bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal Colonization of Preterm Neonates with Carbapenem Resistant Enterobacteria at Hospital Discharge
Authors: Mijac Vera , Brkic Snezana , Milic Marija , Siljic Marina , Cirkovic Valentina , Perovic Vladimir , Markovic Milos , Cirkovic Ivana , Stanojevic Maja
Published: February 2023

Our aim was to investigate gut colonization with carbapenem-resistant Enterobacterales (CRE) in the population of preterm neonates at discharge from a tertiary care center in Serbia. The study included 350 randomly selected neonates/infants discharged in the period April 2018–May 2019. CRE colonization was present in 88/350 (25.1%) of patients. Klebsiella pneumoniae producing KPC and OXA-48 carbapenemase were detected in 45 and 42 subjects, respectively, while NDM producing Escherichia coli was identified in one patient only. All OXA-48 strains harbored blaCTX-M-15, while both blaTEM and blaSHV were present in all but one KPC-producing strain. CRE isolates exhibited a multidrug resistance pattern with uniform fluoroquinolone resistance, universal susceptibility to colistin, and variable susceptibility to aminoglycosides. Administration of carbapenems was common (~50%) and it was strongly associated with colonization, as well as the combinational therapeutic regimens that included meropenem, contrary to ampicillin–sulbactam/colistin therapy and prolonged course of the initial therapy (ampicillin/amikacin ≥ 7 days). Other risk factors for CRE carriage were level of immaturity, admission to neonatal intensive care unit, prolonged hospitalization and invasive procedures. Although the rate of clinically and/or laboratory proven systemic infections was significantly higher among colonized patients, CRE infection was confirmed in one patient only (1.1%) that was colonized with NDM E. coli. Clonal relatedness of CRE isolates was high, with seven and eight clusters detected among KPC (N = 30) and OXA-48 (N = 37) producing strains, respectively. The follow up of the 31 KPC-colonized patients after discharge from hospital revealed common decolonization within one month (~68%). In conclusion, our results demonstrated a high rate of CRE colonization that is most likely related to carbapenem consumption and lack of screening as important infection prevention practice.
Appropriateness of Empirical Prescriptions of Ceftriaxone and Identification of Opportunities for Stewardship Interventions: A Single-Centre Cross-Sectional Study
Authors: Gorgulho Ana , Cunha Flávia , Alves Branco Elsa , Azevedo Ana , Almeida Francisco , Duro Raquel , Andrade Paulo , Rocha Pereira Nuno , Lima Alves Carlos
Published: February 2023

Third-generation cephalosporins are widely used due to the convenient spectrum of activity, safety, and posology. However, they are associated with the emergence of multidrug-resistant organisms, which makes them important targets for antimicrobial stewardship interventions. We aimed to assess the appropriateness of empirical prescriptions of ceftriaxone in a tertiary hospital. This cross-sectional study analysed empirical ceftriaxone prescriptions in January and June 2021. Patients under other antimicrobials 48 h before admission were excluded. The quality of ceftriaxone prescription was assessed regarding the initial appropriateness, duration of inappropriate ceftriaxone therapy, and missed opportunities for de-escalation. Of 465 prescriptions, 46.5% were inappropriate. The ceftriaxone prescription was inappropriate in 95.7% of lower respiratory tract infections (LRTI) globally and in nearly 40% of urinary tract infections (UTI) in medical and intensive care departments. Intensive care, internal medicine, and palliative care departments showed the highest number of inappropriate ceftriaxone prescriptions and longer length of inappropriate ceftriaxone prescriptions compared to the hospital’s average. Improvement of empirical ceftriaxone prescription in LRTI and urinary infections, adherence to local guidelines and de-escalation practices, and targeted interventions focusing on critical departments may significantly reduce the inappropriate empirical use of ceftriaxone.
Relationship between Glucose-6-Phosphate Dehydrogenase Deficiency, X-Chromosome Inactivation and Inflammatory Markers
Authors: Errigo Alessandra , Bitti Angela , Galistu Franca , Salis Roberta , Pes Giovanni Mario , Dore Maria Pina
Published: February 2023

Recent studies suggest that X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency entails a proinflammatory state that may increase the risk of several disease conditions. However, it is not clear how this relates to the degree of enzyme insufficiency and, in heterozygous females, to skewed inactivation of the X chromosome. This study aimed to (i) investigate the enzyme activity in a cohort of 232 subjects (54.3% females) from Northern Sardinia, Italy, further stratified into three subgroups (G6PD normal, partial deficiency and total deficiency); (ii) measure the levels of some non-specific inflammatory markers, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and those derived from cell counts, such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR), in relation to the underlying molecular defect and X inactivation. G6PD activity was measured in red blood cells according to G6PD/6PGD ratio, and X-chromosome inactivation was assessed by the HUMARA method. Overall, ESR was increased in males with total deficiency compared with normal males (15.0 ± 7.2 vs. 11.9 ± 6.2, p = 0.002, Tukey’s test), albeit not in males with partial deficiency. High-sensitivity CRP was slightly increased in males with total deficiency, compared to males with normal G6PD activity (5.96 ± 3.39 vs. 3.95 ± 2.96, p = 0.048). In females, neither marker showed significant differences across the subgroups. MLR was significantly and progressively increased from normal to totally deficient subjects with intermediate values in partially deficient subjects (0.18, 0.31 and 0.37, ANOVA p = 0.008). The NLR and PLR were not different in the three subgroups. Our findings show that G6PD deficiency may be associated with a proinflammatory profile, especially in elderly females, and worsened by the concomitant asymmetric inactivation of the X chromosome.
Metabolic Imaging and Molecular Biology Reveal the Interplay between Lipid Metabolism and DHA-Induced Modulation of Redox Homeostasis in RPE Cells
Authors: Bianchetti Giada , Clementi Maria Elisabetta , Sampaolese Beatrice , Serantoni Cassandra , Abeltino Alessio , De Spirito Marco , Sasson Shlomo , Maulucci Giuseppe
Published: February 2023

