bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Adaptive Response of Pseudomonas aeruginosa to Clindamycin/Rifampicin-Impregnated Catheters
Authors: Sung Kidon , Chon Jungwhan , Kweon Ohgew , Nho Seongwon , Kim Seongjae , Park Miseon , Paredes Angel , Lim Jin-Hee , Khan Saeed A. , Phillips Kenneth Scott , Cerniglia Carl E.
Published: June 2021

Pseudomonas aeruginosa is the most common Gram-negative pathogen causing nosocomial multidrug resistant infections. It is a good biofilm producer and has the potential for contaminating medical devices. Despite the widespread use of antibacterial-impregnated catheters, little is known about the impacts of antibacterial coating on the pathogenesis of P. aeruginosa. In this study, we investigated the adaptive resistance potential of P. aeruginosa strain PAO1 in response to continuous antibiotic exposure from clindamycin/rifampicin-impregnated catheters (CR-IC). During exposure for 144 h to clindamycin and rifampicin released from CR-IC, strain PAO1 formed biofilms featuring elongated and swollen cells. There were 545 and 372 differentially expressed proteins (DEPs) identified in the planktonic and biofilm cells, respectively, by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Both Cluster of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the planktonic cells responded to the released antibiotics more actively than the biofilm cells, with metabolism and ribosomal biosynthesis-associated proteins being significantly over-expressed. Exposure to CR-IC increased the invasion capability of P. aeruginosa for Hela cells and upregulated the expression of certain groups of virulence proteins in both planktonic and biofilm cells, including the outer membrane associated (flagella, type IV pili and type III secretion system) and extracellular (pyoverdine) virulence proteins. Continuous exposure of P. aeruginosa to CR-IC also induced the overexpression of antibiotic resistance proteins, including porins, efflux pumps, translation and transcription proteins. However, these upregulations did not change phenotypic minimum inhibitory concentration (MIC) during the experimental timeframe. The concerning association between CR-IC and overexpression of virulence factors in P. aeruginosa suggests the need for additional investigation to determine if it results in adverse clinical outcomes.
Antimicrobial Resistance Determinants in Genomes and Plasmids from Acinetobacter baumannii Clinical Isolates
Authors: Chapartegui-González Itziar , Lázaro-Díez María , Redondo-Salvo Santiago , Navas Jesús , Ramos-Vivas José
Published: June 2021

Acinetobacter baumannii is a Gram-negative coccoid rod species, clinically relevant as a human pathogen, included in the ESKAPE group. Carbapenem-resistant A. baumannii (CRAB) are considered by the World Health Organization (WHO) as a critical priority pathogen for the research and development of new antibiotics. Some of the most relevant features of this pathogen are its intrinsic multidrug resistance and its ability to acquire rapid and effective new resistant determinants against last-resort clinical antibiotics, mostly from other ESKAPE species. The presence of plasmids and mobile genetic elements in their genomes contributes to the acquisition of new antimicrobial resistance determinants. However, although A. baumannii has arisen as an important human pathogen, information about these elements is still not well understood. Current genomic analysis availability has increased our ability to understand the microevolution of bacterial pathogens, including point mutations, genetic dissemination, genomic stability, and pan- and core-genome compositions. In this work, we deeply studied the genomes of four clinical strains from our hospital, and the reference strain ATCC®19606TM, which have shown a remarkable ability to survive and maintain their effective capacity when subjected to long-term stress conditions. With that, our aim was presenting a detailed analysis of their genomes, including antibiotic resistance determinants and plasmid composition.
CRISPR-Cas, a Revolution in the Treatment and Study of ESKAPE Infections: Pre-Clinical Studies
Authors: González de Aledo Manuel , González-Bardanca Mónica , Blasco Lucía , Pacios Olga , Bleriot Inés , Fernández-García Laura , Fernández-Quejo Melisa , López María , Bou Germán , Tomás María
Published: June 2021

One of the biggest threats we face globally is the emergence of antimicrobial-resistant (AMR) bacteria, which runs in parallel with the lack in the development of new antimicrobials. Among these AMR bacteria pathogens belonging to the ESKAPE group can be highlighted (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) due to their profile of drug resistance and virulence. Therefore, innovative lines of treatment must be developed for these bacteria. In this review, we summarize the different strategies for the treatment and study of molecular mechanisms of AMR in the ESKAPE pathogens based on the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins’ technologies: loss of plasmid or cellular viability, random mutation or gene deletion as well directed mutations that lead to a gene’s loss of function.
Probiotic Potential of a Novel Vitamin B2-Overproducing Lactobacillus plantarum Strain, HY7715, Isolated from Kimchi
Authors: Kim Joo-Yun , Choi Eun-Jung , Lee Jae-Ho , Yoo Myeong-Seok , Heo Keon , Shim Jae-Jung , Lee Jung-Lyoul
Published: June 2021

