bluuebunny/crossref_metadata_2025 huggingface dataset:
Public Opinion Spread and Guidance Strategy under COVID-19: A SIS Model Analysis
Authors: You Ge , Gan Shangqian , Guo Hao , Dagestani Abd Alwahed
Published: June 2022

Both the suddenness and seriousness of COVID-19 have caused a variety of public opinions on social media, which becomes the focus of social attention. This paper aims to analyze the strategies regarding the prevention and guidance of public opinion spread under COVID-19 in social networks from the perspective of the emotional characteristics of user texts. Firstly, a model is established to mine text-based emotional tendency based on the Susceptible-Infectious-Susceptible (SIS) model. In addition, a mathematical and simulation analysis of the model is presented. Finally, an empirical study based on the data of microblog contents regarding COVID-19 public opinion in the Sina Weibo platform from January to March 2020 is conducted to analyze the factors that boost and hinder COVID-19 public opinion. The results show that when positive emotion is higher than 0.8, the spread of negative public opinion can be blocked. When the negative emotion and neutral emotion are both below 0.2, the spread of COVID-19 public opinion would be weakened. To accurately guide public opinion on COVID-19, the government authorities should establish a public opinion risk evaluation and an early warning mechanism. Platforms should strengthen public opinion supervision and users should improve their media literacy. The media organizations should insist on positive reporting, improve social cohesion, and guide the trend of public opinion.
Revisiting the Tigger Transposon Evolution Revealing Extensive Involvement in the Shaping of Mammal Genomes
Authors: Diaby Mohamed , Guan Zhongxia , Shi Shasha , Sang Yatong , Wang Saisai , Wang Yali , Zong Wencheng , Ullah Numan , Gao Bo , Song Chengyi
Published: June 2022

The data of this study revealed that Tigger was found in a wide variety of animal genomes, including 180 species from 36 orders of invertebrates and 145 species from 29 orders of vertebrates. An extensive invasion of Tigger was observed in mammals, with a high copy number. Almost 61% of those species contain more than 50 copies of Tigger; however, 46% harbor intact Tigger elements, although the number of these intact elements is very low. Common HT events of Tigger elements were discovered across different lineages of animals, including mammals, that may have led to their widespread distribution, whereas Helogale parvula and arthropods may have aided Tigger HT incidences. The activity of Tigger seems to be low in the kingdom of animals, most copies were truncated in the mammal genomes and lost their transposition activity, and Tigger transposons only display signs of recent and current activities in a few species of animals. The findings suggest that the Tigger family is important in structuring mammal genomes.
The Status of Posidonia oceanica at Tremiti Islands Marine Protected Area (Adriatic Sea)
Authors: Tursi Andrea , Mastrototaro Francesco , Montesanto Federica , De Giosa Francesco , Lisco Anna , Bottalico Antonella , Chimienti Giovanni
Published: June 2022

Posidonia oceanica meadows are Mediterranean coastal habitats of great conservation importance. This study is focused on a meadow located at Tremiti Islands Marine Protected Area (Adriatic Sea, Italy), which was monitored in 2003, 2015, and 2020 to evaluate its health state over time in relation to coastal human activities, which have been highly affecting this MPA for the last 20 years. To assess any change in the physiognomy of the meadow, rhizome density, percentage coverage, and lower limit progressions and/or regression over time were evaluated by scuba diving, while the distribution and extension of the meadow were assessed through habitat mapping using a side-scan sonar. Moreover, phenological and lepidochronological analyses were performed on the collected rhizomes to assess the leaf area index (LAI, m2m−2) and the rhizome age (lepidochronological years). Our study showed a general deterioration of P. oceanica meadow from 2003 to 2020, with a significant reduction of its absolute and relative rhizome density and LAI at almost all sampling stations, absence of renovation of the meadow, and lower limit regression and overall worsening of the main conservation status indicators. However, appropriate management actions, such as the establishment of mooring buoy fields, supported the improvement of the P. oceanica status at the local scale with a significant increase in density and LAI and the presence of active stolonization processes, suggesting that mitigation actions can play a crucial role in the conservation of this habitat. On the contrary, local anthropogenic impacts, especially anchoring and coastal development, markedly affect the resilience of P. oceanica meadows to global stressors, such as climate change.
Sex-Related Pain Behavioral Differences following Unilateral NGF Injections in a Rat Model of Low Back Pain
Authors: Syrett Michael , Reed Nicholas R. , Reed William R. , Richey Madison L. , Frolov Andrey , Little Joshua W.
Published: June 2022

