bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comprehensive Review on Brain–Computer Interface (BCI)-Based Machine and Deep Learning Algorithms for Stroke Rehabilitation
Authors: Elashmawi Walaa H. , Ayman Abdelrahman , Antoun Mina , Mohamed Habiba , Mohamed Shehab Eldeen , Amr Habiba , Talaat Youssef , Ali Ahmed
Published: July 2024

This literature review explores the pivotal role of brain–computer interface (BCI) technology, coupled with electroencephalogram (EEG) technology, in advancing rehabilitation for individuals with damaged muscles and motor systems. This study provides a comprehensive overview of recent developments in BCI and motor control for rehabilitation, emphasizing the integration of user-friendly technological support and robotic prosthetics powered by brain activity. This review critically examines the latest strides in BCI technology and its application in motor skill recovery. Special attention is given to prevalent EEG devices adaptable for BCI-driven rehabilitation. The study surveys significant contributions in the realm of machine learning-based and deep learning-based rehabilitation evaluation. The integration of BCI with EEG technology demonstrates promising outcomes for enhancing motor skills in rehabilitation. The study identifies key EEG devices suitable for BCI applications, discusses advancements in machine learning approaches for rehabilitation assessment, and highlights the emergence of novel robotic prosthetics powered by brain activity. Furthermore, it showcases successful case studies illustrating the practical implementation of BCI-driven rehabilitation techniques and their positive impact on diverse patient populations. This review serves as a cornerstone for informed decision-making in the field of BCI technology for rehabilitation. The results highlight BCI’s diverse advantages, enhancing motor control and robotic integration. The findings highlight the potential of BCI in reshaping rehabilitation practices and offer insights and recommendations for future research directions. This study contributes significantly to the ongoing transformation of BCI technology, particularly through the utilization of EEG equipment, providing a roadmap for researchers in this dynamic domain.
Protecting Instant Messaging Notifications against Physical Attacks: A Novel Instant Messaging Notification Protocol Based on Signal Protocol
Authors: Almari Raghad , Almosallam Abdullah , Almousa Saleh , Alahmadi Saad
Published: July 2024

Over the years, there has been a significant surge in the popularity of instant messaging applications (IMAs). However, the message notification functionality in IMAs exhibits certain limitations. Some IMAs fail to alert users about new messages after their phone restarts unless they unlock the phone. This is a consequence of end-to-end encryption (E2EE) and the app not knowing the message is in the queue until the app decrypts it. This approach using E2EE is used to prevent offline attacks, as the key is unavailable to decrypt the notification messages. In this paper, we introduce a novel design and implementation of a message notification protocol for IMAs based on the Signal protocol. The proposed protocol aims to securely display notifications on a locked device and ensures that cryptographic keys are stored in a location that is isolated from the user’s device to prevent offline attacks. This approach enhances the security of private key storage, safeguarding private keys against various external threats. The innovative design strengthens the off-site key management system, rendering it resilient against offline attacks and mitigating the risk of key compromise. Additionally, the proposed protocol is highly efficient, requiring no specialized hardware for implementation. It offers confidentiality of cryptographic keys and protection against offline attacks, further enhancing the overall security of the system. We evaluate the protocol’s effectiveness by analyzing multiple independent implementations that pass a suite of formal tests via ProVerif.
Relationship of Vitamin D Status with Biomarkers of Muscle Damage and Body Composition in Spanish Elite Female Football Players: A Cross-Sectional Study
Authors: Mora-Fernandez Agustin , Rojas Julia Peinado , Gimenez-Blasi Nuria , Conde-Pipó Javier , Latorre Jose Antonio , Mariscal-Arcas Miguel
Published: July 2024

Recently, there has been a growing interest in relation to the female athlete, especially in widespread disciplines such as football. Concerns about vitamin D deficiency status have recently been considered due to its effects on the performance and health status of female footballers. However, its relationship to body composition and muscle damage in female football athletes remains unclear to date. The purpose of the present study was to analyse the association of the vitamin D status of Spanish elite female football players with anthropometric variables and markers of muscle damage. Ethical consent was obtained from a total of 21 players from a Spanish elite women’s football team (20–33 years). Anthropometric analysis was carried out according to the standardised protocol of the International Society for the Advancement of Kineanthropometry (ISAK). The clinical analyses, based on urine and blood samples, were carried out by the club’s medical staff at the start of the season in the early morning in a fasting state. The athletes were also asked about the regularity of their menstrual cycle and some dietary habits. Thirty-three percent of the female athletes had vitamin D levels below the reference values. Significantly higher FM values were observed in athletes with low vitamin D status (p < 0.05), as well as statistically significant negative correlations between vitamin D levels and FM (p < 0.05) in the group of female players with vitamin D levels below the baseline values. No significant associations were observed between markers of muscle damage and the other variables. Complementing an assessment of body composition with a biochemical analysis of vitamin D levels may be an interesting strategy in the process of monitoring the elite female football player throughout the season.
Development of Models Relating Screw Conveying Capacity of Concrete to Operating Parameters and Their Use in Conveyor Operating Strategies to Consider Batch Production
Authors: Yu Wenda , Zou Defang , Li Dong , Wang Qingyuan , Peng Peng
Published: July 2024