Diabetes-induced oxidative stress induces the development of vascular complications, which are significant causes of morbidity and mortality in diabetic patients. Among these, diabetic retinopathy (DR) is often caused by functional changes in the blood–retinal barrier (BRB) due to harmful oxidative stress events in lipids, proteins, and DNA. Docosahexaenoic acid (DHA) has a potential therapeutic effect against hyperglycemia-induced oxidative damage and apoptotic pathways in the main constituents of BRB, retinal pigment epithelium cells (ARPE-19). Effective antioxidant response elicited by DHA is driven by the activation of the Nrf2/Nqo1 signaling cascade, which leads to the formation of NADH, a reductive agent found in the cytoplasm. Nrf2 also induces the expression of genes encoding enzymes involved in lipid metabolism. This study, therefore, aims at investigating the modulation of lipid metabolism induced by high-glucose (HG) on ARPE-19 cells through the integration of metabolic imaging and molecular biology to provide a comprehensive functional and molecular characterization of the mechanisms activated in the disease, as well the therapeutic role of DHA. This study shows that HG augments RPE metabolic processes by enhancing lipid metabolism, from fatty acid uptake and turnover to lipid biosynthesis and β-oxidation. DHA exerts its beneficial effect by ameliorating lipid metabolism and reducing the increased ROS production under HG conditions. This investigation may provide novel insight for formulating novel treatments for DR by targeting lipid metabolism pathways.
Hydrogen Peroxide and GA3 Levels Regulate the High Night Temperature Response in Pistils of Wheat (Triticum aestivum L.)
Authors: Mukherjee Purbali , Suriyakumar Pavithra , Vanchinathan S. , Krishnan Veda , Lal Milan Kumar , Jha Prakash Kumar , Chinnusamy Viswanathan , Anand Anjali , Prasad P. V. Vara
Published: February 2023

High night temperature (HNT) impairs crop productivity through the reproductive failure of gametes (pollen and pistil). Though female gametophyte (pistil) is an equal partner in the seed-set, the knowledge of the antioxidant system(s) and hormonal control of HNT tolerance or susceptibility of pistils is limited and lacking. The objectives of this study were to determine the antioxidant mechanism for homeostatic control of free radicals, and the involvement of abscisic acid (ABA) and gibberellic acid (GA3) in HNT stress protection in the wheat pistils of contrasting wheat genotypes. We hypothesized that HNT tolerance is attributed to the homeostatic control of reactive oxygen species (ROS) and hormonal readjustment in pistils of the tolerant genotype. The ears of two contrasting wheat genotypes—HD 2329 (susceptible) and Raj 3765 (tolerant) were subjected to two HNTs (+5 °C and +8 °C) over ambient, in the absence and presence of dimethylthiourea (DMTU), a chemical trap of hydrogen peroxide (H2O2). Results showed that HNTs significantly increased ROS in pistils of susceptible genotype HD 2329 to a relatively greater extent compared to tolerant genotype Raj 3765. The response was similar in the presence or absence of DMTU, but the H2O2 values were lower in the presence of DMTU. The ROS levels were balanced by increased activity of peroxidase under HNT to a greater extent in the tolerant genotype. Cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPC) activity was inversely related to H2O2 production within a critical range in Raj 3765, indicating its modulation by H2O2 levels as no change was observed at the transcriptional level. The hormonal status showed increased ABA and decreased GA3 contents with increasing temperature. Our study elucidates the role of H2O2 and GA3 in stress tolerance of pistils of tolerant genotype where GAPC acts as a ROS sensor due to H2O2-mediated decrease in its activity.
Features of the Practical Implementation of the Method for Managing Observations of the State of Monitored Objects in Intrusion Detection Systems
Authors: Boldyrikhin Nikolay V. , Safaryan Olga A. , Korochentsev Denis A. , Reshetnikova Irina V. , Alferova Irina A. , Manakova Anastasia N.
Published: February 2023

