bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanozybiotics: Nanozyme-Based Antibacterials against Bacterial Resistance
Authors: Zhou Caiyu , Wang Qian , Jiang Jing , Gao Lizeng
Published: March 2022

Infectious diseases caused by bacteria represent a global threat to human health. However, due to the abuse of antibiotics, drug-resistant bacteria have evolved rapidly and led to the failure of antibiotics treatment. Alternative antimicrobial strategies different to traditional antibiotics are urgently needed. Enzyme-based antibacterials (Enzybiotics) have gradually attracted interest owing to their advantages including high specificity, rapid mode-of-action, no resistance development, etc. However, due to their low stability, potential immunogenicity, and high cost of natural enzymes, enzybiotics have limitations in practical antibacterial therapy. In recent years, many nanomaterials with enzyme-like activities (Nanozymes) have been discovered as a new generation of artificial enzymes and perform catalytic antibacterial effects against bacterial resistance. To highlight the progress in this field of nanozyme-based antibacterials (Nanozybiotics), this review discussed the antibacterial mechanism of action of nanozybiotics with a comparison with enzybiotics. We propose that nanozybiotics may bear promising applications in antibacterial therapy, due to their high stability, rapid bacterial killing, biofilm elimination, and low cost.
Evaluation of Bacteriophage-Antibiotic Combination Therapy for Biofilm-Embedded MDR Enterococcus faecium
Authors: Lev Katherine , Kunz Coyne Ashlan J. , Kebriaei Razieh , Morrisette Taylor , Stamper Kyle , Holger Dana J. , Canfield Gregory S. , Duerkop Breck A. , Arias Cesar A. , Rybak Michael J.
Published: March 2022

Multidrug-resistant (MDR) Enterococcus faecium is a challenging pathogen known to cause biofilm-mediated infections with limited effective therapeutic options. Lytic bacteriophages target, infect, and lyse specific bacterial cells and have anti-biofilm activity, making them a possible treatment option. Here, we examine two biofilm-producing clinical E. faecium strains, daptomycin (DAP)-resistant R497 and DAP-susceptible dose-dependent (SDD) HOU503, with initial susceptibility to E. faecium bacteriophage 113 (ATCC 19950-B1). An initial synergy screening was performed with modified checkerboard MIC assays developed by our laboratory to efficiently screen for antibiotic and phage synergy, including at very low phage multiplicity of infection (MOI). The data were compared by one-way ANOVA and Tukey (HSD) tests. In 24 h time kill analyses (TKA), combinations with phage-DAP-ampicillin (AMP), phage-DAP-ceftaroline (CPT), and phage-DAP-ertapenem (ERT) were synergistic and bactericidal compared to any single agent (ANOVA range of mean differences 3.34 to 3.84 log10 CFU/mL; p < 0.001). Furthermore, phage-DAP-AMP and phage-DAP-CPT prevented the emergence of DAP and phage resistance. With HOU503, the combination of phage-DAP-AMP showed the best killing effect, followed closely by phage-DAP-CPT; both showed bactericidal and synergistic effects compared to any single agent (ANOVA range of mean differences 3.99 to 4.08 log10 CFU/mL; p < 0.001).
Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies
Authors: Marsche Gunther , Stadler Julia T. , Kargl Julia , Holzer Michael
Published: March 2022

Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management.
Discretization Approach for the Homogenization of Three-Dimensional Solid-Solid Phononic Crystals in the Quasi-Static Limit: Density and Elastic Moduli
Authors: Flores Méndez J. , Pinón Reyes A. C. , Heredia Jiménez Aurelio H. , Ambrosio Lázaro Roberto C. , Morales-Sánchez A. , Moreno Moreno M. , Luna-López J. A. , Severiano Carrillo F. , Meraz Melo M. A.
Published: March 2022

With the application of a homogenization theory, based on the Fourier formalism (which provides efficient and exact formulas by which to determine all the components of the effective stiffness and mass density tensors, valid in the regime of large wavelengths), a new approach to calculate the effective quasi-static response in three-dimensional solid-solid phononic crystals is reported. The formulas derived in this work for calculating the effective elastic parameters show a dependence, in terms of summations over the vectors, of the reciprocal lattice by the discretization of the volume of the inclusion in small parts (e.g., small cubes), to obtain a system of equations from which we define the effective response. In particular, we present the numerical results calculated for several cubic lattices with solid constituents and different shapes of inclusions in the unit cell versus the filling fraction, as well as for fixed values of it. By this means, we analyzed the effect of the type of Bravais lattice of the materials, and the geometry of the inclusions that constitute the three-dimensional phononic array, on the resulting effective anisotropy. Finally, our theory confirms other well-known results with previous homogenization theories as a particular case study. In this regard, the examples and results shown here can be useful for the design of metamaterials with predetermined elastic properties.
Self-Loosening of a 3D-Printed Bolt by Using Three Different Materials under Cyclical Temperature Changes
Authors: Eraliev Oybek , Lee Kwang-Hee , Lee Chul-Hee
Published: March 2022