Low back pain (LBP) is a globally prevalent and costly societal problem with multifactorial etiologies and incompletely understood pathophysiological mechanisms. To address such shortcomings regarding the role of neurotrophins in the underlying mechanisms of pain, an LBP model was developed in rats involving two unilateral intramuscular injections of nerve growth factor (NGF) into deep trunk muscles. To date, behavioral investigations of this NGF-LBP model have been limited, especially as it pertains to female pain behaviors. This study compared mechanical sensitivity to noxious (hyperalgesia) and non-noxious (hypersensitivity) stimuli in control and NGF-injected male and female rats through pain resolution. Although the baseline testing revealed no differences between males and females, NGF-injected females demonstrated prolonged ipsilateral deep trunk mechanical hyperalgesia that resolved seven days later than males. Moreover, females showed bilateral trunk mechanical sensitivity to noxious and non-noxious stimuli compared to only ipsilateral behaviors in males. Sex differences were also observed in the severity of behavioral responses, with females displaying greater mean differences from baseline at several timepoints. Overall, these NGF-LBP behavioral findings mirror some of the sex differences reported in the clinical presentation of LBP and accentuate the translatability of this NGF-LBP model. Future studies using this LBP-NGF model could help to elucidate the neurobiological mechanisms responsible for the development, severity, and/or resolution of muscular LBP as well as to provide insights into the processes governing the transition from acute to chronic LBP.
Automated Protein Secondary Structure Assignment from Cα Positions Using Neural Networks
Authors: Saqib Mohammad N. , Kryś Justyna D. , Gront Dominik
Published: June 2022

The assignment of secondary structure elements in protein conformations is necessary to interpret a protein model that has been established by computational methods. The process essentially involves labeling the amino acid residues with H (Helix), E (Strand), or C (Coil, also known as Loop). When particular atoms are absent from an input protein structure, the procedure becomes more complicated, especially when only the alpha carbon locations are known. Various techniques have been tested and applied to this problem during the last forty years. The application of machine learning techniques is the most recent trend. This contribution presents the HECA classifier, which uses neural networks to assign protein secondary structure types. The technique exclusively employs Cα coordinates. The Keras (TensorFlow) library was used to implement and train the neural network model. The BioShell toolkit was used to calculate the neural network input features from raw coordinates. The study’s findings show that neural network-based methods may be successfully used to take on structure assignment challenges when only Cα trace is available. Thanks to the careful selection of input features, our approach’s accuracy (above 97%) exceeded that of the existing methods.
Influence of Inhibition of COX-2-Dependent Lipid Metabolism on Regulation of UVB-Induced Keratinocytes Apoptosis by Cannabinoids
Authors: Wójcik Piotr , Biernacki Michał , Domian Natalia , Žarković Neven , Skrzydlewska Elżbieta
Published: June 2022

Inflammation and apoptosis are regulated by similar factors, including ultraviolet B (UVB) radiation and cannabinoids, which are metabolized by cyclooxygenase-2 (COX-2) into pro-apoptotic prostaglandin derivatives. Thus, the aim of this study was to evaluate the impact of cyclooxygenase-2 inhibition by celecoxib on the apoptosis of keratinocytes modulated by UVB, anandamide (AEA) and cannabidiol (CBD). For this purpose, keratinocytes were non-treated/treated with celecoxib and/or with UVB and CBD and AEA. Apoptosis was evaluated using microscopy, gene expressions using quantitate reverse-transcriptase polymerase chain reaction; prostaglandins using liquid chromatography tandem mass spectrometry and cyclooxygenase activity using spectrophotometry. UVB enhances the percentage of apoptotic keratinocytes, which can be caused by the increased prostaglandin generation by cyclooxygenase-2, or/and induced cannabinoid receptor 1/2 (CB1/2) expression. AEA used alone intensifies apoptosis by affecting caspase expression, and in UVB-irradiated keratinocytes, cyclooxygenase-2 activity is increased, while CBD acts as a cytoprotective when used with or without UVB. After COX-2 inhibition, UVB-induced changes are partially ameliorated, when anandamide becomes an anti-apoptotic agent. It can be caused by observed reduced generation of anandamide pro-apoptotic derivative prostaglandin-ethanolamide by COX. Therefore, products of cyclooxygenase-dependent lipid metabolism seem to play an important role in the modulation of UVB-induced apoptosis by cannabinoids, which is particularly significant in case of AEA as inhibition of cyclooxygenase reduces the generation of pro-apoptotic lipid mediators and thus prevents apoptosis.
A High-Throughput MEMS-Based Differential Scanning Calorimeter for Direct Thermal Characterization of Antibodies
Authors: Yu Shifeng , Wu Yongjia , Wang Shuyu , Siedler Michael , Ihnat Peter M. , Filoti Dana I. , Lu Ming , Zuo Lei
Published: June 2022

Calorimeters, which can be used for rapid thermal characterization of biomolecules, are getting intense attention in drug development. This paper presents a novel MEMS-based differential scanning calorimeter (DSC) for direct thermal characterization of protein samples. The DSC consisted of a pair of temperature sensors made by vanadium oxide (VOx) film with a temperature coefficient of resistivity of −0.025/K at 300 K, a microfluidic device with high thermal insulation (2.8 K/mW), and a Peltier heater for linear temperature scanning. The DSC exhibited high sensitivity (6.1 µV/µW), low noise (0.4 µW), high scanning rate (45 K/min), and low sample consumption volume (0.63 µL). The MEMS DSC was verified by measuring the temperature-induced denaturation of lysozyme at different pH, and then used to study the thermal stability of a monoclonal antibody (mAb), an antigen-binding fragment (Fab), and a dual variable domain immunoglobulin (DVD-Ig) at pH = 6. The results showed that lysozyme is a stable protein in the pH range of 4.0–8.0. The protein stability study revealed that the transition temperatures of the intact Fab fragment, mAb, and DVD proteins were comparable with conformational stability results obtained using conventional commercial DSC. These studies demonstrated that the MEMS DSC is an effective tool for directly understanding the thermal stability of antibodies in a high-throughput and low-cost manner compared to conventional calorimeters.
Rapid Quantification of SARS-Cov-2 Spike Protein Enhanced with a Machine Learning Technique Integrated in a Smart and Portable Immunosensor
Authors: Fortunati Simone , Giliberti Chiara , Giannetto Marco , Bolchi Angelo , Ferrari Davide , Donofrio Gaetano , Bianchi Valentina , Boni Andrea , De Munari Ilaria , Careri Maria
Published: June 2022