The screw conveyor is the key equipment used to realize the casting and forming of concrete in prefabricated components (PC), and its performance affects the PC shape, quality, and cost. In batch production, there is a process variable, the residence time. It is affected by the quality of the downstream vibration process. This also results in operating parameters that are difficult to match to the time scales. Eventually, it can lead to problems such as low casting efficiency or poor molded quality. In this paper, the DEM simulation method is used to explain and quantify the relationship between the screw conveying capacity and three important operating parameters: the screw’s outer diameter, residence time, and screw speed. The axial and radial velocity vectors are used as features to analyze the changing rule of particle motion trajectory and mass flow rate. Based on the simulation data, the operating parameters and the mass flow rate are forward-fitted to establish the prediction model of the screw conveying capacity. In addition, the residence time is backward fitted from the screw speed and mass flow rate. It is used to estimate the concrete workability. Furthermore, the fitted forward and backward models explore how to propose feasible operational strategies to achieve automatic discharge during batch production.
Custom Anchorless Object Detection Model for 3D Synthetic Traffic Sign Board Dataset with Depth Estimation and Text Character Extraction
Authors: Soans Rahul , Fukumizu Yohei
Published: July 2024

This paper introduces an anchorless deep learning model designed for efficient analysis and processing of large-scale 3D synthetic traffic sign board datasets. With an ever-increasing emphasis on autonomous driving systems and their reliance on precise environmental perception, the ability to accurately interpret traffic sign information is crucial. Our model seamlessly integrates object detection, depth estimation, deformable parts, and text character extraction functionalities, facilitating a comprehensive understanding of road signs in simulated environments that mimic the real world. The dataset used has a large number of artificially generated traffic signs for 183 different classes. The signs include place names in Japanese and English, expressway names in Japanese and English, distances and motorway numbers, and direction arrow marks with different lighting, occlusion, viewing angles, camera distortion, day and night cycles, and bad weather like rain, snow, and fog. This was done so that the model could be tested thoroughly in a wide range of difficult conditions. We developed a convolutional neural network with a modified lightweight hourglass backbone using depthwise spatial and pointwise convolutions, along with spatial and channel attention modules that produce resilient feature maps. We conducted experiments to benchmark our model against the baseline model, showing improved accuracy and efficiency in both depth estimation and text extraction tasks, crucial for real-time applications in autonomous navigation systems. With its model efficiency and partwise decoded predictions, along with Optical Character Recognition (OCR), our approach suggests its potential as a valuable tool for developers of Advanced Driver-Assistance Systems (ADAS), Autonomous Vehicle (AV) technologies, and transportation safety applications, ensuring reliable navigation solutions.
Open-Vocabulary Part-Level Detection and Segmentation for Human–Robot Interaction
Authors: Yang Shan , Liu Xiongding , Wei Wu
Published: July 2024

Object detection and segmentation have made great progress in robotic application missions. However, intelligent agents require fine-grained recognition algorithms rather than object-level and language instructions to enhance the interaction between humans and robots. To improve the robot’s interactivity in the process of the robot response to language instructions, we propose a method for part-level detection and segmentation by exploiting vision language models. In this approach, Swin Transformer is introduced in the image encoder for extracting image features, and FPNs (Feature Pyramid Networks) are modified to better process the features from Swin Transformer. Next, the image decoder is proposed for model aligning between the image features and text embeddings for achieving human–robot interaction via language. Finally, we verify that the text embeddings are impacted by the command of input and that different prompt templates also affect classification. The method proposed in this paper, which is validated on two datasets (PartImagePart and Pascal Part), possesses the ability to understand and execute part-level missions and accurately segments and detects parts compared with existing interactive methods.
On Some Properties for Cofiniteness of Submonoids and Ideals of an Affine Semigroup
Authors: Cisto Carmelo
Published: July 2024

Let S and C be affine semigroups in Nd such that S⊆C. We provide a characterization for the set C∖S to be finite, together with a procedure and computational tools to check whether such a set is finite and, if so, compute its elements. As a consequence of this result, we provide a characterization for an ideal I of an affine semigroup S so that S∖I is a finite set. If so, we provide some procedures to compute the set S∖I.
Consistent Sampling Approximations in Abstract Hilbert Spaces
Authors: Kang Sinuk , Kwon Kil Hyun , Lee Dae Gwan
Published: July 2024

This paper considers generalized consistent sampling and reconstruction processes in an abstract separable Hilbert space. Using an operator-theoretical approach, quasi-consistent and consistent approximations with optimal properties, such as possessing the minimum norm or being closest to the original vector, are derived. The results are illustrated with several examples.
Probabilistic and Average Gel’fand Widths of Sobolev Space Equipped with Gaussian Measure in the Sq-Norm
Authors: Wu Ruihuan , Liu Yuqi , Li Huan
Published: July 2024