Three-dimensional printing can bring huge advantages when fabricating difficult structures and components in industry. This technology is also used commonly for printing threaded fasteners in the engineering field. The main disadvantage of threated fasteners is self-loosening. In this study, an International Organization for Standardization (ISO) standard M12 × 1.75 bolt and nut were printed by using a 3D printer and three types of 3D printing materials: acrylonitrile butadiene styrene (ABS-2), poly lactic acid (PLA), and glass. Following this, a test system for self-loosening of the 3D-printed bolts under cyclical temperature variations was constructed, and self-loosening of the bolted joints was observed by measuring the bolt preload using a load cell and the rotation displacement of the nut using a dial indicator according to temperature changes (from 10 °C up to 40 °C and 80 °C). The experimental results show that the ABS-2 bolt has good performance in terms of self-loosening phenomena under cyclical temperature changes, while the PLA bolt has poor performance in low temperature changes. The glass bolt indicated the lowest performance in high temperature changes.
Geomagnetic Storm Effect on F2-Region Ionosphere during 2012 at Low- and Mid-Latitude-Latitude Stations in the Southern Hemisphere
Authors: Kumar Edwin A. , Kumar Sushil
Published: March 2022

The ionospheric effects of six intense geomagnetic storms with Dst index ≤ −100 nT that occurred in 2012 were studied at a low-latitude station, Darwin (Geomagnetic coordinates, 21.96° S, 202.84° E), a low-mid-latitude station, Townsville (28.95° S, 220.72° E), and a mid-latitude station, Canberra (45.65° S, 226.30° E), in the Australian Region, by analyzing the storm–time variations in the critical frequency of the F2-region (foF2). Out of six storms, a storm of 23–24 April did not produce any ionospheric effect. The storms of 30 September–3 October (minimum Dst = −122 nT) and 7–10 October (minimum Dst = −109 nT) are presented as case studies and the same analysis was done for the other four storms. The storm of 30 September–3 October, during its main phase, produced a positive ionospheric storm at all three stations with a maximum percentage increase in foF2 (∆foF2%) of 45.3% at Canberra whereas during the recovery phase it produced a negative ionospheric storm at all three stations with a maximum ∆foF2% of −63.5% at Canberra associated with a decrease in virtual height of the F-layer (h’F). The storm of 7–10 October produced a strong long-duration negative ionospheric storm associated with an increase in h’F during its recovery phase at all three stations with a maximum ∆foF2% of −65.1% at Townsville. The negative ionospheric storms with comparatively longer duration were more pronounced in comparison to positive storms and occurred only during the recovery phase of storms. The storm main phase showed positive ionospheric storms for two storms (14–15 July and 30 September–3 October) and other three storms did not produce any ionospheric storm at the low-latitude station indicating prompt penetrating electric fields (PPEFs) associated with these storms did not propagate to the low latitude. The positive ionospheric storms during the main phase are accounted to PPEFs affecting ionospheric equatorial E × B drifts and traveling ionospheric disturbances due to joule heating at the high latitudes. The ionospheric effects during the recovery phase are accounted to the disturbance dynamo electric fields and overshielding electric field affecting E × B drifts and the storm-induced circulation from high latitudes toward low latitudes leading to changes in the natural gas composition [O/N2] ratio.
The Role of Risk Forecast and Risk Tolerance in Portfolio Management: A Case Study of the Chinese Financial Sector
Authors: Liu Jianxu , Cheng Yangnan , Li Xiaoqing , Sriboonchitta Songsak
Published: March 2022

Portfolio decisions are affected by the volatility of financial markets and investors’ risk tolerance levels. To better allocate portfolios; we introduce risk tolerance into the portfolio management problem by considering the risk contribution of portfolio components. In this paper, portfolio weights are allocated to two stages. In the first stage, the portfolio risks and the risk contribution of each share are forecasted. In the second stage, we put forward three weighting techniques—“aggressive”, “moderate” and “conservative”, according to three standard levels of risk tolerance. In addition, a new risk measure called “joint extreme risk probability” (JERP), with risk tolerance taken into account, is proposed. A case study of the Chinese financial industry is conducted to verify the performance of our methods. The empirical results demonstrate that weighting techniques constrained by risk tolerance lead to higher gains in a normal market and less loss when a market is risky. Compared with risk-tolerance-adjusted strategies, the relationship between the performance of the traditional conditional value at risk (CVaR) minimization method and the market risk level is less obviously demonstrated. Viewed from the results, JERP functions as an effective signal that helps investors to deal with potential market risks.
Analysis of the Term Structure of Major Currencies Using Principal Component Analysis and Autoencoders
Authors: Chae Soo Chang , Choi Sun-Yong
Published: March 2022