An IoT-WiFi smart and portable electrochemical immunosensor for the quantification of SARS-CoV-2 spike protein was developed with integrated machine learning features. The immunoenzymatic sensor is based on the immobilization of monoclonal antibodies directed at the SARS-CoV-2 S1 subunit on Screen-Printed Electrodes functionalized with gold nanoparticles. The analytical protocol involves a single-step sample incubation. Immunosensor performance was validated in a viral transfer medium which is commonly used for the desorption of nasopharyngeal swabs. Remarkable specificity of the response was demonstrated by testing H1N1 Hemagglutinin from swine-origin influenza A virus and Spike Protein S1 from Middle East respiratory syndrome coronavirus. Machine learning was successfully used for data processing and analysis. Different support vector machine classifiers were evaluated, proving that algorithms affect the classifier accuracy. The test accuracy of the best classification model in terms of true positive/true negative sample classification was 97.3%. In addition, the ML algorithm can be easily integrated into cloud-based portable Wi-Fi devices. Finally, the immunosensor was successfully tested using a third generation replicating incompetent lentiviral vector pseudotyped with SARS-CoV-2 spike glycoprotein, thus proving the applicability of the immunosensor to whole virus detection.
Wearable Flexible Electronics Based Cardiac Electrode for Researcher Mental Stress Detection System Using Machine Learning Models on Single Lead Electrocardiogram Signal
Authors: Bin Heyat Md Belal , Akhtar Faijan , Abbas Syed Jafar , Al-Sarem Mohammed , Alqarafi Abdulrahman , Stalin Antony , Abbasi Rashid , Muaad Abdullah Y. , Lai Dakun , Wu Kaishun
Published: June 2022

In the modern world, wearable smart devices are continuously used to monitor people’s health. This study aims to develop an automatic mental stress detection system for researchers based on Electrocardiogram (ECG) signals from smart T-shirts using machine learning classifiers. We used 20 subjects, including 10 from mental stress (after twelve hours of continuous work in the laboratory) and 10 from normal (after completing the sleep or without any work). We also applied three scoring techniques: Chalder Fatigue Scale (CFS), Specific Fatigue Scale (SFS), Depression, Anxiety, and Stress Scale (DASS), to confirm the mental stress. The total duration of ECG recording was 1800 min, including 1200 min during mental stress and 600 min during normal. We calculated two types of features, such as demographic and extracted by ECG signal. In addition, we used Decision Tree (DT), Naive Bayes (NB), Random Forest (RF), and Logistic Regression (LR) to classify the intra-subject (mental stress and normal) and inter-subject classification. The DT leave-one-out model has better performance in terms of recall (93.30%), specificity (96.70%), precision (94.40%), accuracy (93.30%), and F1 (93.50%) in the intra-subject classification. Additionally, The classification accuracy of the system in classifying inter-subjects is 94.10% when using a DT classifier. However, our findings suggest that the wearable smart T-shirt based on the DT classifier may be used in big data applications and health monitoring. Mental stress can lead to mitochondrial dysfunction, oxidative stress, blood pressure, cardiovascular disease, and various health problems. Therefore, real-time ECG signals help assess cardiovascular and related risk factors in the initial stage based on machine learning techniques.
Nanocomposite of MgFe2O4 and Mn3O4 as Polyphenol Oxidase Mimic for Sensing of Polyphenols
Authors: Kaur Harmilan , Kaur Manpreet , Aggarwal Renuka , Sharma Sucheta , Singh Davinder
Published: June 2022

Polyphenol oxidase (PPO) mimics have advantage of detection and remediation of polyphenols. This work demonstrates rapid and sensitive colorimetric detection of phenolic compounds using nanocomposite of magnesium ferrite (MgFe2O4) and manganese oxide (Mn3O4) nanoparticles as PPO mimic. The catalytic properties of MgFe2O4 and Mn3O4 displayed synergistic effect in the nanocomposite. The synthesized nanocomposite and nanoparticles were fully characterized using various analytical techniques. The ratio of MgFe2O4 and Mn3O4 in the nanocomposite was optimized. Catechol and resorcinol were taken as model polyphenols. The best PPO-activity was shown by MgFe2O4@Mn3O4 nanocomposite with of w/w ratio 1:2. The results correlated with its higher surface area. Reaction parameters viz. pH, temperature, contact time, substrate concentration, and nanoparticles dose were studied. The synthesized MgFe2O4@Mn3O4 nanocomposite was used for the detection of catechol in the linear range of 0.1–0.8 mM with the detection limit of 0.20 mM, and resorcinol in the range of 0.01–0.08 mM with the detection limit of 0.03 mM. The estimated total phenolic content of green and black tea correlated well with the conventional method. These results authenticate promising future potential of MgFe2O4@Mn3O4 nanocomposite as PPO-mimic
Vitamin D Status and Parkinson’s Disease
Authors: Barichella Michela , Garrì Federica , Caronni Serena , Bolliri Carlotta , Zocchi Luciano , Macchione Maria Carmela , Ferri Valentina , Calandrella Daniela , Pezzoli Gianni
Published: June 2022