Vitamin B2, also known as riboflavin, is essential for maintaining human health. The purpose of this study was to isolate novel lactic acid bacteria that overproduce vitamin B2 and to validate their potential as probiotics. In this study, Lactobacillus plantarum HY7715 (HY7715) was selected among lactic acid bacteria isolated from Kimchi. HY7715 showed a very high riboflavin-producing ability compared to the control strain due to the high expression of ribA, ribB, ribC, ribH, and ribG genes. HY7715 produced 34.5 ± 2.41 mg/L of riboflavin for 24 h without consuming riboflavin in the medium under optimal growth conditions. It was able to produce riboflavin in an in vitro model of the intestinal environment. In addition, when riboflavin deficiency was induced in mice through nutritional restriction, higher levels of riboflavin were detected in plasma and urine in the HY7715 administration group than in the control group. HY7715 showed high survival rate in simulated gastrointestinal conditions and had antibiotic resistance below the cutoff MIC value suggested by the European Food Safety Authority; moreover, it did not cause hemolysis. In conclusion, HY7715 could be considered a beneficial probiotic strain for human and animal applications, suggesting that it could be a new alternative to address riboflavin deficiency.
Decision-Tree-Based Classification of Lifetime Maximum Intensity of Tropical Cyclones in the Tropical Western North Pacific
Authors: Kim Sung-Hun , Moon Il-Ju , Won Seong-Hee , Kang Hyoun-Woo , Kang Sok Kuh
Published: June 2021

The National Typhoon Center of the Korea Meteorological Administration developed a statistical–dynamical typhoon intensity prediction model for the western North Pacific, the CSTIPS-DAT, using a track-pattern clustering technique. The model led to significant improvements in the prediction of the intensity of tropical cyclones (TCs). However, relatively large errors have been found in a cluster located in the tropical western North Pacific (TWNP), mainly because of the large predictand variance. In this study, a decision-tree algorithm was employed to reduce the predictand variance for TCs in the TWNP. The tree predicts the likelihood of a TC reaching a maximum lifetime intensity greater than 70 knots at its genesis. The developed four rules suggest that the pre-existing ocean thermal structures along the track and the latitude of a TC’s position play significant roles in the determination of its intensity. The developed decision-tree classification exhibited 90.0% and 80.5% accuracy in the training and test periods, respectively. These results suggest that intensity prediction with the CSTIPS-DAT can be further improved by developing independent statistical models for TC groups classified by the present algorithm.
Reduced Temperature Sensitivity of Maximum Latewood Density Formation in High-Elevation Corsican Pines under Recent Warming
Authors: Römer Philipp , Hartl Claudia , Schneider Lea , Bräuning Achim , Szymczak Sonja , Huneau Frédéric , Lebre Sébastien , Reinig Frederick , Büntgen Ulf , Esper Jan
Published: June 2021

Maximum latewood density (MXD) measurements from long-lived Black pines (Pinus nigra spp. laricio) growing at the upper treeline in Corsica are one of the few archives to reconstruct southern European summer temperatures at annual resolution back into medieval times. Here, we present a compilation of five MXD chronologies from Corsican pines that contain high-to-low frequency variability between 1168 and 2016 CE and correlate significantly (p < 0.01) with the instrumental April–July and September–October mean temperatures from 1901 to 1980 CE (r = 0.52−0.64). The growth–climate correlations, however, dropped to −0.13 to 0.02 afterward, and scaling the MXD data resulted in a divergence of >1.5 °C between the colder reconstructed and warmer measured temperatures in the early-21st century. Our findings suggest a warming-induced shift from initially temperature-controlled to drought-prone MXD formation, and therefore question the suitability of using Corsican pine MXD data for climate reconstruction.
Solutions for Several Quadratic Trinomial Difference Equations and Partial Differential Difference Equations in C2
Authors: Li Hong , Xu Hongyan
Published: June 2021

This article is to investigate the existence of entire solutions of several quadratic trinomial difference equations f(z+c)2+2αf(z)f(z+c)+f(z)2=eg(z), and the partial differential difference equations f(z+c)2+2αf(z+c)∂f(z)∂z1+∂f(z)∂z12=eg(z),f(z+c)2+2αf(z+c)∂f(z)∂z1+∂f(z)∂z2+∂f(z)∂z1+∂f(z)∂z22=eg(z). We establish some theorems about the forms of the finite order transcendental entire solutions of these functional equations. We also list a series of examples to explain the existence of the finite order transcendental entire solutions of such equations. Meantime, some examples show that there exists a very significant difference with the previous literature on the growth order of the finite order transcendental entire solutions. Our results show that some functional equations can admit the transcendental entire solutions with any positive integer order. These results make a few improvements of the previous theorems given by Xu and Cao, Liu and Yang.
Some New Observations for F-Contractions in Vector-Valued Metric Spaces of Perov’s Type
Authors: Mirkov Nikola , Radenović Stojan , Radojević Slobodan
Published: June 2021

