bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-Input Convolutional Neural Networks for Automatic Pollen Classification
Authors: Boldeanu Mihai , Cucu Horia , Burileanu Corneliu , Mărmureanu Luminița
Published: December 2021

Pollen allergies are a cause of much suffering for an increasing number of individuals. Current pollen monitoring techniques are lacking due to their reliance on manual counting and classification of pollen by human technicians. In this study, we present a neural network architecture capable of distinguishing pollen species using data from an automated particle measurement device. This work presents an improvement over the current state of the art in the task of automated pollen classification, using fluorescence spectrum data of aerosol particles. We obtained a relative reduction in the error rate of over 48%, from 27% to 14%, for one of the datasets, with similar improvements for the other analyzed datasets. We also use a novel approach for doing hyperparameter tuning for multiple input networks.
An Eco-Sustainable Stabilization of Clayey Road Subgrades by Lignin Treatment: An Overview and a Comparative Experimental Investigation
Authors: Vaiana Rosolino , Oliviero Rossi Cesare , Perri Giusi
Published: December 2021

Subgrade conditions significantly affect functionality of the road pavement during its service life. Among the different stabilization techniques for upgrading poorly performing in-situ soil subgrades, an economically attractive example involves the use of waste materials, such as lignin. A deep bibliographic analysis of previous studies is carried out in the first section of this paper. The literature review suggests that use of lignin as a stabilizing agent of road subgrade soils is not completely consolidated. In addition, this study reports an investigation on the strength and performance characteristics of a lignin-treated clayey soil. Several experimental tests were carried out on both the untreated and lignin-treated soils in order to shed some light on different aspects with limited knowledge available, such as the behaviour of the stabilised soil in specific conditions (e.g., the presence of water). Finally, the test results are discussed and compared with those obtained when the same soil is treated with lime, which is more widely used. The most relevant finding is the poor ability of lignin to upgrade the bearing capacity of the soil in wet conditions compared to lime; on the contrary, the presence of lignin helped in controlling the swelling potential of this type of soil.
Reducing the Heart Failure Burden in Romania by Predicting Congestive Heart Failure Using Artificial Intelligence: Proof of Concept
Authors: Pană Maria-Alexandra , Busnatu Ștefan-Sebastian , Serbanoiu Liviu-Ionut , Vasilescu Electra , Popescu Nirvana , Andrei Cătălina , Sinescu Crina-Julieta
Published: December 2021

Due to population aging, we are currently confronted with an increased number of chronic heart failure patients. The primary purpose of this study was to implement a noncontact system that can predict heart failure exacerbation through vocal analysis. We designed the system to evaluate the voice characteristics of every patient, and we used the identified variations as an input for a machine-learning-based approach. We collected data from a total of 16 patients, 9 men and 7 women, aged 65–91 years old, who agreed to take part in the study, with a detailed signed informed consent. We included hospitalized patients admitted with cardiogenic acute pulmonary edema in the study, regardless of the precipitation cause or other known cardiovascular comorbidities. There were no specific exclusion criteria, except age (which had to be over 18 years old) and patients with speech inabilities. We then recorded each patient’s voice twice a day, using the same smartphone, Lenovo P780, from day one of hospitalization—when their general status was critical—until the day of discharge, when they were clinically stable. We used the New York Heart Association Functional Classification (NYHA) classification system for heart failure to include the patients in stages based on their clinical evolution. Each voice recording has been accordingly equated and subsequently introduced into the machine-learning algorithm. We used multiple machine-learning techniques for classification in order to detect which one turns out to be more appropriate for the given dataset and the one that can be the starting point for future developments. We used algorithms such as Artificial Neural Networks (ANN), Support Vector Machine (SVM) and K-Nearest Neighbors (KNN). After integrating the information from 15 patients, the algorithm correctly classified the 16th patient into the third NYHA stage at hospitalization and second NYHA stage at discharge, based only on his voice recording. The KNN algorithm proved to have the best classification accuracy, with a value of 0.945. Voice is a cheap and easy way to monitor a patient’s health status. The algorithm we have used for analyzing the voice provides highly accurate preliminary results. We aim to obtain larger datasets and compute more complex voice analyzer algorithms to certify the outcomes presented.
Verification Methodology for Simulation Models of the Synchronous Generator on Transients Analysis
Authors: Tomičić Branko , Šumiga Antonija , Nađ Josip , Srpak Dunja
Published: December 2021