Parkinson’s disease (PD) is a complex and progressive neurodegenerative disease, characterized by resting tremor, rigidity, slowness of movement, and postural instability. Furthermore, PD is associated with a wide spectrum of non-motor symptoms that add to overall disability. In recent years, some investigations, from basic science to clinical applications, have focused on the role of vitamin D in PD, often with controversial findings. Vitamin D has widespread effects on several biological processes in the central nervous system, including neurotransmission in dopaminergic neural circuits. Various studies have recorded lower levels of vitamin D in PD patients than in healthy controls. Low vitamin D status has also been correlated with the risk for PD and motor severity, whereas less is known about the effects vitamin D has on cognitive function and other non-motor symptoms. This review aims to better characterize the correlation between vitamin D and PD, clarify the role of vitamin D in PD prevention and treatment, and discuss avenues for future research in this field.
Association of High Ratio of CSF/Plasma HIV-1 RNA with Central Nervous System Co-Infection in HIV-1-Positive Treatment-Naive Patients
Authors: Liu Qian , Tao Wendan , Yang Honghong , Wu Yushan , Yu Qing , Liu Min
Published: June 2022

Cerebrospinal fluid (CSF) human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) at higher levels than in plasma has been observed in HIV-1-positive patients and defined as CSF/plasma discordance or CSF escape. Discordance is particularly seen in untreated patients with antiretroviral agents. Quantitative data regarding its association with blood–brain barrier (BBB) damage and intracranial co-infection with other pathogens are limited. Therefore, we used the CSF to plasma HIV-1 RNA ratio (HRR) to determine its relation to central nervous system (CNS) co-infection in HIV-1-positive treatment-naïve individuals. We retrospectively recruited the subjects with HIV-1-positive and potential neurological deficits. A lumbar puncture was performed before the antiretroviral therapy. The paired CSF/plasma HIV-1 RNA samples were analyzed. Univariate and multivariate logistic regression models and multiple spine regression analyses were performed to assess the association between the HRR and CNS co-infection. A total of 195 patients with 78% males (median age: 49 years) were included in this study, of whom 98 (50.2%) had CNS co-infection with other pathogens. The receiver-operating characteristic curve analysis showed that the optimal cutoff value for the HRR to predict the CNS co-infection was 1.00. Higher HRR (≥1) was significantly associated with tuberculous meningitis (OR 6.50, 95% CI 2.08–20.25, p = 0.001), cryptococcus meningitis (OR 7.58, 95% CI 2.10–27.32, p = 0.001), and multiple co-infection (OR 4.04, 95% CI 1.02–16.04, p = 0.047). Higher HRR (≥1) (OR 3.01, 95% CI 1.09–8.73, p = 0.032) was independently associated with the CNS co-infection after adjusting for covariates. No significant nonlinear association was found between the HRR and CNS co-infection in the multivariate spline regression (p > 0.05) and a positive relationship was found between the HRR and CNS co-infection when the HRR was ≥0.78. Higher HRR was associated with an increased risk of CNS co-infection in HIV-1-positive patients. The relationship between the HRR and CNS co-infection may be related to the BBB disturbance and warrants further investigation with a large, longitudinal cohort.
A Single Session of SMR-Neurofeedback Training Improves Selective Attention Emerging from a Dynamic Structuring of Brain–Heart Interplay
Authors: Bouny Pierre , Arsac Laurent M. , Pratviel Yvan , Boffet Alexis , Touré Cuq Emma , Deschodt-Arsac Veronique
Published: June 2022

Research on sensorimotor rhythms (SMR) based on neurofeedback (NFb) emphasizes improvements in selective attention associated with SMR amplification. However, the long-term training proposed in most studies posed the question of acceptability, which led to the evaluation of the potential of a single NFb session. Based on cognitive and autonomic controls interfering with attention processes, we hypothesized changes in selective attention after a single SMR-NFb session, along with changes in brain–heart interplay, which are reflected in the multifractality of heartbeat dynamics. Here, young healthy participants (n = 35, 20 females, 21 ± 3 years) were randomly assigned either to a control group (Ctrl) watching a movie or to a neurofeedback (NFb) group performing a single session of SMR-NFb. A headset with EEG electrodes (positioned on C3 and C4) connected to a smartphone app served to guide and to evaluate NFb training efficacy. A Stroop task was performed for 8 min by each group before and after the intervention (movie vs. SMR-NFb) while collecting heart rate variability and C4-EEG for 20 min. When compared to Ctrl, the NFb group exhibited better Stroop performance, especially when facing incongruent trials. The multifractality and NFb training efficacy were identified as strong predictors of the gain in global Stroop performance, while multifractality was the only predictor regarding incongruent trials. We conclude that a single session of SMR-NFb improves selective attention in healthy individuals through the specific reorganization of brain–heart interplay, which is reflected in multifractal heartbeat dynamics.
SwinBTS: A Method for 3D Multimodal Brain Tumor Segmentation Using Swin Transformer
Authors: Jiang Yun , Zhang Yuan , Lin Xin , Dong Jinkun , Cheng Tongtong , Liang Jing
Published: June 2022

