous methodology used, specifically for ADHD and the outcome questionnaires, as well as a lack of reporting on ADHD subtypes. Conclusion: There is an association between ADHD and celiac disease. The current methodological limitations will be lessened if we examine the subtypes of ADHD.
Associations between Brain Microstructure and Phonological Processing Ability in Preschool Children
Authors: Zhou Ying , Li Guangfei , Song Zeyu , Zhang Zhao , Huang Huishi , Li Hanjun , Tang Xiaoying
Published: May 2022

Neuroimaging studies have associated brain changes in children with future reading and language skills, but few studies have investigated the association between language skills and white matter structure in preschool-aged children. Using 208 data sets acquired in 73 healthy children aged 2–7 years, we investigated the relationship between developmental brain microstructure and phonological processing ability as measured using their phonological processing raw score (PPRS). The correlation analysis showed that across the whole age group, with increasing age, PPRS increased, fractional anisotropy (FA) of the internal capsule and inferior fronto-occipital fasciculus and some other regions increased, and mean diffusivity (MD) of the corpus callosum and internal capsule and some other regions decreased. The results of the mediation analysis suggest that increased FA may be the basis of phonological processing ability development during this period, and the increased number of fiber connections between the right inferior parietal lobule and right supramarginal gyrus may be a key imaging feature of phonological processing ability development. Our study reflects the changes in brain microstructure and contributes to understanding the underlying neural mechanisms of language development in preschool children.
Mental Well-Being during the COVID-19 Confinement among Adolescents in Catalonia: The Role of Demographic and Other COVID-Related Variables
Authors: Folch Cinta , González-Casals Helena , Colom Joan , Bosque-Prous Marina , Barón-Garcia Tivy , Álvarez-Vargas Anaís , Casabona Jordi , Espelt Albert
Published: May 2022

This study aimed to describe the impact of the COVID-19 pandemic on the social situation, self-perceived health status, and mental well-being of adolescents in Catalonia during home confinement, and to evaluate factors that are associated with poor overall mental well-being. An online cross-sectional study among a cohort of students (14–18 years old) of central Catalonia (DESKcohort) was performed during June–July 2020. Poisson regression models with robust variance were used to identify variables associated with “poor overall well-being,” measured by the short version of the Warwick–Edinburgh Mental Wellbeing Scale. Out of 303 participants, 42.1% reported a decrease in family income, and 32.8% a loss of parental employment due to the COVID-19 pandemic, and these percentages were higher among people living in low socioeconomic neighborhoods (53.3% and 43.2%, respectively). Overall, 56.8% presented a poor overall well-being. Participants reporting a decrease in their family’s income (aPR = 1.33) and those knowing a close person or family who died of COVID-19 (aPR = 1.42) were more likely to report a poor overall well-being. This study highlights the patterns of inequality and social vulnerability for COVID-19 pandemic outcomes. Considering social inequalities, interventions are needed to mitigate the impact of COVID-19 pandemic on the physical and the psychological wellbeing of children and their families.