This article discusses the possibility of generalizing the existing methods of optimization of observations to the problems of resource management of intrusion detection systems. The aim of this work is to study the applied aspects of the application of the surveillance optimization method, which increases the efficiency of using the resources of intrusion detection systems. The set goal of the work was achieved through the following tasks: (1) on the basis of experimental data, the development of a dynamic model of the controlled object and the observation model was carried out; and (2) numerical modeling of the solution to the problem of optimizing observations of the state of monitored objects in the intrusion detection system was carried out. As a result of this research, modern approaches to the management of resources of intrusion detection systems have been analyzed. A practical study of the possibility of using the mathematical apparatus for optimizing observations in relation to the problems of resource management of intrusion detection systems has been carried out. The most important scientific findings are as follows: (1) model of the dynamics of the controlled object; (2) model for monitoring the state of controlled objects; and (3) procedure for optimizing the plan for monitoring the state of monitored objects in intrusion detection systems. The significance of the results obtained is confirmed by a numerical experiment, within the framework of which a relative gain in the accuracy of assessing the state of controlled objects of 99.9% was obtained in comparison with a uniform observation plan.
Features of Multiannual Air Temperature Variability in Poland (1951–2021)
Authors: Marosz Michał , Miętus Mirosław , Biernacik Dawid
Published: February 2023

Over the last 71 years, the air temperature in Poland has increased on average by 0.28 °C per decade—which gives a total change in this period exceeding 2 °C. The subject of this study was an analysis of the long-term variability of the Polish climate in terms of thermal characteristics. The aim of the research was to verify the hypothesis on the lack of homogeneity of this change and to identify points of significant acceleration of the observed tendencies. The analysis utilized the average monthly air temperature at selected synoptic stations in Poland over the period 1951–2021. The values were then processed into a reference series using Alexandersson’s method, which provided synthetic information on the variability in thermal conditions in the country. The analyses were carried out on an annual and seasonal basis. The values of the trend coefficients (and their statistical significance) were also calculated in shorter periods (minimum 30 years), which enabled determination of the stability of the observed changes’ tendencies. In addition to the analysis of the basic characteristics, non-parametric tests (Wilcoxon, Kruskal–Wallis) were used to verify shifts between decades. The annual and seasonal analyses showed the existence of sub-periods with different directions and scales of the observed tendencies. Additionally, statistically significant changes in decadal characteristics were noted, e.g., in the decades 2001–2010 and 2011–2020 in the case of annual temperature, and 1961–1970 and 1971–1980 in the case of the winter season.
Electrochemical Performance and Stress Distribution of Sb/Sb2O3 Nanoparticles as Anode Materials for Sodium-Ion Batteries
Authors: Chen Jiajun , Zhao Songnan , Meng Weijia , Guo Meiqing , Wang Genwei , Guo Chunli , Bai Zhongchao , Li Zhiqiang , Ye Jiaye , Song Hui , Wang Xiaojun
Published: February 2023

We synthesize Sb/Sb2O3 nanoparticles by the oxidation of Sb nanoparticles at 100, 200, and 300 °C. The half sodium-ion batteries with Sb/Sb2O3-200 exhibit the optimal performance with a charge capacity of 540 mAh g−1 after 100 cycles at 0.1 A g−1, maintaining up to six times more capacity than pure Sb, and superior rate performance with 95.7% retention after cycling at varied current densities. One reason for this is that Sb/Sb2O3-200 is at exactly the optimum ratio of Sb2O3:Sb and the particle size of Sb/Sb2O3 to ensure both high capacity for Na+ and small stress during sodiation/desodiation, which is confirmed by the diffusion–stress coupled results. It indicates that increasing the ratio of Sb2O3:Sb causes a decrease of Mises equivalent stress, radial stress, and tangential stress in the range of 1:1–3.5:1, and an increase in the range of 3.5:1–4:1. These stresses decrease with a particle radius in the range of 30–50 nm and increase with a particle radius in the range of 50–70 nm. Additionally, another reason is related to the formation of cycling-induced coral-like Sb, which can promote Na+ diffusion, relieve cycling-induced volume changes, and provide exceptional Na+ storage.
General Decoupling and Sampling Technique for Reduced-Sensor Battery Management Systems in Modular Reconfigurable Batteries
Authors: Tashakor Nima , Dusengimana Janvier , Bayati Mahdi , Kersten Anton , Schotten Hans , Götz Stefan
Published: February 2023

The capacity and voltage rating of battery packs for electric vehicles or stationary energy storages are increasing, which challenge battery management and monitoring. Breaking the larger pack into smaller modules and using power electronics to achieve dynamic reconfiguration can be a solution. Reconfigurable batteries come with their own set of problems, including many sensors and complex monitoring systems, high-bandwidth communication interfaces, and additional costs. Online parameter estimation methods can simplify or omit many of these problems and reduce the cost and footprint of the system. However, most methods require many sensors or can only estimate a subset of the elements in the module’s equivalent circuit model (ECM). This paper proposes a simple decoupling technique to derive individual modules’ voltage and current profiles from the output measurements without direct measurement at the modules. The determined profiles can achieve a high sampling rate with minimum communication between the battery management system (BMS) and the modules. With accurate profiles, an estimation technique can easily determine the parameters of the modules. Provided simulations and experiments confirm this claim by estimating the parameters of a first-order ECM with a parallel capacitor. The proposed technique reduces the number of sensors from 2N + 2 to only two at the pack’s output terminals.
Seeking Sweetness: A Systematic Scoping Review of Factors Influencing Sugar-Sweetened Beverage Consumption in Remote Indigenous Communities Worldwide
Authors: Cartwright Jessica , Netzel Michael E. , Sultanbawa Yasmina , Wright Olivia R. L.
Published: February 2023