Brain tumor semantic segmentation is a critical medical image processing work, which aids clinicians in diagnosing patients and determining the extent of lesions. Convolutional neural networks (CNNs) have demonstrated exceptional performance in computer vision tasks in recent years. For 3D medical image tasks, deep convolutional neural networks based on an encoder–decoder structure and skip-connection have been frequently used. However, CNNs have the drawback of being unable to learn global and remote semantic information well. On the other hand, the transformer has recently found success in natural language processing and computer vision as a result of its usage of a self-attention mechanism for global information modeling. For demanding prediction tasks, such as 3D medical picture segmentation, local and global characteristics are critical. We propose SwinBTS, a new 3D medical picture segmentation approach, which combines a transformer, convolutional neural network, and encoder–decoder structure to define the 3D brain tumor semantic segmentation job as a sequence-to-sequence prediction challenge in this research. To extract contextual data, the 3D Swin Transformer is utilized as the network’s encoder and decoder, and convolutional operations are employed for upsampling and downsampling. Finally, we achieve segmentation results using an improved Transformer module that we built for increasing detail feature extraction. Extensive experimental results on the BraTS 2019, BraTS 2020, and BraTS 2021 datasets reveal that SwinBTS outperforms state-of-the-art 3D algorithms for brain tumor segmentation on 3D MRI scanned images.
Temperamental Change in Adolescence and Its Predictive Role on Anxious Symptomatology
Authors: Balle Maria , Fiol-Veny Aina , de la Torre-Luque Alejandro , Llabres Jordi , Bornas Xavier
Published: June 2022

Growing evidence supports the hypothesis that temperamental traits are not static throughout adolescence. The known links between both reactive and regulatory temperament and anxiety symptoms should be investigated bearing this hypothesis in mind. This study collected self-reported data on behavioral inhibition system (BIS) sensitivity, attentional control (AC), and anxiety symptomatology, from 296 adolescents (64.2% girls; M = 12.96 years at the first assessment, SD = 0.47) every six months, four times over eighteen months. The relationships between temperament factors (AC and BIS sensitivity), considered longitudinally (by means of their trajectories) and anxiety symptoms were investigated using Multigroup Latent Growth Modeling (MLGM), as well as the mediating effect of sex on trajectories and anxiety. BIS sensitivity decreased over time and showed differential patterns across sexes. AC remained relatively stable and we found no sex influence on its trajectory. On the other hand, we observed that the BIS sensitivity trajectory was a significant predictor of anxiety symptomatology at age 15. In conclusion, temperamental changes between the ages of 13 and 15 seem to play a relevant role in explaining subsequent anxiety symptomatology, under the mediating influence of sex.
Seismic Resilience Assessment in Optimally Integrated Retrofitting of Existing School Buildings in Italy
Authors: Carofilis Gallo Wilson Wladimir Carofilis , Clemett Nicholas , Gabbianelli Giammaria , O’Reilly Gerard , Monteiro Ricardo
Published: June 2022

Modern society requires that structures exhibit greater levels of resilience, especially under earthquakes. The seismic resilience of buildings is thus gaining increased attention as a particular, beyond-code approach. Seismically retrofitted buildings behave satisfactorily under expected earthquake scenarios; however, this does not guarantee operativity after a seismic event. This study critically reviews several methods currently available in the literature that quantify the seismic resilience level of buildings from different perspectives. An existing reinforced concrete school building, retrofitted according to four distinct strategies, is first evaluated in terms of seismic resilience levels. The overview and critical analysis of available resilience assessment frameworks determine the most suitable parameters to measure the seismic resilience for buildings. Subsequently, this metric is incorporated as an additional decision variable into an integrated seismic and energy retrofitting set of strategies. A multicriteria decision-making analysis is performed to select the optimally combined seismic and energy retrofitting alternative under social, technical, environmental evaluation, and seismic resilience aspects. We show how resilience impacts the preference for integrated seismic and energy retrofitting strategies, especially when this metric is considered as an annualized expected value.
A Real-World Systematic Analysis of Driver Mutations’ Prevalence in Early- and Advanced-Stage NSCLC: Implications for Targeted Therapies in the Adjuvant Setting
Authors: Terrenato Irene , Ercolani Cristiana , Di Benedetto Anna , Gallo Enzo , Melucci Elisa , Casini Beatrice , Rollo Francesca , Palange Aldo , Visca Paolo , Pescarmona Edoardo , Melis Enrico , Gallina Filippo , Sacconi Andrea , Cecere Fabiana Letizia , Landi Lorenza , Cappuzzo Federico , Ciliberto Gennaro , Buglioni Simonetta
Published: June 2022