In this article, we mainly studied the Gel’fand widths of Sobolev space in the probabilistic and average settings. And, we estimated the sharp bounds of the probabilistic Gel’fand (N,δ)-widths of multivariate Sobolev space MW2r(Td) with mixed derivative equipped with the Gaussian measure in the Sq-norm by discretization methods. Later, we estimated the sharp bounds of the p-average Gel’fand N-widths of univariate Sobolev space W2r(T) and multivariate Sobolev space MW2r(Td) with mixed derivative equipped with the Gaussian measure in the Sq-norm.
New Interval-Valued Soft Separation Axioms
Authors: Baek Jong Il , Al-shami Tareq M. , Jafari Saeid , Cheong Minseok , Hur Kul
Published: July 2024

Our research’s main aim is to study two viewpoints: First, we define partial interval-valued soft T i(j)-spaces (i = 0, 1, 2, 3, 4; j = i, ii), study some of their properties and some of relationships among them, and give some examples. Second, we introduce the notions of partial total interval-valued soft T j(i)-spaces (i = 0, 1, 2, 3, 4; j = i, ii) and discuss some of their properties. We present some relationships among them and give some examples.
Phytoplankton Diversity, Spatial Patterns, and Photosynthetic Characteristics Under Environmental Gradients and Anthropogenic Influence in the Pearl River Estuary
Authors: Xia Jing , Hu Haojie , Gao Xiu , Kan Jinjun , Gao Yonghui , Li Ji
Published: July 2024

The Pearl River Estuary (PRE) is one of the world’s most urbanized subtropical coastal systems. It presents a typical environmental gradient suitable for studying estuarine phytoplankton communities’ dynamics and photosynthetic physiology. In September 2018, the maximum photochemical quantum yield (Fv/Fm) of phytoplankton in different salinity habitats of PRE (oceanic, estuarine, and freshwater zones) was studied, revealing a complex correlation with the environment. Fv/Fm of phytoplankton ranged from 0.16 to 0.45, with taxa in the upper Lingdingyang found to be more stressed. Community composition and structure were analyzed using 18S rRNA, accompanied by a pigment analysis utilized as a supplementary method. Nonmetric multidimensional scaling analysis indicated differences in the phytoplankton spatial distribution along the estuarine gradients. Specificity-occupancy plots identified different specialist taxa for each salinity habitat. Dinophyta and Haptophyta were the predominant taxa in oceanic areas, while Chlorophyta and Cryptophyta dominated freshwater. Bacillariophyta prevailed across all salinity gradients. Canonical correlation analysis and Mantel tests revealed that temperature, salinity, and elevated nutrient levels (i.e., NO3−-N, PO43−-P, and SiO32−-Si) associated with anthropogenic activities significantly influenced the heterogeneity of community structure. The spatial distribution of phytoplankton, along with in situ photosynthetic characteristics, serves as a foundational basis to access estuarine primary productivity, as well as community function and ecosystem health.
Candidate Key Proteins in Tinnitus—A Bioinformatic Study of Synaptic Transmission in the Cochlear Nucleus
Authors: Gross Johann , Knipper Marlies , Mazurek Birgit
Published: July 2024

The aim of this study was to identify key proteins of synaptic transmission in the cochlear nucleus (CN) that are involved in normal hearing, acoustic stimulation, and tinnitus. A gene list was compiled from the GeneCards database using the keywords “synaptic transmission” AND “tinnitus” AND “cochlear nucleus” (Tin). For comparison, two gene lists with the keywords “auditory perception” (AP) AND “acoustic stimulation” (AcouStim) were built. The STRING protein–protein interaction (PPI) network and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and their high-score interaction proteins (HSIPs), together referred to as key proteins. The top1 key proteins of the Tin-process were BDNF, NTRK1, NTRK3, and NTF3; the top2 key proteins are FOS, JUN, CREB1, EGR1, MAPK1, and MAPK3. Highly significant GO terms in CN in tinnitus were “RNA polymerase II transcription factor complex”, “late endosome”, cellular response to cadmium ion”, “cellular response to reactive oxygen species”, and “nerve growth factor signaling pathway”, indicating changes in vesicle and cell homeostasis. In contrast to the spiral ganglion, where important changes in tinnitus are characterized by processes at the level of cells, important biological changes in the CN take place at the level of synapses and transcription.
Expanding the Perspective on PARP1 and Its Inhibitors in Cancer Therapy: From DNA Damage Repair to Immunomodulation
Authors: Böhi Flurina , Hottiger Michael O.
Published: July 2024

The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated a multifaceted role of PARP1 beyond its canonical function in DNA damage repair. This review explores the expanding roles of PARP1, highlighting its crucial interplay with the immune system during tumorigenesis. We discuss PARP1’s immunomodulatory effects in macrophages and T cells, with a particular focus on cytokine expression. Understanding these immunomodulatory roles of PARP1 not only holds promise for enhancing the efficacy of PARP inhibitors in cancer therapy but also paves the way for novel treatment regimens targeting immune-mediated inflammatory diseases.
Developing a Polygenic Risk Score with Age and Sex to Identify High-Risk Myopia in Taiwan
Authors: Lin Hui-Ju , Huang Yu-Te , Liao Wen-Ling , Huang Yu-Chuen , Chang Ya-Wen , Weng Angel L. , Tsai Fuu-Jen
Published: July 2024