During transients that occur in an electric network, large currents can flow and large electromagnetic torques can be developed in electric generators. Accurate calculation of currents and magnetic fields during transients is an important element in the optimal design of generators and network parts, as well as mechanical parts of machines and other torque transmission parts. This paper describes the modeling of a sudden three-phase short-circuit on a synchronous generator using the finite element method (FEM) and the dynamic model. The model for simulations that use the FEM was built in the MagNet software package, and the dynamic model is embedded in the MATLAB/Simulink software package. The dynamic simulation model of a part of a network with two identical generators, represented by equivalent parameters, was developed. The results obtained after the simulation of a sudden three-phase fault in the generators by both methods are presented, including three-phase voltages, three-phase currents, machine speeds, excitation voltages, and mechanical power. In particular, the short-circuit current in the phase with the highest peak value was analyzed to determine the accuracy of the equivalent parameters used in the dynamic model. Finally, the results of these two calculation methods are compared, and recommendations are presented for the application of different modeling methods.
A Durability Prediction Method for Historical Square Rebar Reinforced Concrete Buildings
Authors: Jin Hui , Chun Qing , Zhang Chengwen , Han Yidan
Published: December 2021

Square rebars were developed and used for decades in the early development of reinforced concrete (RC) structures; however, the objectives of modern concrete structure durability analyses and standards are centered on round rebars in past decades, which are not suited for RC buildings utilizing square rebars. Considering the absence of proper evaluation techniques to evaluate the square rebar RC structures’ durability accurately, a novel durability prediction method has been proposed for this type of historical building. The method is based on major parts as in-situ investigation, finite element model simulation, component importance analysis, and structural durability prediction. The durability prediction calculation method was established on the experimental results of the realistic historical concrete tests and corrosion-induced cover cracking experiments for square rebar components. It was found that the carbonization-resistant ability of historical concretes was relatively weaker than that of current concretes and the calculation method for critical corrosion depth of square rebar was different from that of round rebar. Furthermore, two typical application cases are presented to introduce the procedure of the method in detail. Consequently, the research outcomes can be directly used on the durability prediction and protection works for historical RC buildings.
Aeroelastic and Aerodynamic Tests of Wind Turbine with Various Polygonal Towers
Authors: Kim Yong Chul
Published: December 2021

Traditionally, circular cross-section towers have been used as supporting systems of wind turbines, but weaknesses have become apparent with recent upsizing of wind turbines. Thus, polygonal cross-section towers have been proposed and used in Europe. In this study, the effects of polygonal cross-sections on the aeroelastic and aerodynamic characteristics of wind turbines were examined through a series of wind tunnel tests. Aeroelastic tests showed that a square cross-section tower showed instability vibrations, and polygonal cross-section towers showed limited vibrations for tower-only cases. However, for wind turbines with various polygonal cross-section towers, no instability vibrations were observed, and displacements increased proportionally to the square of mean wind speed. Furthermore, pressure measurements showed that local force coefficients changed largely depending on wind direction and azimuth angle. Local drag force coefficients decreased with increasing number of tower sides, approaching those of the tower-only case, and local lift force coefficients showed larger absolute values than those of the tower-only case. The maximum mean and fluctuating drag force and the maximum fluctuating lift coefficients at each height decreased with increasing number of tower sides.
Effect of Chitosan on the Removal of Different Types of Tannins from Red Wines
Authors: Picariello Luigi , Errichiello Francesco , Coppola Francesca , Rinaldi Alessandra , Moio Luigi , Gambuti Angelita
Published: December 2021

(1) Background: most premium red wines are rich in tannins but the effect of chitosan on these macromolecules is unknown. In this work, the effect of a treatment with 0.5 g/L of chitosan on red wines, W, enriched with condensed tannins, CT, ellagitannins, ET, and gallotannins, GT, was evaluated. In addition, to understand if the effect of C was stable during wine evolution, treated wines underwent an oxidative stress simulating an exposure to 18 mg/L of oxygen. (2) Methods: parameters describing the reactivity of phenolic compounds were determined: iron reactive phenolics, BSA reactive tannins, vanillin reactive tannins, and the saliva precipitation index. Individual anthocyanins, total and polymeric pigments and chromatic characteristics were evaluated to determine the influence of each treatment on colour parameters. (3) Results: a decrease in BSA reactive tannins after the addition of C was detected for all wines and the effect persisted after oxidation. W and CT wines previously treated with C and oxidized showed a significant decrease in the reactivity towards salivary proteins. C caused a lower formation of polymeric pigments in all wines. (4) Conclusion: these results suggest a possible use of C to treat wines very rich in condensed tannins and excessively astringent.
Stress Level Detection and Evaluation from Phonation and PPG Signals Recorded in an Open-Air MRI Device
Authors: Přibil Jiří , Přibilová Anna , Frollo Ivan
Published: December 2021