It is well-established that remote Indigenous communities have higher rates of sugar-sweetened beverage (SSB) consumption than non-Indigenous counterparts, which results in higher rates of chronic diseases such as type 2 diabetes mellitus (T2DM), obesity, and kidney disease. The aetiology leading to this behaviour remains understudied and overlooked. Therefore, the aim of this literature review is to understand the underpinning factors that contribute to SSB consumption in remote Indigenous communities. Studies were identified through five databases (n = 2529) and grey literature searching (n = 54). Following the PRISMA guidelines, each paper was assessed for eligibility, which left 34 studies for inclusion in the review. Within these papers, 37 different factors were found to influence SSB consumption in remote Indigenous communities. These were organised according to the Determinants of Nutrition and Eating (DONE) framework. SSB consumption was found to influence intake through each main level of the framework; individual (n = 9), interpersonal (n = 18), environmental (n = 9), and policy (n = 3). Preference was identified to be the most common factor to influence intake (n = 19), followed by health literacy (n = 15) and community availability (n = 12). Despite this, interventions to reduce SSB intake have never targeted this factor. This paper highlights the importance of a multi-level whole-of-system approach and suggests that an individual’s taste/preference should shape the direction of future research and intervention in this area.
Simultaneous Estimation of the Vertical Stiffness in the Knee and Hip for Healthy Human Subjects during Walking
Authors: Zhao Huan , Cao Junyi , Liao Wei-Hsin
Published: February 2023

The stiffness of lower limb joints is a critical characteristic of walking. To investigate the potential of establishing a simple and universal model to describe the characteristics related to vertical vibration during human walking, vertical stiffness is introduced at the knee and hip. A multi-mass-spring model of the human body is established in the vertical direction. In the Fourier form, results of experiments on 14 healthy adults show that the vertical displacements of joints are a function of the leg length and walking cadence, while the ground reaction force is a function of the body weight and walking cadence. The obtained universal equations of vertical displacement and ground reaction force are employed as the input parameters to the proposed multi-mass-spring model. Thus, the vertical stiffness in the knee and hip can then be estimated simultaneously by the subject’s weight, leg length, and walking cadence. The variation of vertical stiffness shows different time-varying trends in different gait phases across the entire gait cycle. Finally, the proposed model for vertical stiffness estimation is validated by the vertical oscillation of the pelvis. The average error across three gait cycles for all subjects is 20.48%, with a standard deviation of 5.44%. These results display that the vertical stiffness of knee and hip across the entire gait cycle can be directly estimated by individual parameters that are easy to measure. It provides a different view of human walking analysis and may be applied in future pathological gait recognition, bipedal robots, and lower limb exoskeletons.
Combined Effects of Deep Eutectic Solvents and Pulsed Electric Field Improve Polyphenol-Rich Extracts from Apricot Kernel Biomass
Authors: Makrygiannis Ioannis , Athanasiadis Vassilis , Bozinou Eleni , Chatzimitakos Theodoros , Makris Dimitris P. , Lalas Stavros I.
Published: February 2023

Apricots are one of the most important fruits in the Mediterranean region for both their nutritional and economic value. They are widely cultivated and consumed fresh or dried or are used in the food industry for the production of jams, juices, etc. In any case, the seeds they contain constitute waste. The kernels are very rich in bioactive compounds such as polyphenols, a fact that makes them very appealing in cosmetology. However, the extraction of the bioactive compounds of apricot kernels is poorly examined. In this study, the preparation of polyphenol-rich extracts from apricot kernel biomass is discussed. To this end, a common extraction procedure with water as a solvent was employed. To enhance the extraction yield, the use of a deep eutectic solvent (DES) was examined. In addition, the use of pulsed electric field (PEF) either as a standalone extraction method or as a complementary step was also examined. According to the results, it was evident that when PEF was applied before the extraction procedure, an increase of 88% in the total polyphenol content (TPC) was recorded. Likewise, the use of a glycerol:choline chloride (2:1, w/w) DES increased the TPC by ~70%. When the two approaches were combined, a 173% increase was recorded. According to the above, it can be concluded that apricot kernel biomass is a very good source of polyphenols, especially using the proposed extraction procedure.
Lower Baskets and Smaller Balls Influence Mini-Basketball Players’ Throwing Motions
Authors: Thomas Carina , Nolte Kevin , Schmidt Marcus , Jaitner Thomas
Published: February 2023