Myopia is the leading cause of impaired vision, and its prevalence is increasing among Asian populations. This study aimed to develop a polygenic risk score (PRS) followed by replication to predict myopia in the Taiwanese population. In total, 23,688 participants with cycloplegic autorefraction-measured mean spherical equivalent (SE), genetic, and demographic data were included. The myopia PRS was generated based on genome-wide association study (GWAS) outcomes in a Taiwanese population and previously published GWAS reports. The results demonstrated that the inclusion of age and sex in the PRS had an area under the curve (AUC) of 0.80, 0.78, and 0.73 (p < 0.001) for participants aged >18 years with high (SE < −6.0 diopters (D); n = 1089), moderate (−6.0 D < SE ≤ −3.0 D; n = 3929), and mild myopia (−3.0 D < SE ≤ −1.0 D; n = 2241), respectively. Participants in the top PRS quartile had a 1.30-fold greater risk of high myopia (95% confidence interval = 1.09–1.55, p = 0.003) compared with that in the remaining participants. Further, a higher PRS significantly increased the risk of high myopia (SE ≤ −2.0 D) in children ≤6 years of age (p = 0.027). In conclusion, including the PRS, age, and sex improved the prediction of high myopia risk in the Taiwanese population.
Numerical Study on the Hydrodynamic Performance of a Flexible Caudal Fin with Different Trailing-Edge Shapes
Authors: Khin May Hlaing Win , Obi Shinnosuke
Published: July 2024

This paper presents a three-dimensional fluid-structure-coupled simulation of a flexible caudal fin with different trailing-edge shapes. The influences of caudal-fin shape on hydrodynamic performance are investigated by comparing the results of a simplified model of a square caudal fin with forked and deeply forked caudal fins under a wider range of non-dimensional flapping frequency, 0.6 < f* < 1.5, where f* is the ratio of flapping frequency to the natural frequency of each caudal fin, i.e., f* = f/fn. The leading edge of each caudal fin is forced to oscillate vertically in a water tank with zero free-stream conditions. The numerical results show that the amount of forking in the geometry of the caudal fin has significant effects on its hydrodynamic performance. A comparison of thrust coefficients shows that the square caudal fin has a greater thrust coefficient in the non-dimensional frequency range of 0.6 < f* < 1.2, while the deeply forked caudal fin generates higher thrust when 1.2 < f* < 1.5. In terms of propulsive efficiency, the square caudal fin is more efficient when 0.6 < f* < 0.9, while the propulsive efficiency of a deeply forked caudal fin is significantly enhanced when 0.9 < f* < 1.5. Based on our results, the deeply forked caudal fin has greater thrust coefficients and a higher propulsive efficiency in a higher frequency range than the natural frequency of each caudal fin. The thrust characteristics and flow fields around each caudal fin are investigated in detail.
In Males with Adequate Dietary Needs Who Present No Sleep Disturbances, Is an Acute Intake of Zinc Magnesium Aspartate, Following Either Two Consecutive Nights of 8 or 4 h of Sleep Deprivation, Beneficial for Sleep and Morning Stroop Interference Performance?
Authors: Edwards Ben J. , Adam Ryan L. , Gallagher Chloe , Germaine Mark , Hulton Andrew T. , Pullinger Samuel A. , Chester Neil J.
Published: July 2024

Purpose: Purpose: We examined whether supplementation of zinc magnesium aspartate (ZMA) in two groups of males, either partially sleep-restricted (4 h) or with habitual sleep (8 h) for 2 nights, was beneficial for sleep and subsequent morning Stroop performance. Methods: Participants were randomly allocated to two independent groups who either had 4 h (33 males) or 8 h (36 males) sleep for two nights. Using a double-blinded, randomised counterbalanced design, they then completed five sessions, (i) two familiarisation sessions including 7 days of sleep and dietary intake, (ii) three conditions with 4 h or 8 h sleep and either NoPill control (NoPill), placebo (PLAC) or ZMA (ZMA). Sleep was assessed by actimetry and sleep questionnaires, and cognitive performance was assessed by the Stroop test. The data were analysed using a general linear model with repeated measures. Results: A main effect for “sleep” (4 or 8 h) was found, where more opportunity to sleep resulted in better “sleep” metrics (both objective and subjective) as well as better Stroop scores (lower colour-interference and word-interference scores and lower error in words). No main effect for “Pill” was found other than the mood state depression, where subjective ratings for the PLAC group were lower than the other two conditions. Interactions were found in anger, ease to sleep and waking time. Conclusion: Having 8 h opportunity to sleep resulted in better “sleep” metrics as well as better Stroop scores compared to 4 h. Supplementation of ZMA for 4 or 8 h for 2 nights had no effect on subsequent morning cognitive performance but reduced sleep or total sleep time by ~0.46 h compared to the other conditions. An interaction was found where sleep time was reduced by ~0.94 h in the ZMA group in the 8 h condition compared to NoPill or PLAC.
Cyclic Behavior of Concrete-Filled Tube Columns with Bidirectional Moment Connections Considering the Local Slenderness Effect
Authors: Mata Ramón , Nuñez Eduardo
Published: July 2024