This paper deals with two modalities for stress detection and evaluation—vowel phonation speech signal and photo-plethysmography (PPG) signal. The main measurement is carried out in four phases representing different stress conditions for the tested person. The first and last phases are realized in laboratory conditions. The PPG and phonation signals are recorded inside the magnetic resonance imaging scanner working with a weak magnetic field up to 0.2 T in a silent state and/or with a running scan sequence during the middle two phases. From the recorded phonation signal, different speech features are determined for statistical analysis and evaluation by the Gaussian mixture models (GMM) classifier. A database of affective sounds and two databases of emotional speech were used for GMM creation and training. The second part of the developed method gives comparison of results obtained from the statistical description of the sensed PPG wave together with the determined heart rate and Oliva–Roztocil index values. The fusion of results obtained from both modalities gives the final stress level. The performed experiments confirm our working assumption that a fusion of both types of analysis is usable for this task—the final stress level values give better results than the speech or PPG signals alone.
Optimization of Loading Condition for Maxillary Molar Intrusion with Midpalatal Miniscrews by Using Finite Element Analysis
Authors: Pooktuantong Ornnicha , Ogasawara Takeshi , Uezono Masayoshi , Chantarawaratit Pintu-on , Moriyama Keiji
Published: December 2021

An anterior open bite is one of the most difficult malocclusions in orthodontic treatment. For such malocclusion, orthodontic miniscrew insertion into both buccal and palatal alveolar regions has been indicated for molar intrusion, but it involves a risk of tooth root injury. To solve the problem, a midpalatal miniscrew-attached extension arm (MMEA) is adopted. However, this method causes palatal tipping of the molar because intrusive loads were applied only from the palatal side. Currently, a transpalatal arch is added to avoi0d tipping movement, but it induces the patient’s discomfort. Hence, the objective of this study was to evaluate the loading conditions for maxillary molar intrusion without tipping movement, only by MMEA through finite element (FE) analysis. FE models of maxillary right first molar and surrounding tissues were created. Three hook positions of MMEA were set at 6.0 mm perpendicular intervals in the occluso-apical direction along the mucosal contour. An intrusive unit load was applied from the palatal side of the molar, and various counter loads were applied from the buccal side. An optimal counter load for molar intrusion without palatal tipping was observed in each hook position. In conclusion, an ideal maxillary molar intrusion can be achieved only by MMEA with an optimal counter load.
Investigation of Airflow Distribution and Contamination Control with Different Schemes in an Operating Room
Authors: Wang Fujen , Permana Indra , Rakshit Dibakar , Prasetyo Bowo Yuli
Published: December 2021

Controlling contamination via proper airflow distribution in an operating room becomes vital to ensure the reliable surgery process. The heating, ventilation, and air conditioning (HVAC) systems significantly influence the operating room environment, including temperature, relative humidity, pressurization, particle counts, filtration, and ventilation rate. A full-scale operating room has been investigated extensively through field measurements and numerical analyses. Computational fluid dynamics (CFD) simulation was conducted and verified with the field measurement data. The simulation was analyzed with three different operating room schemes, including at-rest conditions (case 1), normal operational conditions with personnel (case 2), and actual conditions with personnel inside and some medical equipment blocking the return air (case 3). The concentration decay method was used to evaluate this study. The results revealed that the contamination concentration in case 1 could be diluted quickly with the average value of 404 ppm, whereas the concentration in case 2 slightly increased while performing a surgery with the average value of 420 ppm. The return air grilles in case 3, blocked by obstacles from some medical equipment, resulted in the average concentration value of 474 ppm. Other than that, the contaminant dilution could be obstructed dramatically, which revealed that proper and smooth airflow distribution is essential for contamination control. The ventilation efficiency of case 2 and case 3 dropped around 6% and 17.91% compared to case 1 in the unoccupied and ideal condition. Ventilation efficiency also decreased along with decreasing the air change rate per hour (ACH), while with increasing ACH, the ventilation efficiency in case 3 actually increased, approaching case 2 in the ideal condition.
Polarity Asymmetry in Lightning Return Stroke Speed Caused by the Momentum Associated with Radiation
Authors: Cooray Vernon , Cooray Gerald , Rubinstein Marcos , Rachidi Farhad
Published: December 2021

In positive lightning return strokes, the net momentum transported by the radiation field has the same direction as the momentum associated with electrons, whereas the momentum associated with electrons is in opposite direction to the momentum of radiation in negative return strokes. It is shown here that this polarity asymmetry could limit the maximum speed of positive return strokes with respect to the negative return strokes.
Nitrous Oxide Emission Fluxes in Coffee Plantations during Fertilization: A Case Study in Costa Rica
Authors: San Martin Ruiz Macarena , Reiser Martin , Kranert Martin
Published: December 2021