Children have different anthropometrical size ratios in relation to ball and basket compared to adults, but usually compete on the same basket height and field. Therefore, they have to adapt their throwing technique, which might result in movement patterns unfavorable for long-term performance development. In this study, we analyze how children adapt their throwing techniques to different conditions. Seven basketball players (10.14 ± 1.12 years) completed a total of 60 throws, combining different ball sizes, basket heights, and distances. The throwing movements were captured by a 3D motion capture system. Accumulated distances between all time courses of angles, angular accelerations, and velocities served as similarity measures and were analyzed by cluster analysis, including purity measures. Considering all throws, a division into seven clusters separated each individual. For all subjects, distances accounted for the most changes in the throwing motion (purity 0.81–1). In the subclusters, the basket heights were not a decisive condition (purity 0.42–0.63). However, an increase in purity was found compared to the main clusters. Children seem to adapt their movement behavior primarily to throwing distances and subordinately to basket heights, which indicates that changing playing conditions (e.g., closer 3-point line, lower baskets) might be beneficial in mini-basketball.
Status of the Pallas’s Gull Ichthyaetus ichthyaetus during Summer/Autumn in the Fairway Volga–Kama Reservoirs (East European Plain) in Russia
Authors: Golubev Sergey
Published: February 2023

The Pallas’s Gull Ichthyaetus ichthyaetus is a fish-eating predator listed in the category of recovering species of the Red Book of the Russian Federation. The purpose of the research was to study the state of the Pallasʹs Gull in the fairway (navigable zone) of the Volga–Kama reservoirs, in Russia and to assess their role in the current distribution of the species. In the summer and autumn of 2020–2022, at 11 reservoirs of the Volga and Kama rivers, counts of Pallasʹs Gulls were carried out from the bow deck of the R/V Akademik Topchiev. The transect length was 4633.5 km; the duration of observations was 364.3 h. A comprehensive bird count was applied in the direction of the vessel’s movement on transects with a fixed counting strip width of 200 m (100 m in each direction from the bow of the vessel). Birds were usually fixed on 30-min transects. The Pallas’s Gulls were found in 7 of the 11 reservoirs studied, and their status varied between common and very rare. The species was more abundant in the Gorky reservoir than in the Cheboksary, Kuibyshev, Saratov, and Nizhnekamsk reservoirs. The smallest abundance was recorded in the Volgograd and Rybinsk reservoirs. The Pallas’s Gull shows a steady annual presence on most reservoirs. The results indicate that in the Volga Basin, the range of Pallas’s Gull has expanded further north by more than 1000 km over the past 30 years from the species’ original areas of sustainable breeding in the North Caspian. Adult individuals of the Pallasʹs Gull (83.4% of the age composition of the population) play the main role in the dispersal. The most favorable clusters of the stable presence of the species were lake-shaped fragments of the Gorky and Kuibyshev reservoirs. On the territory of the East European Plain, the Volga–Kama reservoirs are important, if not decisive, in expanding the range of Pallas’s Gull to the north.
Input Shape Effect on Classification Performance of Raw EEG Motor Imagery Signals with Convolutional Neural Networks for Use in Brain—Computer Interfaces
Authors: Arı Emre , Taçgın Ertuğrul
Published: February 2023

EEG signals are interpreted, analyzed and classified by many researchers for use in brain–computer interfaces. Although there are many different EEG signal acquisition methods, one of the most interesting is motor imagery signals. Many different signal processing methods, machine learning and deep learning models have been developed for the classification of motor imagery signals. Among these, Convolutional Neural Network models generally achieve better results than other models. Because the size and shape of the data is important for training Convolutional Neural Network models and discovering the right relationships, researchers have designed and experimented with many different input shape structures. However, no study has been found in the literature evaluating the effect of different input shapes on model performance and accuracy. In this study, the effects of different input shapes on model performance and accuracy in the classification of EEG motor imagery signals were investigated, which had not been specifically studied before. In addition, signal preprocessing methods, which take a long time before classification, were not used; rather, two CNN models were developed for training and classification using raw data. Two different datasets, BCI Competition IV 2A and 2B, were used in classification processes. For different input shapes, 53.03–89.29% classification accuracy and 2–23 s epoch time were obtained for 2A dataset, 64.84–84.94% classification accuracy and 4–10 s epoch time were obtained for 2B dataset. This study showed that the input shape has a significant effect on the classification performance, and when the correct input shape is selected and the correct CNN architecture is developed, feature extraction and classification can be done well by the CNN architecture without any signal preprocessing.
Graph-Based Analysis of Brain Connectivity in Multiple Sclerosis Using Functional MRI: A Systematic Review
Authors: Hejazi Sara , Karwowski Waldemar , Farahani Farzad V. , Marek Tadeusz , Hancock P. A.
Published: February 2023