In this research, the cyclic behavior of concrete-filled thin tube (CFTT) columns with bidirectional moment connections was numerically studied within the context of thin-walled structures. Novel considerations in the design of CFTT columns with slenderness sections are proposed through a parametric study. A total of 70 high-fidelity finite element (FE) models are developed using ANSYS software v2022 calibrated from experimental research using similar 3D joint configurations. Furthermore, a comparison of different width-to-thickness ratios in columns was considered. The results showed that the models with a high slenderness ratio reached a stable cyclic behavior until 0.03 rad of drift, and a flexural strength of 0.8 Mp was reached for 4% of the drift ratio according to the Seismic Provisions. However, this effect slightly decreased the strength and the dissipated energy of the moment connection in comparison to columns with a high ductility ratio. Moreover, an evaluation of concrete damages shows concrete cracked for cyclic loads higher than 3% of drift. Finally, the joint configurations studied can achieve a good performance, avoiding brittle failure mechanisms and ensuring the plastic hinges in the beams.
Baseline Blood CD8+ T Cell Activation Potency Discriminates Responders from Non-Responders to Immune Checkpoint Inhibition Combined with Stereotactic Radiotherapy in Non-Small-Cell Lung Cancer
Authors: Kievit Hanneke , Muntinghe-Wagenaar M. Benthe , Abdulahad Wayel H. , Rutgers Abraham , Hijmering-Kappelle Lucie B. M. , Hiddinga Birgitta I. , Ubbels J. Fred , Wijsman Robin , van der Leij Marcel J. , Bijzet Johan , Groen Harry J. M. , Kerstjens Huib A. M. , van der Wekken Anthonie J. , Kroesen Bart-Jan , Hiltermann T. Jeroen N.
Published: July 2024

Background: Tumor-infiltrating immune cells have been correlated with prognosis for patients treated with immune checkpoint inhibitor (ICI) treatment of various cancers. However, no robust biomarker has been described to predict treatment response yet. We hypothesized that the activation potency of circulating T cells may predict response to ICI treatment. Methods: An exploratory analysis was conducted to investigate the association between the response to immune checkpoint inhibition (ICI) combined with stereotactic radiotherapy (SBRT) and the potency of circulating T cells to be activated. Blood-derived lymphocytes from 14 patients were stimulated ex vivo with, among others, Staphylococcal enterotoxin B (SEB) and compared to healthy controls (HCs). Patients were grouped into responders (>median progression free survival (PFS)) and non-responders (<median PFS). The expression of the T cell activation marker CD69 and intracellular cytokines (IL-2, IFNγ, TNFα) in both CD4+ and CD8+ T cells in response to stimulation was measured using flow cytometry. In addition, serum levels of BAFF, IFNγ, and IL-2 receptor (sIL-2R) were measured by Luminex. Results: At baseline, a higher percentage of activated CD8+ T cells (15.8% vs. 3.5% (p = <0.01)) and IL-2+CD69+CD8+ T cells (8.8% vs. 2.9% (p = 0.02)) was observed in responders compared to non-responders upon ex vivo stimulation with SEB. The concurrently measured serum cytokine levels were not different between responders and non-responders. Conclusion: Baseline blood CD8+ T cell activation potency, measured by intracellular cytokine production after ex vivo stimulation, is a potential biomarker to discriminate responders from non-responders to SBRT combined with ICI.
LncRNA LOC730101 Promotes Darolutamide Resistance in Prostate Cancer by Suppressing miR-1-3p
Authors: Zhou Tianyi , Nguyen Steven , Wu Jacky , He Bin , Feng Qin
Published: July 2024

Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen drug, darolutamide. Our RNA sequencing analysis revealed significant overexpression of LOC730101 in darolutamide-resistant cancer cells compared to the parental cells. Elevated LOC730101 levels were also observed in clinical samples of metastatic castration-resistant prostate cancer (CRPC) compared to primary prostate cancer samples. Silencing LOC730101 with siRNA significantly impaired the growth of darolutamide-resistant cells. Additional RNA sequencing analysis identified a set of genes regulated by LOC730101, including key players in the cell cycle regulatory pathway. We further demonstrated that LOC730101 promotes darolutamide resistance by competitively inhibiting microRNA miR-1-3p. Moreover, by Hi-C sequencing, we found that LOC730101 is located in a topologically associating domain (TAD) that undergoes specific gene induction in darolutamide-resistant cells. Collectively, our study demonstrates the crucial role of the lncRNA LOC730101 in darolutamide resistance and its potential as a target for overcoming antiandrogen resistance in CRPC.
Management of Metastatic Renal Cell Carcinoma Following First-Line Immune Checkpoint Therapy Failure: A Systematic Review
Authors: Petrelli Fausto , Vavassori Ivano , Rossitto Mauro , Dottorini Lorenzo
Published: July 2024