The main purpose of this article is to improve, generalize and complement some recently established results for Perov’s type F-contractions. In our approach, we use only the property (F1) of Wardowski while other authors employed all three conditions. Working only with the fact that the function F is strictly increasing on 0,+∞m, we obtain as a consequence new families of contractive conditions in the realm of vector-valued metric spaces of Perov’s type. At the end of the article, we present an example that supports obtained theoretical results and genuinely generalizes several known results in existing literature.
Logic-Sensitivity of Aristotelian Diagrams in Non-Normal Modal Logics
Authors: Demey Lorenz
Published: June 2021

Aristotelian diagrams, such as the square of opposition, are well-known in the context of normal modal logics (i.e., systems of modal logic which can be given a relational semantics in terms of Kripke models). This paper studies Aristotelian diagrams for non-normal systems of modal logic (based on neighborhood semantics, a topologically inspired generalization of relational semantics). In particular, we investigate the phenomenon of logic-sensitivity of Aristotelian diagrams. We distinguish between four different types of logic-sensitivity, viz. with respect to (i) Aristotelian families, (ii) logical equivalence of formulas, (iii) contingency of formulas, and (iv) Boolean subfamilies of a given Aristotelian family. We provide concrete examples of Aristotelian diagrams that illustrate these four types of logic-sensitivity in the realm of normal modal logic. Next, we discuss more subtle examples of Aristotelian diagrams, which are not sensitive with respect to normal modal logics, but which nevertheless turn out to be highly logic-sensitive once we turn to non-normal systems of modal logic.
Biochemical and Molecular Aspects of Phosphorus Limitation in Diatoms and Their Relationship with Biomolecule Accumulation
Authors: Lovio-Fragoso José Pablo , de Jesús-Campos Damaristelma , López-Elías José Antonio , Medina-Juárez Luis Ángel , Fimbres-Olivarría Diana , Hayano-Kanashiro Corina
Published: June 2021

Diatoms are the most abundant group of phytoplankton, and their success lies in their significant adaptation ability to stress conditions, such as nutrient limitation. Phosphorus (P) is a key nutrient involved in the transfer of energy and the synthesis of several cellular components. Molecular and biochemical mechanisms related to how diatoms cope with P deficiency are not clear, and research into this has been limited to a few species. Among the molecular responses that have been reported in diatoms cultured under P deficient conditions is the upregulation of genes encoding enzymes related to the transport, assimilation, remobilization and recycling of this nutrient. Regarding biochemical responses, due to the reduction of the requirements for carbon structures for the synthesis of proteins and phospholipids, more CO2 is fixed than is consumed by the Calvin cycle. To deal with this excess, diatoms redirect the carbon flow toward the synthesis of storage compounds such as triacylglycerides and carbohydrates, which are excreted as extracellular polymeric substances. This review aimed to gather all current knowledge regarding the biochemical and molecular mechanisms of diatoms related to managing P deficiency in order to provide a wider insight into and understanding of their responses, as well as the metabolic pathways affected by the limitation of this nutrient.
Prognostic Impact of BRCA1 and BRCA2 Mutations on Long-Term Survival Outcomes in Egyptian Female Breast Cancer Patients
Authors: AbdelHamid Sherihan , El-Mesallamy Hala , Aziz Hany Abdel , Zekri Abdel-Rahman
Published: June 2021

Evidence on the prognostic relevance of BRCA1/2 mutations on breast cancer survival is still debatable. To address this ambiguity, we sought to elucidate the impact of BRCA1/2 mutation carriership on long-term clinical outcomes for the first time in Egyptian female breast cancer patients. This study comprised 103 Egyptian female breast cancer patients previously tested for BRCA1/2 mutations. Clinicopathological characteristics and long-term follow-up data were retrieved from clinical records until death or loss to follow-up. Overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), and metastasis-free survival (MFS) were compared in BRCA1/2 mutation carriers and non-carriers. Pathogenic variants (Class 5 according to ACMG/AMP guidelines) were observed in 29 cases. The profile of the detected variants was previously reported. After median follow-up time of 6.9 years (range, 4.2–24.4 years), BRCA1/2 carriers exhibited significantly worse RFS compared to non-carriers (p = 0.01; HR = 3.00 (95%CI 1.35–6.68)). However, we couldn’t demonstrate statistically significant difference between carriers of pathogenic mutations and non-carriers regarding MFS (p = 0.24; HR = 1.38 (95%CI 0.8–2.4)), DFS (p = 0.11; HR = 1.23 (95%CI 0.74–2.06)), or OS (p = 0.36; HR = 1.23 (95%CI 0.58–2.61)). Though no significant impact was observed in OS, yet BRCA1/2 mutation carriers were at high risk of recurrence, highlighting the importance of adopting BRCA screening strategies and prophylactic measures.
Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis
Authors: Yuan Yuan , Zhai Yanyu , Chen Jingjiong , Xu Xiaofeng , Wang Hongmei
Published: June 2021