(1) Background: Multiple sclerosis (MS) is an immune system disease in which myelin in the nervous system is affected. This abnormal immune system mechanism causes physical disabilities and cognitive impairment. Functional magnetic resonance imaging (fMRI) is a common neuroimaging technique used in studying MS. Computational methods have recently been applied for disease detection, notably graph theory, which helps researchers understand the entire brain network and functional connectivity. (2) Methods: Relevant databases were searched to identify articles published since 2000 that applied graph theory to study functional brain connectivity in patients with MS based on fMRI. (3) Results: A total of 24 articles were included in the review. In recent years, the application of graph theory in the MS field received increased attention from computational scientists. The graph–theoretical approach was frequently combined with fMRI in studies of functional brain connectivity in MS. Lower EDSSs of MS stage were the criteria for most of the studies (4) Conclusions: This review provides insights into the role of graph theory as a computational method for studying functional brain connectivity in MS. Graph theory is useful in the detection and prediction of MS and can play a significant role in identifying cognitive impairment associated with MS.
Intraoperative Autofluorescence Imaging for Parathyroid Gland Identification during Total Laryngectomy with Thyroidectomy
Authors: Obongo Anga Raïs , Abbaci Muriel , Guerlain Joanne , Breuskin Ingrid , Casiraghi Odile , Marhic Alix , Benmoussa-Rebibo Nadia , de Kermadec Héloïse , Moya-Plana Antoine , Temam Stéphane , Gorphe Philippe , Hartl Dana M.
Published: February 2023

Objective: Hypoparathyroidism is a known complication of total laryngectomy, although parathyroid preservation and/or reimplantation are not routine. Autofluorescence is a new technique for identifying parathyroid glands intraoperatively. The aim of this study was to evaluate the feasibility of autofluorescence in this context. Materials and Methods: A retrospective study of patients undergoing total laryngectomy/pharyngectomy with concomitant thyroidectomy using the Fluobeam® (Fluoptics, Grenoble, France) and frozen section of a parathyroid fragment in case of reimplantation. The rates of identification using autofluorescence, reimplantation, and hypoparathyroidism were evaluated. Results: Eighteen patients (16 males, median age 67) underwent total laryngectomy/pharyngectomy with total thyroidectomy (n = 12) or hemithyroidectomy (n = 6). A median of 2 parathyroid glands were identified per patient. Ninety-two percent were identified by autofluorescence before visualisation. All parathyroids were reimplanted due to devascularization. Temporary hypoparathyroidism occurred in nine patients, and was permanent in one patient. After 34 months of median follow-up (range 1–49), no tumor recurrence was observed in the reimplantation sites. Conclusions: To our knowledge, this is the largest study to evaluate autofluorescence during total laryngectomy with thyroidectomy. No tumor recurrence occurred in the sites of parathyroid reimplantation.
Development of Novel Murine BRAFV600E-Driven Papillary Thyroid Cancer Cell Lines for Modeling of Disease Progression and Preclinical Evaluation of Therapeutics
Authors: Branigan Grace Purvis , Casado-Medrano Victoria , O’Neill Alison B. , Ricarte-Filho Julio C. , Massoll Nicole , Salwen Madeleine , Spangler Zachary , Scheerer Michele , Williamson Edward K. , Bauer Andrew J. , Franco Aime T.
Published: February 2023

The Cancer Genome Atlas study in thyroid cancer exposed the genomic landscape of ~500 PTCs and revealed BRAFV600E-mutant tumors as having different prognosis, contrasting indolent cases and those with more invasive disease. Here, we describe the generation and characterization of six novel BRAFV600E-driven papillary thyroid cancer (PTC) cell lines established from a BrafV600E+/−/Pten+/−/TPO-Cre mouse model that spontaneously develop thyroid tumors. The novel cell lines were obtained from animals representing a range of developmental stages and both sexes, with the goal of establishing a heterogeneous panel of PTC cell lines sharing a common driver mutation. These cell lines recapitulate the genetics and diverse histopathological features of BRAFV600E-driven PTC, exhibiting differing degrees of growth, differentiation, and invasive potential that may help define mechanisms of pathogenesis underlying the heterogeneity present in the patient population. We demonstrate that these cell lines can be used for a variety of in vitro applications and can maintain the potential for in vivo transplantation into immunocompetent hosts. We believe that these novel cell lines will provide powerful tools for investigating the molecular basis of thyroid cancer progression and will lead to the development of more personalized diagnostic and treatment strategies for BRAFV600E-driven PTC.
Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?
Authors: Baxevanis Constantin N.
Published: February 2023

Immune checkpoint inhibitors (ICIs) are in the spotlight of cancer treatment by increasing the probability for long-term survival in patients with metastatic disease and by considerably prolonging progression-free survival in patients at early disease stages [...]
Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma
Authors: Amaro Adriana Agnese , Gangemi Rosaria , Emionite Laura , Castagnola Patrizio , Filaci Gilberto , Jager Martine J. , Tanda Enrica Teresa , Spagnolo Francesco , Mascherini Matteo , Pfeffer Ulrich , Croce Michela
Published: February 2023