Introduction: There is a significant gap in the literature concerning the effective management of second-line therapy for patients with metastatic renal cell carcinoma (RCC) who have received immune checkpoint inhibitors (ICIs). Most of the published articles were small multicenter series or phase 2 studies. To our knowledge, a systematic review that comprehensively outlines the range of treatment options available for patients with metastatic RCC who do not respond to first-line ICIs has not yet been conducted. Our aim was to synthesize evidence on second-line therapies for patients with metastatic RCC after initial treatment with ICIs and to offer recommendations on the best treatment regimens based on the current literature. Material and Methods: We conducted a search in PubMed, Embase, and the Cochrane Library on 29 February 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We selected articles that met the predetermined inclusion criteria (written in English, retrospective observational studies, prospective series, and randomized trials reporting second-line therapy for metastatic RCC after failure of ICI-based therapy). Relevant articles were identified in the reference lists. The main endpoint was the overall response rate (ORR), with the median progression-free survival (PFS) and overall survival (OS) as secondary endpoints. Results: We included 27 studies reporting the outcomes of 1970 patients. Salvage therapies were classified as targeted therapy (VEGFR TKIs) in 18 studies and ICIs in 8 studies. In studies where TKIs were the second line of choice, the pooled ORR was 34% (95% CI: 30.2–38%). In studies where ICIs, alone or in combination with TKIs, were used as second-line therapies, the ORR was 25.7% (95% CI: 15.7–39.2%). In studies where TKIs and ICIs were the second-line choices, the pooled median PFS values were 11.4 months (95% CI: 9.5–13.6 months) and 9.8 months (95% CI: 7.5–12.7 months), respectively. Conclusions: This systematic review shows that VEGFR TKIs and ICIs are effective second-line therapies following an initial treatment with anti-PD(L)1 alone or in combination. The treatment choice should be personalized, taking into account the patient’s response to first-line ICIs, the site of the disease, the type of first-line combination (with or without VEGFR TKIs), and the patient’s overall condition.
Sexual Function in Women Diagnosed with Hereditary Breast and Ovarian Cancer Syndrome
Authors: Ferrari Federico , Amonti Juri , Giannini Andrea , Soleymani Majd Hooman , Zizioli Valentina , Tisi Giancarlo , Della Corte Luigi , Bonetti Emma , Gozzini Elisa , Odicino Franco
Published: July 2024

Background: Hereditary breast and ovarian cancer syndrome (HBOC) predisposes women to an increased risk mainly of breast and tubo-ovarian cancer. The aim of the study is to investigate whether being diagnosed with HBOC syndrome is itself a risk factor for sexual dysfunction. Methods: An ad hoc questionnaire, including baseline demographic and clinical data, and the Sexual Function Questionnaire 28 (SFQ28) were administered to HBOC female carriers (study group) and to a control group. Results: After propensity score matching (1:1), we enrolled 202 women, 101 in the study group and 101 in the control group. In a multivariate analysis, we finally found that menopausal status was the only risk factor for a significant low score in the domains Desire (HR 0.66; CI95% 0.47–0.93; p = 0.017), Arousal (Lubrication) (HR 0.52; CI95% 0.34–0.80; p = 0.003), Arousal (Cognitive) (HR 0.64; CI95% 0.44–0.95; p = 0.027), and Orgasm (HR 0.33; CI95% (0.16–0.70; p = 0.004), independent of risk-reducing surgery for gynecological malignancy. Psycho-oncology support is a protective factor for the Enjoyment domain (HR 1.38; CI95% 1.05–1.81; p = 0.022). Conclusions: HBOC syndrome itself does not affect SFQ28 domains, while menopausal status significantly influences sexual health, with potential mitigating effects of psycho-oncological support.
Radium-223 Treatment Produces Prolonged Suppression of Resident Osteoblasts and Decreased Bone Mineral Density in Trabecular Bone in Osteoblast Reporter Mice
Authors: Lin Song-Chang , Yu Guoyu , Corn Paul G. , Damasco Jossana , Lee Yu-Chen , Song Jian H. , Navone Nora M. , Logothetis Christopher J. , Melancon Marites P. , Panaretakis Theocharis , Lin Sue-Hwa
Published: July 2024

Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223.
Recombinant Human TSH Fails to Induce the Proliferation and Migration of Papillary Thyroid Carcinoma Cell Lines
Authors: Kalampounias Georgios , Varemmenou Athina , Aronis Christos , Mamali Irene , Shaukat Athanasios-Nasir , Chartoumpekis Dionysios V. , Katsoris Panagiotis , Michalaki Marina
Published: July 2024

Thyrotropin (TSH) suppression is required in the management of patients with papillary thyroid carcinoma (PTC) to improve their outcomes, inevitably causing iatrogenic thyrotoxicosis. Nevertheless, the evidence supporting this practice remains limited and weak, and in vitro studies examining the mitogenic effects of TSH in cancerous cells used supraphysiological doses of bovine TSH, which produced conflicting results. Our study explores, for the first time, the impact of human recombinant thyrotropin (rh-TSH) on human PTC cell lines (K1 and TPC-1) that were transformed to overexpress the thyrotropin receptor (TSHR). The cells were treated with escalating doses of rh-TSH under various conditions, such as the presence or absence of insulin. The expression levels of TSHR and thyroglobulin (Tg) were determined, and subsequently, the proliferation and migration of both transformed and non-transformed cells were assessed. Under the conditions employed, rh-TSH was not adequate to induce either the proliferation or the migration rate of the cells, while Tg expression was increased. Our experiments indicate that clinically relevant concentrations of rh-TSH cannot induce proliferation and migration in PTC cell lines, even after the overexpression of TSHR. Further research is warranted to dissect the underlying molecular mechanisms, and these results could translate into better management of treatment for PTC patients.
Protective Effect of Minimally Invasive Approach on Postoperative Peak Transaminase Following Liver Resection: A Single-Center Propensity Score-Based Analysis
Authors: Ardito Francesco , Ingallinella Sara , Lai Quirino , Razionale Francesco , De Sio Davide , Mele Caterina , Vani Simone , Vellone Maria , Giuliante Felice
Published: July 2024