Recently, machine-learning algorithms and existing financial data-analysis methods have been actively studied. Although the term structure of government bonds has been well-researched, the majority of studies only analyze the characteristics of one country in detail using one method. In this paper, we analyze the term structure and determine the common factors using principal component analysis (PCA) and an autoencoder (AE). We collected data on the government bonds of three countries with major currencies (the US, the UK, and Japan), extracted features, and compared them. In the PCA-based analysis, we reduced the number of dimensions by converting the normalized data into a covariance matrix and checked the first five principal components visually using graphs. In the AE-based analysis, the model consisted of two encoder layers, one middle layer, and two decoder layers, and the number of nodes in the middle layer was adjusted from one to five. As a result, no significant similarity was found for each country in the dataset, and it was appropriate to extract three features in both methods. Each feature extracted by PCA and the AE had a completely different form, and this appears to be due to the differences in the feature extraction methods. In the case of PCA, the volatility of the datasets affected the features, but in the case of AE, the results seemed to be more affected by the size of the dataset. Based on the findings of this study, this topic can be expanded to compare the results of other machine-learning algorithms or countries.
Atrial High-Rate Episodes Detected by Cardiac Implantable Electronic Devices: Dynamic Changes in Episodes and Predictors of Incident Atrial Fibrillation
Authors: Imberti Jacopo Francesco , Bonini Niccolò , Tosetti Alberto , Mei Davide Antonio , Gerra Luigi , Malavasi Vincenzo Livio , Mazza Andrea , Lip Gregory Y. H. , Boriani Giuseppe
Published: March 2022

Background. Atrial high rate episodes (AHRE) detected by cardiac implantable electronic devices (CIEDs) may be associated with a risk of progression towards long-lasting episodes (≥24 h) and clinical atrial fibrillation (AF). Methods. Consecutive CIED patients presenting AHRE (with confirmation of an arrhythmia lasting 5 min–23 h 59 min, atrial rate ≥175/min, with no AF at 12-lead ECG and no prior clinical AF) were retrospectively enrolled. The aims of this study were to describe patients’ characteristics and the incidence of adverse events, and second, to identify potential predictors of the composite outcome of clinical AF and/or AHRE episodes lasting ≥24 h. Results. 104/107 (97.2%) patients (median age 79.7 (74.0–84.2), 33.7% female) had available follow-up data. Over a median follow-up of 24.3 (10.6–40.3) months, 31/104 (29.8%) patients experienced the composite outcome of clinical AF or AHRE episodes lasting ≥24 h. Baseline CHA2DS2-VASc score and the longest AHRE episode at enrollment lasting 12 h–23 h 59 min were independently associated with the composite outcome (Hazard ratio (HR); 95% CI: 1.40; 1.07–1.83 and HR: 8.15; 95% CI 2.32–28.65, respectively). Baseline CHA2DS2-VASc score and the longest AHRE episode at enrollment lasting 12 h–23 h 59 min were the only independent predictors of incident clinical AF (HR: 1.45; 95% CI 1.06–2.00 and HR: 4.25; 95% CI 1.05–17.20, respectively). Conclusions. In patients with AHRE, the incidence of clinical AF or AHRE episodes lasting ≥24 h is high in a two-year follow-up. Baseline patients’ characteristics (CHA2DS2-VASc score) and AHRE duration may help to intensify monitoring and decision-making, being independently associated with clinical AF at follow-up.
Investigation of the JASMONATE ZIM-DOMAIN Gene Family Reveals the Canonical JA-Signaling Pathway in Pineapple
Authors: Ye Li , Cao Ling , Zhao Xuemei , Guo Xinya , Ye Kangzhuo , Jiao Sibo , Wang Yu , He Xiaoxue , Dong Chunxing , Hu Bin , Deng Fang , Zhao Heming , Zheng Ping , Aslam Mohammad , Qin Yuan , Cheng Yan
Published: March 2022

JASMONATE ZIM-DOMAIN (JAZ) proteins are negative regulators of the jasmonate (JA)-signaling pathway and play pivotal roles in plant resistance to biotic and abiotic stresses. Genome-wide identification of JAZ genes has been performed in many plant species. However, systematic information about pineapple (Ananas comosus L. Merr.) JAZ genes (AcJAZs) is still not available. In this study, we identified 14 AcJAZ genes and classified them into five groups along with the Arabidopsis and rice orthologs. The AcJAZ genes have 3–10 exons, and the putative AcJAZ proteins have between two and eight conserved regions, including the TIFY motif and Jas domain. The cis-acting element analysis revealed that the putative promoter regions of AcJAZs contain between three and eight abiotic stress-responsive cis-acting elements. The gene-expression analysis suggested that AcJAZs were expressed differentially during plant development and subjected to regulation by the cold, heat, salt, and osmotic stresses as well as by phytohormones. Moreover, the BiFC analysis of protein interactions among the central JA-signaling regulators showed that AcJAZ4, AcMYC2, AcNINJA, and AcJAM1 could interact with AcJAZ5 and AcJAZ13 in vivo, indicating a canonical JA-signaling pathway in pineapple. These results increase our understanding of the functions of AcJAZs and the responses of the core players in the JA-signaling pathway to abiotic stresses.
Transcription Regulation of Tceal7 by the Triple Complex of Mef2c, Creb1 and Myod
Authors: Xiong Zhenzhen , Wang Mengni , You Shanshan , Chen Xiaoyan , Lin Jiangguo , Wu Jianhua , Shi Xiaozhong
Published: March 2022