The approval of osimertinib for adjuvant treatment of stage I–II–III EGFR-mutated NSCLC (early stage) represents a paradigm shift, raising the question of whether other genotype-matched therapeutics approved for advanced-stage NSCLC can also provide clinical benefit in the adjuvant setting. However, there is a paucity of real-world data on the prevalence of actionable genomic alterations (GAs) in early-stage NSCLC. We used next-generation sequencing, complemented by immunohistochemistry and fluorescence in situ hybridization, to screen our single-institution cohort of 1961 NSCLC consecutive cases for actionable molecular targets. The prevalence of actionable GAs was comparable in early versus advanced-stage NSCLC, the only exception being KRAS mutations (more frequent in early-stage cases). Consistent with advanced-stage tumors being more aggressive, co-occurrence of TP53 and EGFR GAs as well as copy number gains were less frequent in early-stage tumors. EGFR mutations and high expression of PD-L1 were inversely associated, whereas KRAS mutations and high PD-L1 reactivity showed positive association. Recapitulating advanced-stage tumors, early-stage NSCLC had the highest share of EGFR mutations in lepidic and acinar subtypes. Resected lepidic tumors contained the highest proportion of the KRAS G12C actionable variant. These results, obtained with routine diagnostic technologies in an unselected clinical setting, provide a significant addition of real-world data in early-stage NSCLC.
Real-World Data on Ramucirumab Therapy including Patients Who Experienced Two or More Systemic Treatments: A Multicenter Study
Authors: Yasui Yutaka , Kurosaki Masayuki , Tsuchiya Kaoru , Hayakawa Yuka , Hasebe Chitomi , Abe Masami , Ogawa Chikara , Joko Kouji , Ochi Hironori , Tada Toshifumi , Nakamura Shinichiro , Furuta Koichiro , Kimura Hiroyuki , Tsuji Keiji , Kojima Yuji , Akahane Takehiro , Tamada Takashi , Uchida Yasushi , Kondo Masahiko , Mitsuda Akeri , Izumi Namiki
Published: June 2022

Background: The present study aimed to clarify the efficacy and safety of ramucirumab in a real-world setting, including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. Methods: In total, 79 patients with hepatocellular carcinoma (HCC) from 14 institutes throughout Japan were retrospectively analyzed. The response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and AEs were recorded according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. Results: Median overall survival (OS) in the total cohort was 7.5 months (m). Median OS was 8.8 m in patients who were administered ramucirumab as a second-line treatment, while it was 7.3 m in third- or later-line treatment. Progression-free survival rates in the second- and third- or later-line therapies were 3.2 m and 3.2 m, respectively. The disease control rate (DCR) in the study was 43%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events (AEs), the development of ascites was observed significantly more frequently in modified albumin–bilirubin (mALBI) 2b/3 patients than in mALBI 1/2a patients (54.5% vs. 25.0%, p = 0.03). Conclusions: Ramucirumab is useful as a second-line therapy and feasible as a third- or later-line treatment for HCC.
Role of Brachytherapy Boost in Clinically Localized Intermediate and High-Risk Prostate Cancer: Lack of Benefit in Patients with Very High-Risk Factors T3b–4 and/or Gleason 9–10
Authors: Yamazaki Hideya , Suzuki Gen , Masui Koji , Aibe Norihiro , Shimizu Daisuke , Kimoto Takuya , Yamada Kei , Okihara Koji , Ueda Takashi , Narukawa Tsukasa , Shiraishi Takumi , Fujihara Atsuko , Yoshida Ken , Nakamura Satoaki , Kato Takashi , Hashimoto Yasutoshi , Okabe Haruumi
Published: June 2022

This study examined the role of brachytherapy boost (BT-boost) and external beam radiotherapy (EBRT) in intermediate- to high-risk prostate cancer, especially in patients with very high-risk factors (VHR: T3b–4 or Gleason score 9–10) as patients with double very high-risk factors (VHR-2: T3b–4 and Gleason score 9–10) previously showed worst prognosis in localized prostate cancer. We retrospectively reviewed multi-institutional data of 1961 patients that were administered radiotherapy (1091 BT-boost and 872 EBRT: 593 conventional-dose RT (Conv RT: equivalent to doses of 2 Gy per fraction = EQD2 ≤ 72 Gy) and 216 dose-escalating RT (DeRT = EQD2 ≥ 74 Gy). We found that BT-boost improved PSA control and provided an equivalent overall survival rate in the intermediate- and high-risk groups, except for patients within the VHR factor group. In the VHR-1 group (single VHR), BT-boost showed a superior biochemical control rate to the Conv RT group but not to the DeRT group. In the VHR-2 group, BT-boost did not improve outcomes of either Conv RT or DeRT groups. In conclusion, BT-boost showed no benefit to modern DeRT in the patients with VHR; therefore, they are not good candidates for BT-boost to improve outcome and may be amenable to clinical trials using multimodal intensified systemic treatments.
Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial
Authors: Manji Arif , Samson Yvan , Deyell Rebecca J. , Johnston Donna L. , Lewis Victor A. , Zorzi Alexandra P. , Berman Jason N. , Brodeur-Robb Kathy , Morrison Ellen , Kee Lynn , Kumar Sushil , Baruchel Sylvain , Whitlock James A. , Morgenstern Daniel A.
Published: June 2022

Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.
Prostate-Specific Membrane Antigen (PSMA)-Positive Extracellular Vesicles in Urine—A Potential Liquid Biopsy Strategy for Prostate Cancer Diagnosis?
Authors: Allelein Susann , Aerchlimann Keshia , Rösch Gundula , Khajehamiri Roxana , Kölsch Andreas , Freese Christian , Kuhlmeier Dirk
Published: June 2022

All cells release extracellular vesicles (EVs) to communicate with adjacent and distant cells. Consequently, circulating EVs are found in all bodily fluids, providing information applicable for liquid biopsy in early cancer diagnosis. Studies observed an overexpression of the membrane-bound prostate-specific membrane antigen (PSMA) on prostate cancer cells. To investigate whether EVs derived from communicating prostate cells allow for reliable conclusions on prostate cancer development, we isolated PSMA-positive, as well as CD9-positive, EVs from cell-free urine with the use of magnetic beads. These populations of EVs were subsequently compared to CD9-positive EVs isolated from female urine in Western blotting, indicating the successful isolation of prostate-derived and ubiquitous EVs, respectively. Furthermore, we developed a device with an adapted protocol that enables an automated immunomagnetic enrichment of EVs of large sample volumes (up to 10 mL), while simultaneously reducing the overall bead loss and hands-on time. With an in-house spotted antibody microarray, we characterized PSMA as well as other EV surface markers of a prostate cohort of 44 urine samples in a more simplified way. In conclusion, the automated and specific enrichment of EVs from urine has a high potential for future diagnostic applications.
Combination of Whole-Body Baseline CT Radiomics and Clinical Parameters to Predict Response and Survival in a Stage-IV Melanoma Cohort Undergoing Immunotherapy
Authors: Peisen Felix , Hänsch Annika , Hering Alessa , Brendlin Andreas S. , Afat Saif , Nikolaou Konstantin , Gatidis Sergios , Eigentler Thomas , Amaral Teresa , Moltz Jan H. , Othman Ahmed E.
Published: June 2022

Background: This study investigated whether a machine-learning-based combination of radiomics and clinical parameters was superior to the use of clinical parameters alone in predicting therapy response after three months, and overall survival after six and twelve months, in stage-IV malignant melanoma patients undergoing immunotherapy with PD-1 checkpoint inhibitors and CTLA-4 checkpoint inhibitors. Methods: A random forest model using clinical parameters (demographic variables and tumor markers = baseline model) was compared to a random forest model using clinical parameters and radiomics (extended model) via repeated 5-fold cross-validation. For this purpose, the baseline computed tomographies of 262 stage-IV malignant melanoma patients treated at a tertiary referral center were identified in the Central Malignant Melanoma Registry, and all visible metastases were three-dimensionally segmented (n = 6404). Results: The extended model was not significantly superior compared to the baseline model for survival prediction after six and twelve months (AUC (95% CI): 0.664 (0.598, 0.729) vs. 0.620 (0.545, 0.692) and AUC (95% CI): 0.600 (0.526, 0.667) vs. 0.588 (0.481, 0.629), respectively). The extended model was not significantly superior compared to the baseline model for response prediction after three months (AUC (95% CI): 0.641 (0.581, 0.700) vs. 0.656 (0.587, 0.719)). Conclusions: The study indicated a potential, but non-significant, added value of radiomics for six-month and twelve-month survival prediction of stage-IV melanoma patients undergoing immunotherapy.
Vaccination Therapy for Acute Myeloid Leukemia: Where Do We Stand?
Authors: Barbullushi Kordelia , Rampi Nicolò , Serpenti Fabio , Sciumè Mariarita , Fabris Sonia , De Roberto Pasquale , Fracchiolla Nicola Stefano
Published: June 2022

Immunotherapy is changing the therapeutic landscape of many hematologic diseases, with immune checkpoint inhibitors, bispecific antibodies, and CAR-T therapies being its greatest expression. Unfortunately, immunotherapy in acute myeloid leukemia (AML) has given less brilliant results up to now, and the only approved drug is the antiCD33 antibody-drug conjugate gemtuzumab ozogamicin. A promising field of research in AML therapy relies on anti-leukemic vaccination to induce remission or prevent disease relapse. In this review, we analyze recent evidence on AML vaccines and their biological mechanisms. The principal proteins that have been exploited for vaccination strategies and have reached clinical experimental phases are Wilm’s tumor 1, proteinase 3, and RHAMM. the majority of data deals with WT1-base vaccines, given also the high expression and mutation rates of WT1 in AML cells. Stimulators of immune responses such as TLR7 agonist and interleukin-2 have also proven anti-leukemic activity both in vivo and in vitro. Lastly, cellular vaccines mainly based on autologous or allogeneic off-the-shelf dendritic cell-based vaccines showed positive results in terms of T-cell response and safety, also in elderly patients. Compared to other immunotherapeutic strategies, anti-AML vaccines have the advantage of being a less toxic and a more manageable approach, applicable also to elderly patients with poorer performance status, and may be used in combination with currently available therapies. As for the best scenario in which to use vaccination, whether in a therapeutic, prophylactic, or preemptive setting, further studies are needed, but available evidence points to poorer results in the presence of active or high-burden disease. Given the poor prognosis of relapsed/refractory or high-risk AML, further research is urgently needed to better understand the biological pathways that sustain its pathogenesis. In this setting, research on novel frontiers of immunotherapy-based agents, among which vaccines represent important actors, is warranted to develop new and efficacious strategies to obtain long-term disease control by immune patrolling.
Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain
Authors: Li Huili , Guo Ruijuan , Guan Yun , Li Junfa , Wang Yun
Published: June 2022