The main source of N2O emissions is agriculture, and coffee monocultures have become an important part of these emissions. The demand for coffee has increased in the last five decades. Thus, its production in agricultural fields and the excess of fertilizers have increased. This study quantified N2O emissions from different dose applications and types of nitrogen fertilizer in a region of major coffee production in Costa Rica. A specific methodology to measure N2O fluxes from coffee plants was developed using Fourier-transform infrared spectroscopy (FTIR). Measurements were performed in a botanical garden in Germany and plots in Costa Rica, analyzing the behavior of a fertilizer in two varieties of coffee (Catuai and Geisha), and in a field experiment, testing two types of fertilizers (chemical (F1) and physical mixture (F2)) and compost (SA). As a result, the additions of synthetic fertilizer increased the N2O fluxes. F2 showed higher emissions than F1 by up to 90% in the field experiment, and an increase in general emissions occurred after a rain event in the coffee plantation. The weak levels of N2O emissions were caused by a rainfall deficit, maintaining low water content in the soil. Robust research is suggested for the inventories.
Screening of Potential Indonesia Herbal Compounds Based on Multi-Label Classification for 2019 Coronavirus Disease
Authors: Fadli Aulia , Kusuma Wisnu Ananta , Annisa  , Batubara Irmanida , Heryanto Rudi
Published: December 2021

Coronavirus disease 2019 pandemic spreads rapidly and requires an acceleration in the process of drug discovery. Drug repurposing can help accelerate the drug discovery process by identifying new efficacy for approved drugs, and it is considered an efficient and economical approach. Research in drug repurposing can be done by observing the interactions of drug compounds with protein related to a disease (DTI), then predicting the new drug-target interactions. This study conducted multilabel DTI prediction using the stack autoencoder-deep neural network (SAE-DNN) algorithm. Compound features were extracted using PubChem fingerprint, daylight fingerprint, MACCS fingerprint, and circular fingerprint. The results showed that the SAE-DNN model was able to predict DTI in COVID-19 cases with good performance. The SAE-DNN model with a circular fingerprint dataset produced the best average metrics with an accuracy of 0.831, recall of 0.918, precision of 0.888, and F-measure of 0.89. Herbal compounds prediction results using the SAE-DNN model with the circular, daylight, and PubChem fingerprint dataset resulted in 92, 65, and 79 herbal compounds contained in herbal plants in Indonesia respectively.
A Wireless Wearable Doppler Ultrasound Detects Changing Stroke Volume: Proof-of-Principle Comparison with Trans-Esophageal Echocardiography during Coronary Bypass Surgery
Authors: Kenny Jon-Émile Stuart , Clarke Geoffrey , Myers Matt , Elfarnawany Mai , Eibl Andrew M. , Eibl Joseph K. , Nalla Bhanu , Atoui Rony
Published: December 2021

Background: A novel, wireless, ultrasound biosensor that adheres to the neck and measures real-time Doppler of the carotid artery may be a useful functional hemodynamic monitor. A unique experimental set-up during elective coronary artery bypass surgery is described as a means to compare the wearable Doppler to trans-esophageal echocardiography (TEE). Methods: A total of two representative patients were studied at baseline and during Trendelenburg position. Carotid Doppler spectra from the wearable ultrasound and TEE were synchronously captured. Areas under the receiver operator curve (AUROC) were performed to assess the accuracy of changing common carotid artery velocity time integral (ccVTI∆) at detecting a clinically significant change in stroke volume (SV∆). Results: Synchronously measuring and comparing Doppler spectra from the wearable ultrasound and TEE is feasible during Trendelenburg positioning. In two representative cardiac surgical patients, the ccVTI∆ accurately detected a clinically significant SV∆ with AUROCs of 0.89, 0.91, and 0.95 when single-beat, 3-consecutive beat and 10-consecutive beat averages were assessed, respectively. Conclusion: In this proof-of-principle research communication, a wearable Doppler ultrasound system is successfully compared to TEE. Preliminary data suggests that the diagnostic accuracy of carotid Doppler ultrasonography at detecting clinically significant SV∆ is enhanced by averaging more cardiac cycles.
Conductive Bioimprint Using Soft Lithography Technique Based on PEDOT:PSS for Biosensing
Authors: Abd. Wahid Nor Azila , Hashemi Azadeh , Evans John J. , Alkaisi Maan M.
Published: December 2021