Tceal7 has been identified as a direct, downstream target gene of MRF in the skeletal muscle. The overexpression of Tceal7 represses myogenic proliferation and promotes cell differentiation. Previous studies have defined the 0.7 kb upstream fragment of the Tceal7 gene. In the present study, we have further determined two clusters of transcription factor-binding motifs in the 0.7 kb promoter: CRE#2–E#1–CRE#1 in the proximal region and Mef2#3–CRE#3–E#4 in the distal region. Utilizing transcription assays, we have also shown that the reporter containing the Mef2#3–CRE#3–E#4 motifs is synergistically transactivated by Mef2c and Creb1. Further studies have mapped out the protein–protein interaction between Mef2c and Creb1. In summary, our present studies support the notion that the triple complex of Mef2c, Creb1 and Myod interacts with the Mef2#3–CRE#3–E#4 motifs in the distal region of the Tceal7 promoter, thereby driving Tceal7 expression during skeletal muscle development and regeneration.
Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia’s Protein-Protein Interaction Network
Authors: Lalwani Amit Kumar , Krishnan Kushagra , Bagabir Sali Abubaker , Alkhanani Mustfa F. , Almalki Atiah H. , Haque Shafiul , Sharma Saurabh Kumar , Singh R. K. Brojen , Malik Md. Zubbair
Published: March 2022

Dementia—a syndrome affecting human cognition—is a major public health concern given to its rising prevalence worldwide. Though multiple research studies have analyzed disorders such as Alzheimer’s disease and Frontotemporal dementia using a systems biology approach, a similar approach to dementia syndrome as a whole is required. In this study, we try to find the high-impact core regulating processes and factors involved in dementia’s protein–protein interaction network. We also explore various aspects related to its stability and signal propagation. Using gene interaction databases such as STRING and GeneMANIA, a principal dementia network (PDN) consisting of 881 genes and 59,085 interactions was achieved. It was assortative in nature with hierarchical, scale-free topology enriched in various gene ontology (GO) categories and KEGG pathways, such as negative and positive regulation of apoptotic processes, macroautophagy, aging, response to drug, protein binding, etc. Using a clustering algorithm (Louvain method of modularity maximization) iteratively, we found a number of communities at different levels of hierarchy in PDN consisting of 95 “motif-localized hubs”, out of which, 7 were present at deepest level and hence were key regulators (KRs) of PDN (HSP90AA1, HSP90AB1, EGFR, FYN, JUN, CELF2 and CTNNA3). In order to explore aspects of network’s resilience, a knockout (of motif-localized hubs) experiment was carried out. It changed the network’s topology from a hierarchal scale-free topology to scale-free, where independent clusters exhibited greater control. Additionally, network experiments on interaction of druggable genome and motif-localized hubs were carried out where UBC, EGFR, APP, CTNNB1, NTRK1, FN1, HSP90AA1, MDM2, VCP, CTNNA1 and GRB2 were identified as hubs in the resultant network (RN). We finally concluded that stability and resilience of PDN highly relies on motif-localized hubs (especially those present at deeper levels), making them important therapeutic intervention candidates. HSP90AA1, involved in heat shock response (and its master regulator, i.e., HSF1), and EGFR are most important genes in pathology of dementia apart from KRs, given their presence as KRs as well as hubs in RN.
Applications of Single-Cell Sequencing Technology to the Enteric Nervous System
Authors: Guyer Richard A. , Mueller Jessica L. , Goldstein Allan M.
Published: March 2022

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, thus revealing cellular diversity within organs and permitting lineage reconstruction in developing tissues. Application of these methods to the enteric nervous system has yielded a wealth of data and biological insights. We review recent papers applying single-cell sequencing tools to the nascent neural crest and to the developing and mature enteric nervous system. These studies have shown significant diversity of enteric neurons and glia, suggested paradigms for neuronal specification, and revealed signaling pathways active during development. As technology evolves and multiome techniques combining two or more of transcriptomic, genomic, epigenetic, and proteomic data become prominent, we anticipate these modalities will become commonplace in ENS research and may find a role in diagnostic testing and personalized therapeutics.
New Frontiers of Extracorporeal Shock Wave Medicine in Urology from Bench to Clinical Studies
Authors: Chen Po-Yen , Cheng Jai-Hong , Wu Zong-Sheng , Chuang Yao-Chi
Published: March 2022