Synapses serve as the interface for the transmission of information between neurons in the central nervous system. The structural and functional characteristics of synapses are highly dynamic, exhibiting extensive plasticity that is shaped by neural activity and regulated primarily by trans-synaptic cell-adhesion molecules (CAMs). Prototypical trans-synaptic CAMs, such as neurexins (Nrxs) and neuroligins (Nlgs), directly regulate the assembly of presynaptic and postsynaptic molecules, including synaptic vesicles, active zone proteins, and receptors. Therefore, the trans-synaptic adhesion mechanisms mediated by Nrx–Nlg interaction can contribute to a range of synaptopathies in the context of pathological pain and other neurological disorders. The present review provides an overview of the current understanding of the roles of Nrx–Nlg interaction in the regulation of trans-synaptic connections, with a specific focus on Nrx and Nlg structures, the dynamic shaping of synaptic function, and the dysregulation of Nrx–Nlg in pathological pain. Additionally, we discuss a range of proteins capable of modulating Nrx–Nlg interactions at the synaptic cleft, with the objective of providing a foundation to guide the future development of novel therapeutic agents for managing pathological pain.
Current and Novel Therapeutic Approaches for Treatment of Diabetic Macular Edema
Authors: Chauhan Muhammad Z. , Rather Peyton A. , Samarah Sajida M. , Elhusseiny Abdelrahman M. , Sallam Ahmed B.
Published: June 2022

Diabetic macular edema (DME) is a major ocular complication of diabetes mellitus (DM), leading to significant visual impairment. DME’s pathogenesis is multifactorial. Focal edema tends to occur when primary metabolic abnormalities lead to a persistent hyperglycemic state, causing the development of microaneurysms, often with extravascular lipoprotein in a circinate pattern around the focal leakage. On the other hand, diffusion edema is due to a generalized breakdown of the inner blood–retinal barrier, leading to profuse early leakage from the entire capillary bed of the posterior pole with the subsequent extravasation of fluid into the extracellular space. The pathogenesis of DME occurs through the interaction of multiple molecular mediators, including the overexpression of several growth factors, including vascular endothelial growth factor (VEGF), insulin-like growth factor-1, angiopoietin-1, and -2, stromal-derived factor-1, fibroblast growth factor-2, and tumor necrosis factor. Synergistically, these growth factors mediate angiogenesis, protease production, endothelial cell proliferation, and migration. Treatment for DME generally involves primary management of DM, laser photocoagulation, and pharmacotherapeutics targeting mediators, namely, the anti-VEGF pathway. The emergence of anti-VEGF therapies has resulted in significant clinical improvements compared to laser therapy alone. However, multiple factors influencing the visual outcome after anti-VEGF treatment and the presence of anti-VEGF non-responders have necessitated the development of new pharmacotherapies. In this review, we explore the pathophysiology of DME and current management strategies. In addition, we provide a comprehensive analysis of emerging therapeutic approaches to the treatment of DME.
The Roles of TNFR2 Signaling in Cancer Cells and the Tumor Microenvironment and the Potency of TNFR2 Targeted Therapy
Authors: Takahashi Hiroyuki , Yoshimatsu Gumpei , Faustman Denise Louise
Published: June 2022

The appreciation that cancer growth is promoted by a dynamic tumor microenvironment (TME) has spawned novel approaches to cancer treatment. New therapies include agents that activate quiescent T effector cells and agents that interfere with abnormal neovascularity. Although promising, many experimental therapies targeted at the TME have systemic toxicity. Another approach is to target the TME with greater specificity by taking aim at the tumor necrosis factor receptor 2 (TNFR2) signaling pathway. TNFR2 is an attractive molecular target because it is rarely expressed in normal tissues (thus, has low potential for systemic toxicity) and because it is overexpressed on many types of cancer cells as well as on associated TME components, such as T regulatory cells (Tregs), tumor-associated macrophages, and other cells that facilitate tumor progression and spread. Novel therapies that block TNFR2 signaling show promise in cell culture studies, animal models, and human studies. Novel antibodies have been developed that expressly kill only rapidly proliferating cells expressing newly synthesized TNFR2 protein. This review traces the origins of our understanding of TNFR2’s multifaceted roles in the TME and discusses the therapeutic potential of agents designed to block TNFR2 as the cornerstone of a TME-specific strategy.
Reciprocal Interactions between Oligodendrocyte Precursor Cells and the Neurovascular Unit in Health and Disease
Authors: Pfeiffer Friederike
Published: June 2022

Oligodendrocyte precursor cells (OPCs) are mostly known for their capability to differentiate into oligodendrocytes and myelinate axons. However, they have been observed to frequently interact with cells of the neurovascular unit during development, homeostasis, and under pathological conditions. The functional consequences of these interactions are largely unclear, but are increasingly studied. Although OPCs appear to be a rather homogenous cell population in the central nervous system (CNS), they present with an enormous potential to adapt to their microenvironment. In this review, it is summarized what is known about the various roles of OPC-vascular interactions, and the circumstances under which they have been observed.