Culture platform surface topography plays an important role in the regulation of biological cell behaviour. Understanding the mechanisms behind the roles of surface topography in cell response are central to many developments in a Lab on a Chip, medical implants and biosensors. In this work, we report on a novel development of a biocompatible conductive hydrogel (CH) made of poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) and gelatin with bioimprinted surface features. The bioimprinted CH offers high conductivity, biocompatibility and high replication fidelity suitable for cell culture applications. The bioimprinted conductive hydrogel is developed to investigate biological cells’ response to their morphological footprint and study their growth, adhesion, cell–cell interactions and proliferation as a function of conductivity. Moreover, optimization of the conductive hydrogel mixture plays an important role in achieving high imprinting resolution and conductivity. The reason behind choosing a conducive hydrogel with high resolution surface bioimprints is to improve cell monitoring while mimicking cells’ natural physical environment. Bioimprints which are a 3D replication of cellular morphology have previously been shown to promote cell attachment, proliferation, differentiation and even cell response to drugs. The conductive substrate, on the other hand, enables cell impedance to be measured and monitored, which is indicative of cell viability and spread. Two dimensional profiles of the cross section of a single cell taken via Atomic Force Microscopy (AFM) from the fixed cell on glass, and its replicas on polydimethylsiloxane (PDMS) and conductive hydrogel (CH) show unprecedented replication of cellular features with an average replication fidelity of more than 90%. Furthermore, crosslinking CH films demonstrated a significant increase in electrical conductivity from 10−6 S/cm to 1 S/cm. Conductive bioimprints can provide a suitable platform for biosensing applications and potentially for monitoring implant-tissue reactions in medical devices.
Implantable Drug Delivery Systems and Foreign Body Reaction: Traversing the Current Clinical Landscape
Authors: Fayzullin Alexey , Bakulina Alesia , Mikaelyan Karen , Shekhter Anatoly , Guller Anna
Published: December 2021

Precise delivery of therapeutics to the target structures is essential for treatment efficiency and safety. Drug administration via conventional routes requires overcoming multiple transport barriers to achieve and maintain the local drug concentration and commonly results in unwanted off-target effects. Patients’ compliance with the treatment schedule remains another challenge. Implantable drug delivery systems (IDDSs) provide a way to solve these problems. IDDSs are bioengineering devices surgically placed inside the patient’s tissues to avoid first-pass metabolism and reduce the systemic toxicity of the drug by eluting the therapeutic payload in the vicinity of the target tissues. IDDSs present an impressive example of successful translation of the research and engineering findings to the patient’s bedside. It is envisaged that the IDDS technologies will grow exponentially in the coming years. However, to pave the way for this progress, it is essential to learn lessons from the past and present of IDDSs clinical applications. The efficiency and safety of the drug-eluting implants depend on the interactions between the device and the hosting tissues. In this review, we address this need and analyze the clinical landscape of the FDA-approved IDDSs applications in the context of the foreign body reaction, a key aspect of implant–tissue integration.
Spectrum of Clinical Research in Juvenile Idiopathic Arthritis: A Cross-Sectional Analysis of Registered Studies in Clinicaltrials.gov and Clinicaltrialsregister.eu
Authors: Lehmann Ronny , Ries Markus
Published: December 2021

The management of juvenile idiopathic arthritis (JIA) has improved tremendously in recent years due to the introduction of new drug therapies but remains complex in terms of non-pharmaceutical issues. In order to determine the direction of scientific progress by characterizing the current spectrum of ongoing clinical research in JIA, we analyzed all ongoing studies in the field of JIA—registered in clinicaltrials.gov and clinicaltrialsregister.eu—concerning sponsoring, enrollment, duration, localization, and particularly objectives. The close of the database was 7 January 2021. After identifying double-registered studies, n = 72 went into further analysis. Of these, 61.1% were academia-sponsored and 37.5% were sponsored by the pharma industry. The majority of the studies was of the interventional type (77.8%), while others (22.2%) were observational. The median planned enrollments were 100 participants (interventional studies) and 175 participants (observational studies), respectively. The duration differed remarkably from one month to more than 15 years, with a median of 42.5 months. A total of 61.1% of studies were located in a single country, and 38.9% were in several. Europe and North America clearly dominated the study localizations. The study objectives were DMARDs (56.9%), followed by diagnostics and disease activity measurement (18.1%), and medication other than DMARD (12.5%), besides others. Studies on DMARDs were mainly sponsored by industry, predominantly interventional studies on established and novel biologics, with several on specific issues such as systemic JIA and others. The spectrum of registered studies is currently centered on drug therapy and diagnostics, while other issues in JIA play a subordinated role in current research. Drug development was transferred from adult rheumatology into the JIA population with little innovation for children. Future research should take specific pediatric needs better into account.
A Novel Orf Virus D1701-VrV-Based Dengue Virus (DENV) Vaccine Candidate Expressing HLA-Specific T Cell Epitopes: A Proof-of-Concept Study
Authors: Reguzova Alena , Fischer Nico , Müller Melanie , Salomon Ferdinand , Jaenisch Thomas , Amann Ralf
Published: December 2021