A shock wave (SW), which carries energy and propagates through a medium, is a type of continuous transmitted sonic wave that can achieve rapid energy transformations. SWs have been applied for many fields of medical science in various treatment settings. In urology, high-energy extracorporeal SWs have been used to disintegrate urolithiasis for 30 years. However, at lower energy levels, SWs enhance the expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), proliferating cell nuclear antigen (PCNA), chemoattractant factors, and the recruitment of progenitor cells, and inhibit inflammatory molecules. Low energy extracorporeal shock wave (LESW) therapy has been used in urology for treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), interstitial cystitis/bladder pain syndrome (IC/BPS), overactive bladder, stress urinary incontinence, and erectile dysfunction through the mechanisms of anti-inflammation, neovascularization, and tissue regeneration. Additionally, LESW have been proven to temporarily increase tissue permeability and facilitate intravesical botulinum toxin delivery for treating overactive bladders in animal studies and in a human clinical trial. LESW assisted drug delivery was also suggested to have a synergistic effect in combination with cisplatin to improve the anti-cancer effect for treating urothelial cancer in an in vitro and in vivo study. LESW assisted drug delivery in uro-oncology is an interesting suggestion, but no comprehensive clinical trials have been conducted as of yet. Taken together, LESW is a promising method for the treatment of various diseases in urology. However, further investigation with a large scale of clinical studies is necessary to confirm the real role of LESW in clinical use. This article provides information on the basics of SW physics, mechanisms of action on biological systems, and new frontiers of SW medicine in urology.
Simultaneously Acquiring Optical and Acoustic Properties of Individual Microalgae Cells Suspended in Water
Authors: Wang Hongjian , Liao Ran , Xiong Zhihang , Wang Zhao , Li Jiajin , Zhou Qian , Tao Yi , Ma Hui
Published: March 2022

Microalgae play a vital role in aquatic ecological research, but the fine classification of these tiny and various microalgae cells is still challenging for the community. In this paper, we propose a multimodality technique to simultaneously acquire the polarized light scattering, fluorescence and laser-induced acoustic wave signals originated from individual microalgae cells in water. Experiments of different species of Spirulina and different states of Microcystis have been conducted to test our experiment setup, and the results demonstrate that this method can well discriminate microalgae cells with pigment or microstructural differences. Moreover, with these modalities, the consumption of absorbed energy is evaluated quantitively, and a possible way to assess photosynthesis on a single-cell level is presented. This work is expected to be a powerful technique to probe the biophysical states of microalgae in the aquatic ecosystem.
Gender Differences in Dual Diagnoses Associated with Cannabis Use: A Review
Authors: Prieto-Arenas Laura , Díaz Ignacio , Arenas M. Carmen
Published: March 2022

Gender differences in psychiatric disorders and drug use are well known. Cannabis is the most widely used illegal drug among young people. In recent years, its use has been related to the development of psychiatric pathologies; however, few studies have incorporated the gender perspective as of yet. The present work analyses the literature to determine the existence of gender differences in the development of psychotic, depressive and anxious symptoms associated with cannabis use. First, we describe cannabis misuse and its consequences, paying special attention to adolescent subjects. Second, the main gender differences in psychiatric disorders, such as psychosis, depression, anxiety and cannabis use disorders, are enumerated. Subsequently, we discuss the studies that have evaluated gender differences in the association between cannabis use and the appearance of psychotic, depressive and anxious symptoms; moreover, we consider the possible explanations for the identified gender differences. In conclusion, the studies referred to in this review reveal the existence of gender differences in psychiatric symptoms associated with cannabis use, although the direction of such differences is not always clear. Future research is necessary to discern the causal relationship between cannabis use and the development of psychiatric symptoms, as well as the gender differences found.
Autistic-like Behaviors Associated with a Novel Non-Canonical Splice-Site DDX3X Variant: A Case Report of a Rare Clinical Syndrome
Authors: Stefaniak Urszula , Malak Roksana , Mojs Ewa , Samborski Włodzimierz
Published: March 2022

Background. Heterozygous pathogenic variants in the DDX3X gene account for 1–3% of females with intellectual and developmental disabilities (IDD). The clinical presentation is variable, including a wide range of neurological and behavioral deficits and structural defects of the brain. Approximately 52% of affected females remain nonverbal after five years of age. Case presentation: We report a 7 year old nonverbal female with a likely novel de novo pathogenic heterozygous variant in the DDX3X gene affecting the non-canonical splice-site in the intron 1 (NM_001356:c.45+12G>A). The patient presents with features typical for the DDX3X phenotype, such as: movement disorders, behavioral problems, a diagnosis of autism spectrum disorder (ASD), and some other features uncommon for DDX3X such as: muscle hypertonia and spinal asymmetry evaluated through the scoliometer. Conclusions. Due to its rare occurrence, the clinical picture of DDX3X syndrome is yet to be fully determined. So far, behavioral disorders, including those from ASD, and neurological abnormalities seem to be the dominant features of this disorder.
Relationship between Behavioral and Objective Measures of Sound Intensity in Normal-Hearing Listeners and Hearing-Aid Users: A Pilot Study
Authors: Legris Elsa , Galvin John , Mofid Yassine , Aguillon-Hernandez Nadia , Roux Sylvie , Aoustin Jean-Marie , Gomot Marie , Bakhos David
Published: March 2022