Background: Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in Gα-proteins GNAQ and GNA11 activate MAP-kinase and YAP/TAZ pathways of oncogenic signalling. MAP-kinase and MEK-inhibitors do not significantly block MUM progression, likely due to persisting YAP/TAZ signalling. Statins inhibit YAP/TAZ activation by blocking the mevalonate pathway, geranyl-geranylation, and subcellular localisation of the Rho-GTPase. We investigated drugs that affect the YAP/TAZ pathway, valproic acid, verteporfin and statins, in combination with MEK-inhibitor trametinib. Methods: We established IC50 values of the individual drugs and monitored the effects of their combinations in terms of proliferation. We selected trametinib and cerivastatin for evaluation of cell cycle and apoptosis. Synergism was detected using isobologram and Chou–Talalay analyses. The most synergistic combination was tested in vivo. Results: Synergistic concentrations of trametinib and cerivastatin induced a massive arrest of proliferation and cell cycle and enhanced apoptosis, particularly in the monosomic, BAP1-mutated UPMM3 cell line. The combined treatment reduced ERK and AKT phosphorylation, increased the inactive, cytoplasmatic form of YAP and significantly impaired the growth of UM cells with monosomy of chromosome 3 in NSG mice. Conclusion: Statins can potentiate the efficacy of MEK inhibitors in the therapy of UM.
Comparison of Recurrence Patterns between Adenocarcinoma and Squamous Cell Carcinoma after Stereotactic Body Radiotherapy for Early-Stage Lung Cancer
Authors: Kita Nozomi , Tomita Natsuo , Takaoka Taiki , Sudo Shuou , Tsuzuki Yusuke , Okazaki Dai , Niwa Masanari , Torii Akira , Takano Seiya , Niimi Akio , Hiwatashi Akio
Published: February 2023

We compared recurrence patterns between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) after stereotactic body radiotherapy (SBRT) for early-stage lung cancer. Patients with ADC and SCC histology, who were treated with SBRT for clinical stage IA1-IIA lung cancer at our institution, were included in the analysis. The rates of disease-free survival (DFS), overall survival (OS), local recurrence (LR), lymph node metastasis (LNM), and distant metastasis (DM) were calculated using the Kaplan–Meier method or the cumulative incidence function. Among the 204 patients analyzed, 138 and 66 were in the ADC and SCC groups, respectively. The median follow-up period was 60 months. The five-year DFS and OS rates were 57% vs. 41% and 69% vs. 48% in the ADC and SCC groups, respectively (p = 0.015 and 0.019, respectively). In the multivariate analysis, the histological type was not associated with DFS or OS. Five-year LR, LNM, and DM rates were 10% vs. 24%, 12% vs. 20%, and 25% vs. 27% in the ADC and SCC groups, respectively (p = 0.0067, 0.074, and 0.67, respectively). The multivariate analysis identified the histological type of SCC as an independent factor for LR (hazard ratio, 2.41; 95% confidence interval, 1.21–4.77; p = 0.012). The present results suggest that the risk of LR after SBRT is higher for SCC than for ADC.
Molecular Identification and In Silico Protein Analysis of a Novel BCOR-CLGN Gene Fusion in Intrathoracic BCOR-Rearranged Sarcoma
Authors: Chang Chien Yi-Che , Madarász Kristóf , Csoma Szilvia Lilla , Mótyán János András , Huang Hsuan-Ying , Méhes Gábor , Mokánszki Attila
Published: February 2023

BCOR (BCL6 corepressor)-rearranged sarcomas (BRSs) are a heterogeneous group of sarcomas previously classified as part of the group of “atypical Ewing” or “Ewing-like” sarcomas, without the prototypical ESWR1 gene translocation. Due to their similar morphology and histopathological features, diagnosis is challenging. The most common genetic aberrations are BCOR-CCNB3 fusion and BCOR internal tandem duplication (ITD). Recently, various new fusion partners of BCOR have been documented, such as MAML3, ZC3H7B, RGAG1, and KMT2D, further increasing the complexity of such tumor entities, although the molecular pathogenetic mechanism remains to be elucidated. Here, we present an index case of intrathoracic BRS that carried a novel BCOR-CLGN (calmegin) gene fusion, exhibited by a 52-year-old female diagnosed initially by immunohistochemistry due to the positivity of a BCOR stain; the fusion was identified by next-generation sequencing and was confirmed by Sanger sequencing. In silico protein analysis was performed to demonstrate the 3D structure of the chimera protein. The physicochemical properties of the fusion protein sequence were calculated using the ProtParam web-server tool. Our finding further broadens the fusion partner gene spectrum of BRS. Due to the heterogeneity, molecular ancillary tests serve as powerful tools to discover these unusual variants, and an in silico analysis of the fusion protein offers an appropriate approach toward understanding the exact pathogenesis of such a rare variant.
Multi-Fold Computational Analysis to Discover Novel Putative Inhibitors of Isethionate Sulfite-Lyase (Isla) from Bilophila wadsworthia: Combating Colorectal Cancer and Inflammatory Bowel Diseases
Authors: Waqas Muhammad , Halim Sobia Ahsan , Ullah Atta , Ali Assim Alaa Mohammed , Khalid Asaad , Abdalla Ashraf N. , Khan Ajmal , Al-Harrasi Ahmed
Published: February 2023

A glycal radical enzyme called isethionate sulfite-lyase (Isla) breaks the C–S bond in isethionate to produce acetaldehyde and sulfite. This enzyme was found in the Gram-negative, colonial Bilophila wadsworthia bacteria. Sulfur dioxide, acetate, and ammonia are produced by the anaerobic respiration route from (sulfonate isethionate). Strong genotoxic H2S damages the colon’s mucous lining, which aids in the development of colorectal cancer. H2S production also contributes to inflammatory bowel diseases such as colitis. Here, we describe the structure-based drug designing for the Isla using an in-house database of naturally isolated compounds and synthetic derivatives. In structure-based drug discovery, a combination of methods was used, including molecular docking, pharmacokinetics properties evaluation, binding free energy calculations by the molecular mechanics/generalized born surface area (MM/GBSA) method, and protein structure dynamics exploration via molecular dynamic simulations, to retrieve novel and putative inhibitors for the Isla protein. Based on the docking score, six compounds show significant binding interaction with the Isla active site crucial residues and exhibit drug-like features, good absorption, distribution, metabolism, and excretion profile with no toxicity. The binding free energy reveals that these compounds have a strong affinity with the Isla. In addition, the molecular dynamics simulations reveal that these compounds substantially affect the protein structure dynamics. As per our knowledge, this study is the first attempt to discover Isla potential inhibitors. The compounds proposed in the study using a multi-fold computational technique may be verified in vitro as possible inhibitors of Isla and possess the potential for the future development of new medications that target Isla.
Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models
Authors: Troschke-Meurer Sascha , Zumpe Maxi , Meißner Lena , Siebert Nikolai , Grabarczyk Piotr , Forkel Hannes , Maletzki Claudia , Bekeschus Sander , Lode Holger N.
Published: February 2023

Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy.
SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation
Authors: Khan Md Gulam Musawwir , Boufaied Nadia , Yeganeh Mehdi , Kandhi Rajani , Petkiewicz Stephanie , Sharma Ankur , Yoshimura Akihiko , Ferbeyre Gerardo , Labbé David P. , Ramanathan Sheela , Ilangumaran Subburaj
Published: February 2023

SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.
PET/CT with Fibroblast Activation Protein Inhibitors in Breast Cancer: Diagnostic and Theranostic Application—A Literature Review
Authors: Taralli Silvia , Lorusso Margherita , Perrone Elisabetta , Perotti Germano , Zagaria Luca , Calcagni Maria Lucia
Published: February 2023

Growing studies have recently reported on the promising application of radiolabeled-fibroblast activation protein inhibitors (FAPIs) as diagnostic and therapeutic agents in various oncological populations. To exclusively evaluate the current evidence on the diagnostic and therapeutic role of FAPI radiotracers in patients with breast cancer (BC), a narrative review of the available literature was performed. A search algorithm from PubMed/MEDLINE, based on the combination of “PET” OR “positron emission tomography” and “FAPI” and ”cancer”, with a last update in February 2022, was applied. From 233 identified articles, 33 studies conducted in BC patients and with available data on PET imaging or radiolabeled-FAPI therapy were finally considered, for a total of 191 patients. Despite some clinical and methodological heterogeneity among the reviewed articles, 68Ga-FAPI PET/CT emerges as a valuable diagnostic tool in BC patients both at staging and restaging, also demonstrating several technical advantages and an overall better performance than 18F-FDG, especially in histotypes with well-known low 18F-FDG avidity. Moreover, although with still limited clinical evidence in BC, radiolabeled FAPIs emerge as promising therapeutic agents in a theranostic perspective, increasing the possibility of more personalized treatments. From these results, future research directions on FAPI radiotracers application in BC patients are suggested.
Outcomes of Radiofrequency Ablation for Solitary T1a Renal Cell Carcinoma: A 20-Year Tertiary Cancer Center Experience
Authors: Abdelsalam Mohamed E. , Awad Ahmed , Baiomy Ali , Irwin David , Karam Jose A. , Matin Surena F. , Sheth Rahul A. , Habibollahi Peiman , Odisio Bruno C. , Lu Thomas , Ahrar Kamran
Published: February 2023

Background: The aim is to determine the long-term oncologic and survival outcomes of the radiofrequency ablation (RFA) of solitary de novo T1a renal cell carcinoma (RCC). Materials and methods: We retrospectively reviewed our renal ablation registry and included only patients with new solitary, biopsy-proven T1a RCC (<4 cm) who underwent RFA from January 2001 through December 2020. We collected patient and tumor characteristics. Survival rates were estimated using the Kaplan–Meier method. Results: Of the 243 patients who met our inclusion criteria (160 male and 83 female, median age 68 years), 128 (52.6%) had another primary malignancy other than renal malignancy. Two-hundred forty-three RFA procedures were performed for 243 renal tumors of a median tumor size of 2.5 cm. The median follow-up period was 3.7 years. Most tumors (68.6%) were clear cell RCC. Ten patients (4.1%) experienced Clavien–Dindo Grade III complications. Seven patients(3.1%) developed recurrence at the ablation zone, and 11 (4.5%) developed recurrence elsewhere in the kidney. The 15-year local-recurrence- and disease-free survival were 96.5% and 88.6%, respectively. The 15-year metastasis-free survival and cancer-specific survival were 100%. Conclusions: RFA is a highly effective modality for the management of T1a RCC, with low complication and recurrence rates. Long-term data revealed favorable oncologic and survival outcomes.