Although dengue virus (DENV) affects almost half of the world’s population there are neither preventive treatments nor any long-lasting and protective vaccines available at this time. The complexity of the protective immune response to DENV is still not fully understood. The most advanced vaccine candidates focus specifically on humoral immune responses and the production of virus-neutralizing antibodies. However, results from several recent studies have revealed the protective role of T cells in the immune response to DENV. Hence, in this study, we generated a novel and potent DENV vaccine candidate based on an Orf virus (ORFV, genus Parapoxvirus) vector platform engineered to encode five highly conserved or cross-reactive DENV human leukocyte antigen (HLA)-A*02- or HLA-B*07-restricted epitopes as minigenes (ORFV-DENV). We showed that ORFV-DENV facilitates the in vitro priming of CD8+ T cells from healthy blood donors based on responses to each of the encoded immunogenic peptides. Moreover, we demonstrated that peripheral blood mononuclear cells isolated from clinically confirmed DENV-positive donors stimulated with ORFV-DENV generate cytotoxic T cell responses to at least three of the expressed DENV peptides. Finally, we showed that ORFV-DENV could activate CD8+ T cells isolated from donors who had recovered from Zika virus (ZIKV) infection. ZIKV belongs to the same virus family (Flaviviridae) and has epitope sequences that are homologous to those of DENV. We found that highly conserved HLA-B*07-restricted ZIKV and DENV epitopes induced functional CD8+ T cell responses in PBMCs isolated from confirmed ZIKV-positive donors. In summary, this proof-of-concept study characterizes a promising new ORFV D1701-VrV-based DENV vaccine candidate that induces broad and functional epitope-specific CD8+ T cell responses.
Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1
Authors: Chen Nan , Higashiyama Nicole , Hoyos Valentina
Published: December 2021

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.
Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis
Authors: Fu Yu-Hsuan , Tseng Chi-Yang , Lu Jeng-Wei , Lu Wen-Hui , Lan Pei-Qi , Chen Chien-Yuan , Ou Da-Liang , Lin Liang-In
Published: December 2021

Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10−6] and to endoplasmic reticulum stress [p-value = 8.67 × 10−7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10−8], and responses to a redox state [p-value = 5.80 × 10−5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10−8] and an ATP metabolic process [p-value = 3.95 × 10−4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.
Validity of Anti-PSMA ScFvD2B as a Theranostic Tool: A Narrative-Focused Review
Authors: Frigerio Barbara , Luison Elena , Desideri Alessandro , Iacovelli Federico , Camisaschi Chiara , Seregni Ettore C. , Canevari Silvana , Figini Mariangela
Published: December 2021

Prostate cancer (PCa) is the second leading cause of cancer among men, and its diagnosis and adequate staging are fundamental. Among the biomarkers identified in recent years for PCa management, prostate-specific-membrane-antigen (PSMA), physiologically expressed at a low level on healthy prostate and in other normal tissues and highly overexpressed in PCa, represents a reliable marker ideal for imaging and therapy. The development of anti-PSMA antibodies, such as D2B, demonstrated slow clearance of intact antibodies compared with fragments resulting in low tumor-to-blood ratios; however, the modular structural and functional nature of antibodies allowed the generation of smaller fragments, such as scFvs. In this review of the anti-PSMA antibody fragment scFvD2B, we combined further characterization of its biomolecular and tissue cross-reactivity characteristics with a comprehensive summary of what has already been performed in preclinical models to evaluate imaging and therapeutic activities. A molecular dynamics study was performed, and ScFvD2B occupied a limited conformational space, characterized by low-energy conformational basins, confirming the high stability of the protein structure. In the cross-reactivity study, the weak/absent immunoreactivity in non-tumor tissues was comparable to the PSMA expression reported in the literature. Biodistribution studies and therapeutic treatments were conducted in different animal models obtained by subcutaneous or locoregional injection of PSMA-positive-versus-negative xenografts. The maximum tumor uptake was observed for 123I(SPECT), 124I(PET), and optical imaging, which avoids kidney accumulation (compared with radiometals) and leads to an optimal tumor-to-kidney and tumor-to-background ratios. Regarding its possible use in therapy, experimental data suggested a strong and specific antitumor activity, in vitro and in vivo, obtained using CAR-T or NK-92/CAR cells expressing scFvD2B. Based on presented/reviewed data, we consider that scFvD2B, due to its versatility and robustness, seems to: (i) overcome some problems observed in other studied scFvs, very often relatively unstable and prone to form aggregates; (ii) have sufficient tumor-to-background ratios for targeting and imaging PSMA-expressing cancer; (iii) significantly redirect immune killing cells to PSMA-positive tumors when inserted in second-generation CAR-T or NK-92/CAR cells. These data suggest that our product can be considered the right reagent to fill the gap that still exists in PCa diagnosis and treatment.
Vitamin D Prevents High Glucose-Induced Lipid Droplets Accumulation in Cultured Endothelial Cells: The Role of Thioredoxin Interacting Protein
Authors: Scrimieri Roberta , Cazzaniga Alessandra , Castiglioni Sara , Maier Jeanette A. M.
Published: December 2021

Vitamin D (VitD) exerts protective effects on the endothelium, which is fundamental for vascular integrity, partly by inhibiting free radical formation. We found that VitD prevents high glucose-induced Thioredoxin Interacting Protein (TXNIP) upregulation. Increased amounts of TXNIP are responsible for the accumulation of reactive oxygen species and, as a consequence, of lipid droplets. This is associated with increased amounts of triglycerides as the result of increased lipogenesis and reduced fatty acid oxidation. Remarkably, VitD rebalances the redox equilibrium, restores normal lipid content, and prevents the accumulation of lipid droplets. Our results highlight TXNIP as one of the targets of VitD in high glucose-cultured endothelial cells and shed some light on the protective effect of VitD on the endothelium.
α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson’s Disease
Authors: Stokholm Kathrine , Thomsen Majken Borup , Phan Jenny-Ann , Møller Line K. , Bay-Richter Cecilie , Christiansen Søren H. , Woldbye David P. D. , Romero-Ramos Marina , Landau Anne M.
Published: December 2021

Progressive degeneration of dopaminergic neurons, immune activation, and α-synuclein pathology characterize Parkinson’s disease (PD). We previously reported that unilateral intranigral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human α-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding α-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: (1) in situ hybridization of nigral tyrosine hydroxylase mRNA, (2) HPLC of striatal dopamine content, and (3) autoradiography with [3H]raclopride, [3H]DTBZ, [3H]GBR12935, [3H]PK11195, and [3H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mitochondrial translocator protein, and SV2A, respectively. rAAV-α-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, α-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.
Brochosome-Inspired Metal-Containing Particles as Biomimetic Building Blocks for Nanoplasmonics: Conceptual Generalizations
Authors: Jakšić Zoran , Obradov Marko , Jakšić Olga
Published: December 2021

Recently, biological nanostructures became an important source of inspiration for plasmonics, with many described implementations and proposed applications. Among them are brochosome-inspired plasmonic microstructures—roughly spherical core-shell particles with submicrometer diameters and with indented surfaces. Our intention was to start from the nanoplasmonic point of view and to systematically classify possible alternative forms of brochosome-inspired metal-containing particles producible by the state-of-the-art nanofabrication. A wealth of novel structures arises from this systematization of bioinspired metal-containing nanocomposites. Besides various surface nanoapertures, we consider structures closely related to them in electromagnetic sense like surface nano-protrusions, shell reliefs obtained by nano-sculpting, and various combinations of these. This approach helped us build a new design toolbox for brochosome-inspired structures. Additionally, we used the finite elements method to simulate the optical properties of simple brochosome-inspired structures. We encountered a plethora of advantageous optical traits, including enhanced absorption, antireflective properties, and metamaterial behavior (effective refractive index close to zero or negative). We conclude that the presented approach offers a wealth of traits useful for practical applications. The described research represents our attempt to outline a possible roadmap for further development of bioinspired nanoplasmonic particles and to offer a source of ideas and directions for future research.
Conventional and Algorithmic Music Listening before Radiotherapy Treatment: A Randomized Controlled Pilot Study
Authors: Raglio Alfredo , Oddone Enrico , Meaglia Ilaria , Monti Maria Cristina , Gnesi Marco , Gontero Giulia , Imbriani Chiara , Ivaldi Giovanni Battista
Published: December 2021