Background: For hearing-impaired individuals, hearing aids are clinically fit according to subjective measures of threshold and loudness. The goal of this study was to evaluate objective measures of loudness perception that might benefit hearing aid fitting. Method: Seventeen adult hearing aid users and 17 normal-hearing adults participated in the study. Outcome measures including categorical loudness scaling, cortical auditory evoked potentials (CAEPs), and pupillometry. Stimuli were 1-kHz tone bursts presented at 40, 60, and 80 dBA. Results: Categorical loudness scaling showed that loudness significantly increased with intensity for all participants (p < 0.05). For CAEPs, high intensity was associated with greater P1, N1, and P2 peak amplitude for all listeners (p < 0.05); a significant but small effect of hearing aid amplification was observed. For all participants, pupillometry showed significant effects of high intensity on pupil dilation (p < 0.05); there was no significant effect of hearing aid amplification. A Focused Principal Component analysis revealed significant correlations between subjective loudness and some of the objective measures. Conclusion: The present data suggest that intensity had a significant impact on loudness perception, CAEPs, and pupil response. The correlations suggest that pupillometry and/or CAEPs may be useful in determining comfortable amplification for hearing aids.
The Nexus between Study Burnout Profiles and Social Support —The Differences between Domestic (Finnish) and International Master’s Degree Students
Authors: Rönkkönen Sara , Mattsson Markus T. , Virtanen Viivi , Pyhältö Kirsi , Inkinen Mikko
Published: March 2022

The present study investigated the variation in higher education students’ study burnout experiences and how they are related to academic success and social support needs. Similarities and differences between the international and domestic students were also explored. In this mixed-methods study, the data were collected through a self-reported questionnaire, and a total of 902 (response rate 42%) first year master’s students from the fields of arts, business and technology responded. Using Latent Profile Analysis (LPA), we detected three distinct study burnout risk profiles (No exhaustion or cynicism; Exhausted; Exhausted and cynical). The following distinct forms of social support needs were found using theory-based qualitative content analysis: informational, instrumental, emotional, and co-constructional support. We found out that the students with highest risk of burnout had the lowest grade point averages (GPAs). Further investigation showed that international students pass their courses despite the experiences of study burnout, even though the GPAs might deteriorate. When the domestic students experience study burnout symptoms, they both gain fewer study credits and earn lower GPAs. Finally, a relationship between the form of support needed and the burnout profile was identified.
Exploring the Barriers against Using Cryptocurrencies in Managing Construction Supply Chain Processes
Authors: Gurgun Asli Pelin , Genc Mehmet Ilker , Koc Kerim , Arditi David
Published: March 2022

Various stakeholders are involved in managing supply chain processes in construction. Suppliers can hardly tolerate upfront costs when faced with flaws in the payment pipeline. This is a serious problem in building construction that uses a large variety of materials as opposed to civil construction that requires fewer types of materials. Alternative secure payment systems are needed, and the use of cryptocurrencies can be an option. However, cryptocurrencies are seldom used in building construction projects due to several challenges that are mostly ignored in the existing literature. To fill this gap, this study investigates the use of cryptocurrencies in construction supply chains as an alternative payment solution to improve the financial performance of the stakeholders by taking advantage of this economical and traceable financial transaction system. The study involves exploratory, descriptive, and empirical survey research. Accordingly, a literature review, focus group discussions, and statistical analyses (Friedman test, Wilcoxon test, and Mann–Whitney U test) were performed. The results imply that a lack of technical knowledge about cryptocurrencies, fluctuations in the value of cryptocurrencies, limited market opportunities, security gaps, personal information required by cryptocurrency systems, no assurance of permanent use, and government actions limiting the use of cryptocurrencies were the most significant barriers against using cryptocurrencies in construction supply chain management. The findings are expected to provide critical information to construction professionals and regulatory agencies about the potential advantages and shortcomings of cryptocurrencies, hence motivating policymakers to create strategies that minimize the concerns of construction professionals about using cryptocurrencies in the building construction industry.
The Occurrence of MET Ectodomain Shedding in Oral Cancer and Its Potential Impact on the Use of Targeted Therapies
Authors: De Herdt Maria J. , van der Steen Berdine , Baatenburg de Jong Robert J. , Looijenga Leendert H. J. , Koljenović Senada , Hardillo Jose A.
Published: March 2022

The receptor tyrosine kinase MET has gained attention as a therapeutic target. Although MET immunoreactivity is associated with progressive disease, use of targeted therapies has not yet led to major survival benefits. A possible explanation is the lack of companion diagnostics (CDx) that account for proteolytic processing. During presenilin-regulated intramembrane proteolysis, MET’s ectodomain is shed into the extracellular space, which is followed by γ-secretase-mediated cleavage of the residual membranous C-terminal fragment. The resulting intracellular fragment is degraded by the proteasome, leading to downregulation of MET signaling. Conversely, a membrane-bound MET fragment lacking the ectodomain (MET-EC-) can confer malignant potential. Use of C- and N-terminal MET monoclonal antibodies (moAbs) has illustrated that MET-EC- occurs in transmembranous C-terminal MET-positive oral squamous cell carcinoma (OSCC). Here, we propose that ectodomain shedding, resulting from G-protein-coupled receptor transactivation of epidermal growth factor receptor signaling, and/or overexpression of ADAM10/17 and/or MET, stabilizes and possibly activates MET-EC- in OSCC. As MET-EC- is associated with poor prognosis in OSCC, it potentially has impact on the use of targeted therapies. Therefore, MET-EC- should be incorporated in the design of CDx to improve patient stratification and ultimately prolong survival. Hence, MET-EC- requires further investigation seen its oncogenic and predictive properties.
Impact of BRCA Status on Reproductive Decision-Making and Self-Concept: A Mixed-Methods Study Informing the Development of Tailored Interventions
Authors: Hesse-Biber Sharlene , Seven Memnun , Jiang Jing , Schaik Sara , Dwyer Andrew A.
Published: March 2022