Background: Postoperative serum ALT levels are one of the most frequently used marker to detect liver tissue damage following liver resection. The aim of this study was to evaluate if minimally invasive liver surgery (MILS) may result in less hepatic injury than open hepatectomy by assessing the differences of postoperative ALT levels. Methods: Patients who underwent MILS between 2009 and 2019 at our unit were included and compared with open liver resections. Median ALT levels was measured on postoperative day (POD) 1, 3 and 5. Postoperative peak transaminase (PPT) of ALT was determined on POD 1. The stabilized inverse probability treatment weighing (SIPTW) process was used to balance the two groups. A multivariable logistic regression analysis was used to analyze factors associated with high PPT. Results: After SIPTW, 292 MILS were compared with 159 open resections. Median ALT levels on POD 1, 3 and 5 were significantly higher in the open group than in the MILS group (301 vs. 187, p = 0.002; 180 vs. 121, p < 0.0001; 104 vs. 60, p < 0.0001; respectively). At the multivariable logistic regression analysis, MILS showed a protective effect for high PPT. Conclusions: MILS was associated with significantly lower postoperative ALT levels compared with open liver resections. MILS showed a protective effect for high PPT.
The Spectrum of CAR Cellular Effectors: Modes of Action in Anti-Tumor Immunity
Authors: Nguyen Ngoc Thien Thu , Müller Rasmus , Briukhovetska Daria , Weber Justus , Feucht Judith , Künkele Annette , Hudecek Michael , Kobold Sebastian
Published: July 2024

Chimeric antigen receptor-T cells have spearheaded the field of adoptive cell therapy and have shown remarkable results in treating hematological neoplasia. Because of the different biology of solid tumors compared to hematological tumors, response rates of CAR-T cells could not be transferred to solid entities yet. CAR engineering has added co-stimulatory domains, transgenic cytokines and switch receptors to improve performance and persistence in a hostile tumor microenvironment, but because of the inherent cell type limitations of CAR-T cells, including HLA incompatibility, toxicities (cytokine release syndrome, neurotoxicity) and high costs due to the logistically challenging preparation process for autologous cells, the use of alternative immune cells is gaining traction. NK cells and γδ T cells that do not need HLA compatibility or macrophages and dendritic cells with additional properties such as phagocytosis or antigen presentation are increasingly seen as cellular vehicles with potential for application. As these cells possess distinct properties, clinicians and researchers need a thorough understanding of their peculiarities and commonalities. This review will compare these different cell types and their specific modes of action seen upon CAR activation.
Alectinib in Early-Stage Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Current Evidence and Future Challenges
Authors: Cortinovis Diego Luigi , Leonetti Alessandro , Morabito Alessandro , Sala Luca , Tiseo Marcello
Published: July 2024

Background: Targeted therapies changed the treatment of advanced oncogene-addicted non-small cell lung cancer and could also improve outcomes in resectable disease. Results: The ALINA trial evaluated the clinical benefit of adjuvant alectinib compared with standard chemotherapy and met the primary endpoint with a significant increase in disease-free survival at 2 years among anaplastic lymphoma kinase positive patients with stage IB-IIIA disease; two phase II trials (ALNEO and NAUTIKA1) are currently evaluating perioperative treatment with alectinib, and the results of the case reports published to date are encouraging. Conclusion: In resectable anaplastic lymphoma kinase-positive lung cancer, adjuvant alectinib represents the new standard of care and could soon be used in perioperative treatment.
Effect of Support Functionalization on Catalytic Direct Hydrogenation and Catalytic Transfer Hydrogenation of Muconic Acid to Adipic Acid
Authors: Zanella Elisa , Franchi Stefano , Jabbarli Narmin , Barlocco Ilaria , Stucchi Marta , Pirola Carlo
Published: July 2024

The liquid-phase hydrogenation of muconic acid (MA) to produce bio-adipic acid (AdA) is a prominent environmentally friendly chemical process, that can be achieved through two distinct methodologies: catalytic direct hydrogenation using molecular hydrogen (H2), or catalytic transfer hydrogenation utilizing a hydrogen donor. In this study, both approaches were explored, with formic acid (FA) selected as the hydrogen source for the latter method. Palladium-based catalysts were chosen for these processes. Metal’s nanoparticles (NPs) were supported on high-temperature heat-treated carbon nanofibers (HHT-CNFs) due to their known ability to enhance the stability of this metal catalyst. To assess the impact of support functionalization on catalyst stability, the HHT-CNFs were further functionalized with phosphorus and oxygen to obtain HHT-P and HHT-O, respectively. In the hydrogenation reaction, catalysts supported on functionalized supports exhibited higher catalytic activity and stability compared to Pd/HHT, reaching an AdA yield of about 80% in less than 2 h in batch reactor. The hydrogen-transfer process also yielded promising results, particularly with the 1%Pd/HHT-P catalyst. This work highlights the efficacy of support functionalization in improving catalyst performance, particularly when formic acid is used as a safer and more cost-effective hydrogen donor in the hydrogen-transfer process.
A First-Principles Study on the Reaction Mechanisms of Electrochemical CO2 Reduction to C1 and C2 Products on Cu(110)
Authors: Xu Yangyang , Zhang Lixin
Published: July 2024

The mechanism of the electrochemical CO2 reduction reaction on a Cu(110) surface has yet to be fully revealed. In this work, based on first-principles calculations, we investigate the mechanisms of the CO2 reduction reaction to produce C1 (including one C atom) and C2 (including two C atoms) products on a Cu(110) surface. The results show that CH4 and C2H5OH are the main C1 and C2 products on the Cu(110) surface, respectively. CH4 is produced along the pathway CO2 → COOH* → CO* → CHO* → CH2O* → CH3O* → CH4. C2H5OH is produced via the C-C coupling pathway between CO* and CH2O* intermediates, which is the key reaction step. This is because CO* and CH2O* coupling to CO-CH2O* has the lowest barrier among the CHxO* (x = 0–2) coupling pathways. Therefore, it is the most likely C-C coupling pathway. Further, CO-CH2O* is gradually hydrogenated to C2H5OH along the following pathway: CO-CH2O* → CHO-CH2O* → CHOH-CH2* → CH2OH-CH2* → CH2OH-CH3* → C2H5OH.
Achyranthis radix Extract Enhances Antioxidant Effect of Placenta-Derived Mesenchymal Stem Cell on Injured Human Ocular Cells
Authors: Lee Dae-Hyun , Han Ji Woong , Park Hyeri , Hong Se Jin , Kim Chan-Sik , Kim Young Sook , Lee Ik Soo , Kim Gi Jin
Published: July 2024

Age-related ocular diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy are major causes of irreversible vision impairment in the elderly. Conventional treatments focus on symptom relief and disease slowdown, often involving surgery, but fall short of providing a cure, leading to substantial vision loss. Regenerative medicine, particularly mesenchymal stem cells (MSCs), holds promise for ocular disease treatment. This study investigates the synergistic potential of combining placenta-derived MSCs (PD-MSCs) with Achyranthis radix extract (ARE) from Achyranthes japonica to enhance therapeutic outcomes. In a 24-h treatment, ARE significantly increased the proliferative capacity of PD-MSCs and delayed their senescence (* p < 0.05). ARE also enhanced antioxidant capabilities and increased the expression of regeneration-associated genes in an in vitro injured model using chemical damages on human retinal pigment epithelial cell line (ARPE-19) (* p < 0.05). These results suggest that ARE-primed PD-MSC have the capability to enhance the activation of genes associated with regeneration in the injured eye via increasing antioxidant properties. Taken together, these findings support the conclusion that ARE-primed PD-MSC may serve as an enhanced source for stem cell-based therapy in ocular diseases.
A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders
Authors: Marshall Randall D. , Menniti Frank S. , Tepper Mark A.
Published: July 2024

Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. Methods: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. Results: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05–0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A’s inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. Conclusions: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.
Novel Technologies to Address the Lower Motor Neuron Injury and Augment Reconstruction in Spinal Cord Injury
Authors: Bazarek Stanley F. , Krenn Matthias J. , Shah Sameer B. , Mandeville Ross M. , Brown Justin M.
Published: July 2024

Lower motor neuron (LMN) damage results in denervation of the associated muscle targets and is a significant yet under-appreciated component of spinal cord injury (SCI). Denervated muscle undergoes a progressive degeneration and fibro-fatty infiltration that eventually renders the muscle non-viable unless reinnervated within a limited time window. The distal nerve deprived of axons also undergoes degeneration and fibrosis making it less receptive to axons. In this review, we describe the LMN injury associated with SCI and its clinical consequences. The process of degeneration of the muscle and nerve is broken down into the primary components of the neuromuscular circuit and reviewed, including the nerve and Schwann cells, the neuromuscular junction, and the muscle. Finally, we discuss three promising strategies to reverse denervation atrophy. These include providing surrogate axons from local sources; introducing stem cell-derived spinal motor neurons into the nerve to provide the missing axons; and finally, instituting a training program of high-energy electrical stimulation to directly rehabilitate these muscles. Successful interventions for denervation atrophy would significantly expand reconstructive options for cervical SCI and could be transformative for the predominantly LMN injuries of the conus medullaris and cauda equina.
Reply to Damaševičius, R. Comment on “Cárdenas-García, J.F. Info-Autopoiesis and the Limits of Artificial General Intelligence. Computers 2023, 12, 102”
Authors: Cárdenas-García Jaime F.
Published: July 2024

The author thanks and acknowledges the many positive and critical comments by Robertas Damaševičius [...]