Kaempferol has been shown to protect cells against cerebral ischemia/reperfusion injury through inhibition of apoptosis. In the present study, we sought to investigate whether ferroptosis is involved in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal injury and the effects of kaempferol on ferroptosis in OGD/R-treated neurons. Western blot, immunofluorescence, and transmission electron microscopy were used to analyze ferroptosis, whereas cell death was detected using lactate dehydrogenase (LDH) release. We found that OGD/R attenuated SLC7A11 and glutathione peroxidase 4 (GPX4) levels as well as decreased endogenous antioxidants including nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and superoxide dismutase (SOD) in neurons. Notably, OGD/R enhanced the accumulation of lipid peroxidation, leading to the induction of ferroptosis in neurons. However, kaempferol activated nuclear factor-E2-related factor 2 (Nrf2)/SLC7A11/GPX4 signaling, augmented antioxidant capacity, and suppressed the accumulation of lipid peroxidation in OGD/R-treated neurons. Furthermore, kaempferol significantly reversed OGD/R-induced ferroptosis. Nevertheless, inhibition of Nrf2 by ML385 blocked the protective effects of kaempferol on antioxidant capacity, lipid peroxidation, and ferroptosis in OGD/R-treated neurons. These results suggest that ferroptosis may be a significant cause of cell death associated with OGD/R. Kaempferol provides protection from OGD/R-induced ferroptosis partly by activating Nrf2/SLC7A11/GPX4 signaling pathway.
Biosensors Designed for Clinical Applications
Authors: Rusling James F. , Forster Robert J.
Published: June 2021

Emerging and validated biomarkers promise to revolutionize clinical practice, shifting the emphasis away from the management of chronic disease towards prevention, early diagnosis and early intervention. The challenge of detecting these low abundance protein and nucleic acid biomarkers within the clinical context demands the development of highly sensitive, even single molecule, assays that are also capable of selectively measuring a small number of defined analytes in complex samples such as whole blood, interstitial fluid, saliva or urine. Success relies on significant innovations in nanomaterials, bioreceptor engineering, transduction strategies and microfluidics. Primarily using examples from our work, this article discusses some recent advance in the selective and sensitive detection of disease biomarkers, highlights key innovations in sensor materials and identifies issues and challenges that need to be carefully considered especially for researchers entering the field.
Efficacy of Facial Exercises in Facial Expression Categorization in Schizophrenia
Authors: Pancotti Francesco , Mele Sonia , Callegari Vincenzo , Bivi Raffaella , Saracino Francesca , Craighero Laila
Published: June 2021

Embodied cognition theories suggest that observation of facial expression induces the same pattern of muscle activation, and that this contributes to emotion recognition. Consequently, the inability to form facial expressions would affect emotional understanding. Patients with schizophrenia show a reduced ability to express and perceive facial emotions. We assumed that a physical training specifically developed to mobilize facial muscles could improve the ability to perform facial movements, and, consequently, spontaneous mimicry and facial expression recognition. Twenty-four inpatient participants with schizophrenia were randomly assigned to the experimental and control group. At the beginning and at the end of the study, both groups were submitted to a facial expression categorization test and their data compared. The experimental group underwent a training period during which the lip muscles, and the muscles around the eyes were mobilized through the execution of transitive actions. Participants were trained three times a week for five weeks. Results showed a positive impact of the physical training in the recognition of others’ facial emotions, specifically for the responses of “fear”, the emotion for which the recognition deficit in the test is most severe. This evidence suggests that a specific deficit of the sensorimotor system may result in a specific cognitive deficit.
Circulating Tumor DNA as a Marker for Treatment Response in Metastatic Melanoma Patients Using Next-Generation Sequencing—A Prospective Feasibility Study
Authors: Berger Marina , Thueringer Andrea , Franz Doritt , Dandachi Nadia , Talakić Emina , Richtig Georg , Richtig Erika , Rohrer Peter Michael , Koch Lukas , Wolf Ingrid Hildegard , Koch Catharina , Rainer Barbara Margaretha , Koeller Maximilian , Pichler Martin , Gerritsmann Hanno , Kashofer Karl , Aigelsreiter Ariane
Published: June 2021

We prospectively performed a longitudinal analysis of circulating tumor DNA (ctDNA) from 149 plasma samples and CT scans in Stage III and IV metastatic melanoma patients (n = 20) treated with targeted agents or immunotherapy using two custom next-generation sequencing (NGS) Ion AmpliSeq™ HD panels including 60 and 81 amplicons in 18 genes, respectively. Concordance of matching cancer-associated mutations in tissue and plasma was 73.3%. Mutant allele frequency (MAF) levels showed a range from 0.04% to 28.7%, well detectable with NGS technologies utilizing single molecule tagging like the AmpliSeq™ HD workflow. Median followup time of the tissue and/or plasma positive cohort (n = 15) was 24.6 months and median progression-free survival (PFS) was 7.8 months. Higher MAF ≥ 1% at baseline was not significantly associated with a risk of progression (Odds Ratio = 0.15; p = 0.155). Although a trend could be seen, MAF levels did not differ significantly over time between patients with and without a PFS event (p = 0.745). Depending on the cell-free DNA amount, NGS achieved a sensitivity down to 0.1% MAF and allowed for parallel analysis of multiple mutations and previously unknown mutations. Our study indicates that NGS gene panels could be useful for monitoring disease burden during therapy with ctDNA in melanoma patients.
Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β
Authors: Kaushal Jyoti , Bhatia Rakesh , Kanchan Ranjana , Raut Pratima , Mallapragada Surya , Ly Quan , Batra Surinder , Rachagani Satyanarayana
Published: June 2021

Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.
Discovering Digital Tumor Signatures—Using Latent Code Representations to Manipulate and Classify Liver Lesions
Authors: Kleesiek Jens , Kersjes Benedikt , Ueltzhöffer Kai , Murray Jacob M. , Rother Carsten , Köthe Ullrich , Schlemmer Heinz-Peter
Published: June 2021

Modern generative deep learning (DL) architectures allow for unsupervised learning of latent representations that can be exploited in several downstream tasks. Within the field of oncological medical imaging, we term these latent representations “digital tumor signatures” and hypothesize that they can be used, in analogy to radiomics features, to differentiate between lesions and normal liver tissue. Moreover, we conjecture that they can be used for the generation of synthetic data, specifically for the artificial insertion and removal of liver tumor lesions at user-defined spatial locations in CT images. Our approach utilizes an implicit autoencoder, an unsupervised model architecture that combines an autoencoder and two generative adversarial network (GAN)-like components. The model was trained on liver patches from 25 or 57 inhouse abdominal CT scans, depending on the experiment, demonstrating that only minimal data is required for synthetic image generation. The model was evaluated on a publicly available data set of 131 scans. We show that a PCA embedding of the latent representation captures the structure of the data, providing the foundation for the targeted insertion and removal of tumor lesions. To assess the quality of the synthetic images, we conducted two experiments with five radiologists. For experiment 1, only one rater and the ensemble-rater were marginally above the chance level in distinguishing real from synthetic data. For the second experiment, no rater was above the chance level. To illustrate that the “digital signatures” can also be used to differentiate lesion from normal tissue, we employed several machine learning methods. The best performing method, a LinearSVM, obtained 95% (97%) accuracy, 94% (95%) sensitivity, and 97% (99%) specificity, depending on if all data or only normal appearing patches were used for training of the implicit autoencoder. Overall, we demonstrate that the proposed unsupervised learning paradigm can be utilized for the removal and insertion of liver lesions at user defined spatial locations and that the digital signatures can be used to discriminate between lesions and normal liver tissue in abdominal CT scans.
A Prediction Model for Severe Complications after Elective Colorectal Cancer Surgery in Patients of 70 Years and Older
Authors: Souwer Esteban T. D. , Bastiaannet Esther , Steyerberg Ewout W. , Dekker Jan Willem T. , Steup Willem H. , Hamaker Marije M. , Sonneveld Dirk J. A. , Burghgraef Thijs A. , van den Bos Frederiek , Portielje Johanna E. A.
Published: June 2021

Introduction Older patients have an increased risk of morbidity and mortality after colorectal cancer (CRC) surgery. Existing CRC surgical prediction models have not incorporated geriatric predictors, limiting applicability for preoperative decision-making. The objective was to develop and internally validate a predictive model based on preoperative predictors, including geriatric characteristics, for severe postoperative complications after elective surgery for stage I–III CRC in patients ≥70 years. Patients and Methods: A prospectively collected database contained 1088 consecutive patients from five Dutch hospitals (2014–2017) with 171 severe complications (16%). The least absolute shrinkage and selection operator (LASSO) method was used for predictor selection and prediction model building. Internal validation was done using bootstrapping. Results: A geriatric model that included gender, previous DVT or pulmonary embolism, COPD/asthma/emphysema, rectal cancer, the use of a mobility aid, ADL assistance, previous delirium and polypharmacy showed satisfactory discrimination with an AUC of 0.69 (95% CI 0.73–0.64); the AUC for the optimism corrected model was 0.65. Based on these predictors, the eight-item colorectal geriatric model (GerCRC) was developed. Conclusion: The GerCRC is the first prediction model specifically developed for older patients expected to undergo CRC surgery. Combining tumour- and patient-specific predictors, including geriatric predictors, improves outcome prediction in the heterogeneous older population.
Recent Advances on the Pathobiology and Treatment of Multiple Myeloma
Authors: Amodio Nicola
Published: June 2021

Worldwide experts in the field of multiple myeloma (MM) have promptly answered to the call in the Special Issue entitled “Recent advances on the pathobiology and treatment of multiple myeloma”, submitting basic, translational or clinical works under the form of original article, review or perspective [...]
BRENDA-Score, a Highly Significant, Internally and Externally Validated Prognostic Marker for Metastatic Recurrence: Analysis of 10,449 Primary Breast Cancer Patients
Authors: Wischnewsky Manfred , Schwentner Lukas , Diessner Joachim , de Gregorio Amelie , Joukhadar Ralf , Davut Dayan , Salmen Jessica , Bekes Inga , Kiesel Matthias , Müller-Reiter Max , Blettner Maria , Wolters Regine , Janni Wolfgang , Kreienberg Rolf , Wöckel Achim , Ebner Florian
Published: June 2021

Background Current research in breast cancer focuses on individualization of local and systemic therapies with adequate escalation or de-escalation strategies. As a result, about two-thirds of breast cancer patients can be cured, but up to one-third eventually develop metastatic disease, which is considered incurable with currently available treatment options. This underscores the importance to develop a metastatic recurrence score to escalate or de-escalate treatment strategies. Patients and methods Data from 10,499 patients were available from 17 clinical cancer registries (BRENDA-project. In total, 8566 were used to develop the BRENDA-Index. This index was calculated from the regression coefficients of a Cox regression model for metastasis-free survival (MFS). Based on this index, patients were categorized into very high, high, intermediate, low, and very low risk groups forming the BRENDA-Score. Bootstrapping was used for internal validation and an independent dataset of 1883 patients for external validation. The predictive accuracy was checked by Harrell’s c-index. In addition, the BRENDA-Score was analyzed as a marker for overall survival (OS) and compared to the Nottingham prognostic score (NPS). Results: Intrinsic subtypes, tumour size, grading, and nodal status were identified as statistically significant prognostic factors in the multivariate analysis. The five prognostic groups of the BRENDA-Score showed highly significant (p < 0.001) differences regarding MFS:low risk: hazard ratio (HR) = 2.4, 95%CI (1.7–3.3); intermediate risk: HR = 5.0, 95%CI.(3.6–6.9); high risk: HR = 10.3, 95%CI (7.4–14.3) and very high risk: HR = 18.1, 95%CI (13.2–24.9). The external validation showed congruent results. A multivariate Cox regression model for OS with BRENDA-Score and NPS as covariates showed that of these two scores only the BRENDA-Score is significant (BRENDA-Score p < 0.001; NPS p = 0.447). Therefore, the BRENDA-Score is also a good prognostic marker for OS. Conclusion: The BRENDA-Score is an internally and externally validated robust predictive tool for metastatic recurrence in breast cancer patients. It is based on routine parameters easily accessible in daily clinical care. In addition, the BRENDA-Score is a good prognostic marker for overall survival. Highlights: The BRENDA-Score is a highly significant predictive tool for metastatic recurrence of breast cancer patients. The BRENDA-Score is stable for at least the first five years after primary diagnosis, i.e., the sensitivities and specificities of this predicting system is rather similar to the NPI with AUCs between 0.76 and 0.81 the BRENDA-Score is a good prognostic marker for overall survival.
Hymenoptera Venom Immunotherapy: Immune Mechanisms of Induced Protection and Tolerance
Authors: Demšar Luzar Ajda , Korošec Peter , Košnik Mitja , Zidarn Mihaela , Rijavec Matija
Published: June 2021

Hymenoptera venom allergy is one of the most severe allergic diseases, with a considerable prevalence of anaphylactic reaction, making it potentially lethal. In this review, we provide an overview of the current knowledge and recent findings in understanding induced immune mechanisms during different phases of venom immunotherapy. We focus on protection mechanisms that occur early, during the build-up phase, and on the immune tolerance, which occurs later, during and after Hymenoptera venom immunotherapy. The short-term protection seems to be established by the early desensitization of mast cells and basophils, which plays a crucial role in preventing anaphylaxis during the build-up phase of treatment. The early generation of blocking IgG antibodies seems to be one of the main reasons for the lower activation of effector cells. Long-term tolerance is reached after at least three years of venom immunotherapy. A decrease in basophil responsiveness correlates with tolerated sting challenge. Furthermore, the persistent decline in IgE levels and, by monitoring the cytokine profiles, a shift from a Th2 to Th1 immune response, can be observed. In addition, the generation of regulatory T and B cells has proven to be essential for inducing allergen tolerance. Most studies on the mechanisms and effectiveness data have been obtained during venom immunotherapy (VIT). Despite the high success rate of VIT, allergen tolerance may not persist for a prolonged time. There is not much known about immune mechanisms that assure long-term tolerance post-therapy.
Immunoproteasome Function in Normal and Malignant Hematopoiesis
Authors: Tubío-Santamaría Nuria , Ebstein Frédéric , Heidel Florian H. , Krüger Elke
Published: June 2021

The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.
Live Fluorescence Imaging of F-Actin Organization in Chick Whole Embryo Cultures Using SiR-Actin
Authors: Schmitz-Elbers Manuel , Lukinavičius Gražvydas , Smit Theodoor H.
Published: June 2021

Morphogenesis is a continuous process of pattern formation so complex that it requires in vivo monitoring for better understanding. Changes in tissue shape are initiated at the cellular level, where dynamic intracellular F-actin networks determine the shape and motility of cells, influence differentiation and cytokinesis and mediate mechanical signaling. Here, we stain F-actin with the fluorogenic probe SiR-actin for live fluorescence imaging of whole chick embryos. We found that 50 nM SiR-actin in the culture medium is a safe and effective concentration for this purpose, as it provides high labeling density without inducing morphological malformations.
CD44 Sorted Cells Have an Augmented Potential for Proliferation, Epithelial-Mesenchymal Transition, Stemness, and a Predominantly Inflammatory Cytokine and Angiogenic Secretome
Authors: Patil Shankargouda
Published: June 2021

Cancer stem cells (CSCs) have garnered attention with their potential for early diagnosis and prognosis of oral squamous cell carcinoma (OSCC). It is still indistinct whether CSCs are recognized with a specific set of characteristics. The present study aimed to assess the association of CD44 with stemness-related, Epithelial Mesenchymal Transition EMT-related genes and the secretome of the CSCs. The single-cell suspension from primary OSCC tumors was prepared by enzymatic digestion and the cells were cultured in-vitro. The cancer stem cells were isolated by CD44+ selection using magnetic cell-sorting. The expression of CD44, proliferation rate, gene expression of EMT-related transcription factors, stemness markers, cytokine levels and angiogenic factors in both cell population was assessed. The sorted CD44+ cells showed significantly higher proliferation rate than heterogenous population. The CD44 expression was >90% in the sorted cells which was higher than the heterogenous cells. The CD44+ CSCs cells demonstrated significant increased levels of EMT-related genes TWIST1 and CDH2 (N-cadherin), CSC-related genes CD44 and CD133 (PROM1), stemness-related genes OCT4, SOX2, inflammatory cytokines IL-1ß, IL-12, IL-18 and TNF-α and angiogenic factors Angiopoietin-1, Angiopoietin-2, bFGF and VEGF while levels of epithelial gene CDH1 (E-cadherin) decreased in comparison to mixed cell population. The genetic and secretome profiling of the CD44+ CSCs could serve as diagnostic and prognostic tools in the treatment of oral cancers.
Reply to Astarita et al. Comment on “Celentano et al. Suitability of a Progenitor Cell-Enriching Device for In Vitro Applications. Coatings 2021, 11, 146”
Authors: Celentano Antonio , Yap Tami , Pantaleo Giuseppe , Paolini Rita , McCullough Michael , Cirillo Nicola
Published: June 2021

We would like to thank HBW representatives for their comments [...]
Facile Synthesis of Copper(I) Oxide Nanochains and the Photo-Thermal Conversion Performance of Its Nanofluids
Authors: Ni Zhongjin , Cao Xiaohai , Wang Xinyi , Zhou Shiyu , Zhang Caixia , Xu Bin , Ni Yihua
Published: June 2021

In this thesis, Cu2O nanochains were synthesized by thermal decomposition with copper formate-octylamine as the precursor, oleic acid and oleylamine as the catalyst stabilizer agent and paraffin as the solvent. The phase structure and micromorphology of Cu2O nanochains were characterized by X-ray diffraction and transmission electron microscopy. The effect of reaction time and concentration of the precursor on the Cu2O nanochains were discussed, and the formation mechanism of the Cu2O nanochains was analyzed. The results show that Cu2O nanochains were self-assembled by Cu2O nanocrystals; with the extension of the reaction time, Cu2O nanochains gradually become granular; increasing the concentration of the precursor will increase the entanglement degree of the nanochains. Oleic acid contributes to the formation of Cu2O, and oleylamine plays a directional role in the formation of nanochains. On the basis of those phenomenon, a comparison of the Cu2O nanochain-water nanofluids with that of a water-based liquid showed that after irradiating for 3000 s, the temperature of nanofluids reached 91.1 °C while the water was only 75.7 °C. This demonstrates the better performance of the Cu2O nanochain-water nanofluid in the ability of light absorption, thermal conductivity and photothermal conversion.
The Impact of Titanium Dioxide Type Combined with Coffee Oil Obtained from Coffee Industry Waste on Sunscreen Product Performance
Authors: Chiari-Andréo Bruna G. , Marto Joana , Ascenso Andreia , Carneiro Carlos , Rodríguez Laura , Guillot Antonio José , Garrigues Teresa M. , Ribeiro Helena M. , Melero Ana , Isaac Vera
Published: June 2021

(1) Background: Titanium dioxide (TiO2) consists of three polymorphs, including anatase, rutile and brookite. This work aimed to elucidate the influence of rutile and anatase forms in the performance of sunscreens formulated with green coffee oil (GCO) from coffee beans discarded in the agri-food industry. (2) Methods: TiO2 particles were characterized in terms of size and wettability. The sunscreens formulated with GCO were characterized regarding the droplet size, rheology, texture profile analysis (TPA), in vitro Sun Protection Factor and Water Resistance Retention. Topical delivery and permeation studies were performed to confirm caffeine release and skin penetration. (3) Results: Particle size distributions of rutile and anatase TiO2 particles were similar, however, smaller droplets as well as decreased viscosity and increased thixotropy were obtained for anatase TiO2 and GCO formulation compared to rutile form formulations. Notwithstanding, all formulations exhibited linear viscoelastic behavior. Regarding the TPA, a wide range of mechanical properties improved mainly by GCO rather than TiO2 form has been demonstrated. The influence of TiO2 form on UV protection was better evidenced in absence of GCO. The sunscreen formulations containing GCO presented a favorable topical delivery as confirmed by caffeine release and permeation. (4) Conclusions: Both TiO2 forms combined with GCO provided suitable properties including an effective ultraviolet (UV)-light protection.
Third-Age Learners and Approaches to Language Teaching
Authors: Kacetl Jaroslav , Klímová Blanka
Published: June 2021

Foreign language learning in the third age is one of the popular activities among the elderly. The question remains as to how to teach a foreign language to older adults properly. The first objective of this review was to identify suitable pedagogical approaches, teaching methods, or strategies for teaching foreign languages to third-age learners. The second objective was to determine whether foreign language learning later in life is beneficial. The authors used a method of literature review to achieve these goals. The former objective was not fully achieved as there is no clear outcome, although some generalizations based on other review studies can be made. Namely, foreign language teaching among the older generation should be student-centred and a communicative method should be implemented with a special focus on talking about familiar topics and listening comprehension to facilitate a senior’s foreign language learning. In addition, the teaching methods ought to incorporate real life experiences and provide relevant content. Respect should also be paid to the fact that older adults have intrinsic rather than extrinsic motivation to learn a foreign language. The latter objective was attained since older people can benefit from learning a foreign language at a later age in many ways, including areas like travelling, social inclusiveness, improvement of cognitive skills, and overall well-being.
Associative Learning of New Word Forms in a First Language (L1) and Haptic Referents in a Single-Day Experiment
Authors: Yang Yutao , Yan Yan , Ando Misa , Liu Xinyi , Kambara Toshimune
Published: June 2021

This study focused on the associative learning of new word forms in the first language and haptic stimuli. In this study, healthy Japanese participants performed three-step tasks. First, participants made nine subjective evaluations of haptic stimuli using five-point semantic differential scales (e.g., regarding stickiness, scored from 1 (not sticky) to 5 (sticky)). Second, the participants carried out learning and recognition tasks for associative pairs of new (meaningless) word forms in their first language (Japanese) and haptic stimulus (H condition), and performed learning and recognition tasks for new (meaningless) word forms only (W condition). The order of conditions was counterbalanced among participants. Third, participants performed free recall tasks. The results of the recognition tasks showed that the proportions and response times of the W condition were better and faster, respectively, than those of the H condition. Furthermore, preference of haptic features negatively correlated with free recall scores of the H condition; however, there was no significant difference between the free recall scores of the H and W conditions. Our results suggest that new word forms were learned better than associative pairs of new word forms and haptic stimuli in a single day of learning. Furthermore, the free recall performance of word forms associated with haptic features could also be affected by their subjective evaluation (preference).
Algorithms for Finding Vulnerabilities and Deploying Additional Sensors in a Region with Obstacles
Authors: Kim Kibeom , Lee Sunggu
Published: June 2021

Consider a two-dimensional rectangular region guarded by a set of sensors, which may be smart networked surveillance cameras or simpler sensor devices. In order to evaluate the level of security provided by these sensors, it is useful to find and evaluate the path with the lowest level of exposure to the sensors. Then, if desired, additional sensors can be placed at strategic locations to increase the level of security provided. General forms of these two problems are presented in this paper. Next, the minimum exposure path is found by first using the sensing limits of the sensors to compute an approximate “feasible area” of interest, and then using a grid within this feasible area to search for the minimum exposure path in a systematic manner. Two algorithms are presented for the minimum exposure path problem, and an additional subsequently executed algorithm is proposed for sensor deployment. The proposed algorithms are shown to require significantly lower computational complexity than previous methods, with the fastest proposed algorithm requiring O(n2.5) time, as compared to O(mn3) for a traditional grid-based search method, where n is the number of sensors, m is the number of obstacles, and certain assumptions are made on the parameter values.
BRNN-LSTM for Initial Access in Millimeter Wave Communications
Authors: Aldalbahi Adel , Shahabi Farzad , Jasim Mohammed
Published: June 2021

The use of beamforming technology in standalone (SA) millimeter wave communications results in directional transmission and reception modes at the mobile station (MS) and base station (BS). This results in initial beam access challenges, since the MS and BS are now compelled to perform spatial search to determine the best beam directions that return highest signal levels. The high number of signal measurements here prolongs access times and latencies, as well as increasing power and energy consumption. Hence this paper proposes a first study on leveraging deep learning schemes to simplify the beam access procedure in standalone mmWave networks. The proposed scheme combines bidirectional recurrent neural network (BRNN) and long short-term memory (LSTM) to achieve fast initial access times. Namely, the scheme predicts the best beam index for use in the next time step once a MS accesses the network, e.g., transition from sleep to active (or idle) modes. The scheme eliminates the need for beam scanning, thereby achieving ultra-low access times and energy efficiencies as compared to existing methods.