This mixed-methods study sought to deepen our understanding of self-concept and experiences in balancing cancer risk/reproductive decisions after learning of BRCA+ status. First, a quantitative survey of BRCA+ women (n = 505) examined the childbearing status, risk-reducing surgery, and self-concept. At the time of testing, 307/505 (60.8%) women were of reproductive age (<40 years-old), 340/505 (67.3%) had children, and 317/505 (62.8%) had undergone risk-reducing surgery. A younger age at the time of the testing was significantly associated with the decision to have children after learning BRCA+ status or undergoing risk-reducing surgery (p < 0.001). Compared to older women, BRCA+ women of reproductive age, exhibited a more negative self-concept with significantly higher vulnerability ratings (p < 0.01). Women with a cancer diagnosis exhibited a more negative mastery ratings and worse vulnerability ratings (p < 0.01) than women without a cancer history. Compared to childless counterparts, significantly higher vulnerability ratings were observed among BRCA+ women who had children before learning their BRCA status and/or undergoing risk-reducing surgery (p < 0.001). Subsequently, a subset of women (n = 40) provided in-depth interviews to explore their experiences in decision-making. The interviews provided insights into the effects of BRCA status on decisions regarding relationships, childbearing, cancer risk management, and communicating BRCA risk to children. Integrating quantitative and qualitative findings identifies targets for tailored interventions to enhance precision health for BRCA+ women of reproductive age.
Decisional Conflict after Deciding on Potential Participation in Early Phase Clinical Cancer Trials: Dependent on Global Health Status, Satisfaction with Communication, and Timing
Authors: van Lent Liza G. G. , de Jonge Maja J. A. , van der Ham Mirte , van Mil Marjolein , Gort Eelke H. , Hasselaar Jeroen , Oomen-de Hoop Esther , van der Rijt Carin C. D. , van Weert Julia C. M. , Lolkema Martijn P.
Published: March 2022

When standard treatment options are not available anymore, patients with advanced cancer may participate in early phase clinical trials. Improving this complex decision-making process may improve their quality of life. Therefore, this prospective multicenter study with questionnaires untangles several contributing factors to decisional conflict (which reflects the quality of decision-making) in patients with advanced cancer who recently decided upon early phase clinical trial participation (phase I or I/II). We hypothesized that health-related quality of life, health literacy, sense of hope, satisfaction with the consultation, timing of the decision, and the decision explain decisional conflict. Mean decisional conflict in 116 patients was 30.0 (SD = 16.9). Multivariate regression analysis showed that less decisional conflict was reported by patients with better global health status (β = −0.185, p = 0.018), higher satisfaction (β = −0.246, p = 0.002), and who made the decision before (β = −0.543, p < 0.001) or within a week after the consultation (β = −0.427, p < 0.001). These variables explained 37% of the variance in decisional conflict. Healthcare professionals should realize that patients with lower global health status and who need more time to decide may require additional support. Although altering such patient intrinsic characteristics is difficult, oncologists can impact the satisfaction with the consultation. Future research should verify whether effective patient-centered communication could prevent decisional conflict.
Cytopenia after CAR-T Cell Therapy—A Brief Review of a Complex Problem
Authors: Sharma Naman , Reagan Patrick M. , Liesveld Jane L.
Published: March 2022

Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has emerged as an efficacious and life extending treatment modality with high response rates and durable remissions in patients with relapsed and refractory non-Hodgkin lymphoma (NHL), follicular lymphoma, and B-cell acute lymphoblastic leukemia (B-ALL) as well as in other diseases. Prolonged or recurrent cytopenias after CAR-T therapy have increasingly been reported at varying rates, and the pathogenesis of this complication is not yet well-understood but is likely contributed to by multiple factors. Current studies reported are primarily retrospective, heterogeneous in terms of CAR-Ts used and diseases treated, non-uniform in definitions of cytopenias and durations for end points, and vary in terms of recommended management. Prospective studies and correlative laboratory studies investigating the pathophysiology of prolonged cytopenias will enhance our understanding of this phenomenon. This review summarizes knowledge of these cytopenias to date.
Systemic Treatments for Advanced Small Bowel Adenocarcinoma: A Systematic Review
Authors: Di Nardo Paola , Garattini Silvio Ken , Torrisi Elena , Fanotto Valentina , Miolo Gianmaria , Buonadonna Angela , Puglisi Fabio
Published: March 2022