Music listening is a widespread approach in the field of music therapy. In this study, the effects of music listening on anxiety and stress in patients undergoing radiotherapy are investigated. Sixty patients with breast cancer who were candidates for postoperative curative radiotherapy were recruited and randomly assigned to three groups: Melomics-Health (MH) group (music listening algorithmically created, n = 20); individualized music listening (IML) group (playlist of preferred music, n = 20); no music group (n = 20). Music listening was administered for 15 min immediately before simulation and during the first five radiotherapy sessions. The State-Trait Anxiety Inventory (STAI) and the Psychological Distress Inventory (PDI) were administered before/after treatment. Cochran’s Q test and McNemar test for paired proportions were performed to evaluate if the proportion of subjects having an outcome score below the critical value by treatment and over time was different, and if there was a change in that proportion. The MH group improved in STAI and PDI. The IML group worsened in STAI at T1 and improved STAI-Trait at T2. The IML group worsened in PDI at T2. The No music group generally improved in STAI and PDI. Clinical and music listening-related implications are discussed defining possible research perspectives in this field.
Effect of Sensory Deprivation of Nasal Respiratory on Behavior of C57BL/6J Mice
Authors: Zhu Yongji , Ye Yujing , Zhou Chenyang , Sun Siqi , Zhang Jingjing , Zhao Zixuan , Sun Tingting , Li Jing , Yang Jing , Li Weiyun , Li Shanshan
Published: December 2021

Nasal breathing is a dynamic cortical organizer involved in various behaviors and states, such as locomotion, exploration, memory, emotion, introspection. However, the effect of sensory deprivation of nasal respiratory breath (NRD) on behavior remain poorly understood. Herein, general locomotor activity, emotion, learning and memory, social interaction, and mechanical pain were evaluated using a zinc sulfate nasal irrigation induced nasal respiratory sensory deprivation animal model (ZnSO4-induced mouse model). In the open field test, the elevated O-maze test, and forced swim test, NRD mice exhibited depressive and anxiety-like behaviors. In memory-associated tests, NRD mice showed cognitive impairments in the hippocampal-dependent memory (Y maze, object recognition task, and contextual fear conditioning (CFC)) and amygdala-dependent memory (the tone-cued fear conditioning test (TFC)). Surprisingly, NRD mice did not display deficits in the acquisition of conditional fear in both CFC and TFC tests. Still, they showed significant memory retrieval impairment in TFC and enhanced memory retrieval in CFC. At the same time, in the social novelty test using a three-chamber setting, NRD mice showed impaired social and social novelty behavior. Lastly, in the von Frey filaments test, we found that the pain sensitivity of NRD mice was reduced. In conclusion, this NRD mouse model showed a variety of behavioral phenotypic changes, which could offer an important insight into the behavioral impacts of patients with anosmia or those with an impaired olfactory bulb (OB) (e.g., in COVID-19, Alzheimer’s disease, Parkinson’s disease, etc.).
Prediction of Clinically Significant Cancer Using Radiomics Features of Pre-Biopsy of Multiparametric MRI in Men Suspected of Prostate Cancer
Authors: Ogbonnaya Chidozie N. , Zhang Xinyu , Alsaedi Basim S. O. , Pratt Norman , Zhang Yilong , Johnston Lisa , Nabi Ghulam
Published: December 2021

Background: Texture features based on the spatial relationship of pixels, known as the gray-level co-occurrence matrix (GLCM), may play an important role in providing the accurate classification of suspected prostate cancer. The purpose of this study was to use quantitative imaging parameters of pre-biopsy multiparametric magnetic resonance imaging (mpMRI) for the prediction of clinically significant prostate cancer. Methods: This was a prospective study, recruiting 200 men suspected of having prostate cancer. Participants were imaged using a protocol-based 3T MRI in the pre-biopsy setting. Radiomics parameters were extracted from the T2WI and ADC texture features of the gray-level co-occurrence matrix were delineated from the region of interest. Radical prostatectomy histopathology was used as a reference standard. A Kruskal–Wallis test was applied first to identify the significant radiomic features between the three groups of Gleason scores (i.e., G1, G2 and G3). Subsequently, the Holm–Bonferroni method was applied to correct and control the probability of false rejections. We compared the probability of correctly predicting significant prostate cancer between the explanatory GLCM radiomic features, PIRADS and PSAD, using the area under the receiver operation characteristic curves. Results: We identified the significant difference in radiomic features between the three groups of Gleason scores. In total, 12 features out of 22 radiomics features correlated with the Gleason groups. Our model demonstrated excellent discriminative ability (C-statistic = 0.901, 95%CI 0.859–0.943). When comparing the probability of correctly predicting significant prostate cancer between explanatory GLCM radiomic features (Sum Variance T2WI, Sum Entropy T2WI, Difference Variance T2WI, Entropy ADC and Difference Variance ADC), PSAD and PIRADS via area under the ROC curve, radiomic features were 35.0% and 34.4% more successful than PIRADS and PSAD, respectively, in correctly predicting significant prostate cancer in our patients (p < 0.001). The Sum Entropy T2WI score had the greatest impact followed by the Sum Variance T2WI. Conclusion: Quantitative GLCM texture analyses of pre-biopsy MRI has the potential to be used as a non-invasive imaging technique to predict clinically significant cancer in men suspected of having prostate cancer.