Small bowel adenocarcinoma (SBA) is a rare disease for which scarce evidence is available. We summarized data available on systemic treatment of advanced SBA. Methods: Scientific literature was evaluated to find phase II or phase III clinical trials on systemic treatment for advanced SBA. MeSH terms were selected and combined for the initial search, then inclusion and exclusion criteria were set in a search protocol. Four medical oncologists looked for evidence on Medline, EMBASE and Cochrane databases. Moreover, abstracts from 2016 to June 2021 from the American Society for Clinical Oncology, European Society for Medical Oncology, Gastrointestinal Cancer Symposium and World Congress on Gastrointestinal Cancer were browsed. The selected studies, matching the inclusion and exclusion criteria, were finally tabulated and analyzed. Results: The trials finally selected were 18 phase II/III clinical trials. Four small phase II trials support the activity of oxaliplatin-based doublets in first-line treatment (CAPOX and mFOLFOX). Conclusion: No good level evidence is available on the use of bevacizumab, anti-epidermal growth factor receptor, targeted agents or immunotherapy. First-line treatments are largely derived from colorectal cancer protocols, mainly oxaliplatin-based doublets.
Development of Low-Grade Serous Ovarian Carcinoma from Benign Ovarian Serous Cystadenoma Cells
Authors: Dey Puja , Nakayama Kentaro , Razia Sultana , Ishikawa Masako , Ishibashi Tomoka , Yamashita Hitomi , Kanno Kosuke , Sato Seiya , Kiyono Tohru , Kyo Satoru
Published: March 2022

Despite the knowledge about numerous genetic mutations essential for the progression of low-grade serous ovarian carcinoma (LGSOC), the specific combination of mutations required remains unclear. Here, we aimed to recognize the oncogenic mutations responsible for the stepwise development of LGSOC using immortalized HOVs-cyst-1 cells, developed from ovarian serous cystadenoma cells, and immortalized via cyclin D1, CDK4R24C, and hTERT gene transfection. Furthermore, oncogenic mutations, KRAS and PIK3CA, were individually and simultaneously introduced in immortalized HOV-cyst-1 cells. Cell functions were subsequently analyzed via in vitro assays. KRAS or PIK3CA double mutant HOV-cyst-1 cells exhibited higher cell proliferation and migration capacity than the wild-type cells, or those with either a KRAS or a PIK3CA mutation, indicating that these mutations play a causative role in LGSOC tumorigenesis. Moreover, KRAS and PIK3CA double mutants gained tumorigenic potential in nude mice, whereas the cells with a single mutant exhibited no signs of tumorigenicity. Furthermore, the transformation of HOV-cyst-1 cells with KRAS and PIK3CA mutants resulted in the development of tumors that were grossly and histologically similar to human LGSOCs. These findings suggest that simultaneous activation of the KRAS/ERK and PIK3CA/AKT signaling pathways is essential for LGSOC development.
Expression of PD-1, PD-L1 and PD-L2 in Lymphomas in Patients with Pre-Existing Rheumatic Diseases—A Possible Association with High Rheumatoid Arthritis Disease Activity
Authors: Hellbacher Erik , Sundström Christer , Molin Daniel , Baecklund Eva , Hollander Peter
Published: March 2022

Current research seeks to identify subgroups of non-Hodgkin lymphoma (NHL) patients responsive to PD-1 blocking agents. Whether patients with pre-existing rheumatic diseases might constitute such a subgroup is unknown. We determined intratumoral expression of PD-1 and its ligands in lymphoma patients with pre-existing rheumatic diseases. We included 215 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or Sjögren’s syndrome with subsequent lymphoma and 74 diffuse large B-cell lymphoma (DLBCL) controls without rheumatic disease. PD-1 and PD-ligand immunohistochemical markers were applied on tumor tissue microarrays. The number of PD-1+ tumor infiltrating leukocytes (TILs) and proportions of PD-L1+ and PD-L2+ tumor cells and TILs were calculated and correlated with clinical data. Expression of PD-L1 in tumor cells and TILs was highest in classical Hodgkin lymphoma and DLBCL. In DLBCLs, expression of PD-1 in TILs and PD-L1 in tumor cells was similar in RA, SLE and controls. In RA-DLBCL, high expression of PD-L1 in tumor cells was significantly more common in patients with the most severe RA disease and was associated with inferior overall survival in multivariable analysis.
Distinct Genomic Profiles Are Associated with Treatment Response and Survival in Ovarian Cancer
Authors: de Witte Chris J. , Kutzera Joachim , van Hoeck Arne , Nguyen Luan , Boere Ingrid A. , Jalving Mathilde , Ottevanger Petronella B. , van Schaik-van de Mheen Christa , Stevense Marion , Kloosterman Wigard P. , Zweemer Ronald P. , Cuppen Edwin , Witteveen Petronella O.
Published: March 2022

The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment.