bluuebunny/crossref_metadata_2025 huggingface dataset:
Bletilla striata polysaccharide-coated andrographolide nanomicelles for targeted drug delivery to enhance anti-colon cancer efficacy
Authors: Yue Zhongqun , Zhu Yue , Chen Teng , Feng Tingting , Zhou Ying , Zhang Jiaojiao , Zhang Ning , Yang Jing , Luo Gang , Wang Zuhua
Published: June 2024

Background

Vitamin E, which is also known as tocopherol, is a compound with a polyphenol structure. Its esterified derivative, Vitamin E succinate (VES), exhibits unique anticancer and healthcare functions as well as immunomodulatory effects. Natural polysaccharides are proved to be a promising material for nano-drug delivery systems, which show excellent biodegradability and biocompatibility. In this study, we employed a novel bletilla striata polysaccharide-vitamin E succinate polymer (BSP-VES) micelles to enhance the tumor targeting and anti-colon cancer effect of andrographolide (AG).

Methods

BSP-VES polymer was synthesized through esterification and its structure was confirmed using 1H NMR. AG@BSP-VES was prepared via the dialysis method and the drug loading, entrapment efficiency, stability, and safety were assessed. Furthermore, the tumor targeting ability of AG@BSP-VES was evaluated through targeted cell uptake and in vivo imaging. The antitumor activity of AG@BSP-VES was measured in vitro using MTT assay, Live&Dead cell staining, and cell scratch test.

Results

In this study, we successfully loaded AG into BSP-VES micelles (AG@BSP-VES), which exhibited good stability, biosafety and sustained release effect. In addition, AG@BSP-VES also showed excellent internalization capability into CT26 cells compared with NCM460 cells in vitro. Meanwhile, the specific delivery of AG@BSP-VES micelles into subcutaneous and in-situ colon tumors was observed compared with normal colon tissues in vivo during the whole experiment process (1–24 h). What’s more, AG@BSP-VES micelles exhibited significant antitumor activities than BSP-VES micelles and free AG.

Conclusion

The study provides a meaningful new idea and method for application in drug delivery system and targeted treatment of colon cancer based on natural polysaccharides.
Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events
Authors: Koch Elias A. T. , Petzold Anne , Dippel Edgar , Erdmann Michael , Gesierich Anja , Gutzmer Ralf , Hassel Jessica C. , Haferkamp Sebastian , Kähler Katharina C. , Kreuzberg Nicole , Leiter Ulrike , Loquai Carmen , Meier Friedegund , Meissner Markus , Mohr Peter , Pföhler Claudia , Rahimi Farnaz , Schell Beatrice , Terheyden Patrick , Thoms Kai-Martin , Ugurel Selma , Ulrich Jens , Utikal Jochen , Weichenthal Michael , Ziller Fabian , Berking Carola , Heppt Markus V.
Published: June 2024

Introduction

Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable.

Methods

In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57).

Results

In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively).

Conclusions

This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.
Epigenetic remodeling in insect immune memory
Authors: Mukherjee Krishnendu , Dobrindt Ulrich
Published: June 2024

The innate immune system of insects can respond more swiftly and efficiently to pathogens based on previous experience of encountering antigens. The understanding of molecular mechanisms governing immune priming, a form of immune memory in insects, including its transgenerational inheritance, remains elusive. It is still unclear if the enhanced expression of immune genes observed in primed insects can persist and be regulated through changes in chromatin structure via epigenetic modifications of DNA or histones, mirroring observations in mammals. Increasing experimental evidence suggests that epigenetic changes at the level of DNA/RNA methylation and histone acetylation can modulate the activation of insects’ immune responses to pathogen exposure. Moreover, transgenerational inheritance of certain epigenetic modifications in model insect hosts can influence the transmission of pre-programmed immune responses to the offspring, leading to the development of evolved resistance. Epigenetic research in model insect hosts is on the brink of significant progress in the mechanistic understanding of chromatin remodeling within innate immunity, particularly the direct relationships between immunological priming and epigenetic alterations. In this review, we discuss the latest discoveries concerning the involvement of DNA methylation and histone acetylation in shaping the development, maintenance, and inheritance of immune memory in insects, culminating in the evolution of resistance against pathogens.
Advancing precision rheumatology: applications of machine learning for rheumatoid arthritis management
Authors: Shi Yiming , Zhou Mi , Chang Cen , Jiang Ping , Wei Kai , Zhao Jianan , Shan Yu , Zheng Yixin , Zhao Fuyu , Lv Xinliang , Guo Shicheng , Wang Fubo , He Dongyi
Published: June 2024

Rheumatoid arthritis (RA) is an autoimmune disease causing progressive joint damage. Early diagnosis and treatment is critical, but remains challenging due to RA complexity and heterogeneity. Machine learning (ML) techniques may enhance RA management by identifying patterns within multidimensional biomedical data to improve classification, diagnosis, and treatment predictions. In this review, we summarize the applications of ML for RA management. Emerging studies or applications have developed diagnostic and predictive models for RA that utilize a variety of data modalities, including electronic health records, imaging, and multi-omics data. High-performance supervised learning models have demonstrated an Area Under the Curve (AUC) exceeding 0.85, which is used for identifying RA patients and predicting treatment responses. Unsupervised learning has revealed potential RA subtypes. Ongoing research is integrating multimodal data with deep learning to further improve performance. However, key challenges remain regarding model overfitting, generalizability, validation in clinical settings, and interpretability. Small sample sizes and lack of diverse population testing risks overestimating model performance. Prospective studies evaluating real-world clinical utility are lacking. Enhancing model interpretability is critical for clinician acceptance. In summary, while ML shows promise for transforming RA management through earlier diagnosis and optimized treatment, larger scale multisite data, prospective clinical validation of interpretable models, and testing across diverse populations is still needed. As these gaps are addressed, ML may pave the way towards precision medicine in RA.
CAR-T cell therapy in advanced thyroid cancer: from basic to clinical
Authors: Sun Zhenhua , Wang Chaohui , Zhao Yuyang , Ling Qingyi
Published: June 2024

The majority of patients with thyroid cancer can attain a favorable prognosis with a comprehensive treatment program based on surgical treatment. However, the current treatment options for advanced thyroid cancer are still limited. In recent years, chimeric antigen receptor-modified T-cell (CAR-T) therapy has received widespread attention in the field of oncology treatment. It has achieved remarkable results in the treatment of hematologic tumors. However, due to the constraints of multiple factors, the therapeutic efficacy of CAR-T therapy for solid tumors, including thyroid cancer, has not yet met expectations. This review outlines the fundamental structure and treatment strategies of CAR-T cells, provides an overview of the advancements in both preclinical investigations and clinical trials focusing on targets associated with CAR-T cell therapy in treating thyroid cancer, and discusses the challenges and solutions to CAR-T cell therapy for thyroid cancer. In conclusion, CAR-T cell therapy is a promising therapeutic approach for thyroid cancer, and we hope that our review will provide a timely and updated study of CAR-T cell therapy for thyroid cancer to advance the field.
Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis
Authors: Sanna Krizia , Bruno Antonio , Balletta Sara , Caioli Silvia , Nencini Monica , Fresegna Diego , Guadalupi Livia , Dolcetti Ettore , Azzolini Federica , Buttari Fabio , Fantozzi Roberta , Borrelli Angela , Stampanoni Bassi Mario , Gilio Luana , Lauritano Gianluca , Vanni Valentina , De Vito Francesca , Tartacca Alice , Mariani Fabrizio , Rovella Valentina , Musella Alessandra , Centonze Diego , Mandolesi Georgia
Published: June 2024

Background

Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients.

Methods

Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery.

Results

SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod’s protective effects.

Conclusion

Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target.
MHC1/LILRB1 axis as an innate immune checkpoint for cancer therapy
Authors: Hu Ziyi , Zhang Qiaodong , He Zehua , Jia Xiaojian , Zhang Wencan , Cao Xu
Published: June 2024

Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a small subset of patients and relapse can occur in patients who initially respond to the treatment. Recent breakthroughs in this field have identified innate immune checkpoints harnessed by cancer cells to escape immunosurveillance from innate immunity. MHC1 appears to be such a molecule expressed on cancer cells which can transmit a negative signal to innate immune cells through interaction with leukocyte immunoglobulin like receptor B1 (LILRB1). The review aims to summarize the current understanding of MHC1/LILRB1 axis on mediating cancer immune evasion with an emphasis on the therapeutic potential to block this axis for cancer therapy. Nevertheless, one should note that this field is still in its infancy and more studies are warranted to further verify the effectiveness and safety in clinical as well as the potential to combine with existing immune checkpoints.
Spatio-temporal dynamics of the carbonate system during macroalgae farming season in a semi-closed bay in southeast China
Authors: Zhang Zhi , Wang Feipeng , Lei Lingyi , Zheng Nan , Shen Zhongyuan , Mu Jingli
Published: June 2024

Ocean Negative Carbon Emission (ONCE) involves utilizing natural marine chemistry and biology, along with mariculture, to achieve carbon sink goals. Growing awareness of the interplay between aquaculture and the coastal carbonate system has drawn researchers’ attention amid ring CO2 concentrations and the negative impacts of aquaculture on the environment. In this study, twelve sites representing different maricultural types were selected, including macroalgae, shellfish, fish, and non-farming areas. The environmental factors, dissolved inorganic carbon (DIC), total alkalinity (TA), and pCO2, were measured monthly during kelp farming periods. Nitrate is a major component of total nitrogen, and the NO3-N concentration in the macroalgal culture zone was lower than others, indicating effective nitrogen removal by macroalgae aquaculture. TA and DIC in non-farmed areas demonstrated larger variation ranges than in farming areas, probably due to the effects of precipitation on salinity. Aquaculture activities effectively maintained TA and DIC, with macroalgae cultivation playing an important role in TA stability, potentially resisting acidification. The pCO2sea-air of macroalgae culture areas in spring was slightly negative, suggesting carbon sink potential. However, further research is needed to assess the full extent of this “fourth type” of blue carbon, including accurate carbon footprint calculation and the contributions of particulate organic carbon and recalcitrant dissolved organic carbon. This study provided insight into the comprehensive contribution of different aquaculture types to the fishery environment and carbonate system, which can help guide aquaculture management and facilitate the carbon-neutral transition of aquaculture.
Flexural behaviour of damaged concrete T-beams reinforced with ultra-high performance concrete filling
Authors: Huang Shuai , Xi Yonglei , Li Xin , Men Pengfei , Wu Gangan
Published: June 2024

To improve the flexural performance of damaged reinforced concrete T-beams, a method of filling ultra-high performance concrete (UHPC) in the damaged area was adopted. Experimental studies were conducted on two UHPC-reinforced concrete T-beams with different lengths of damaged areas and one undamaged concrete T-beam as a reference. Crack distribution, failure modes, cracking loads, flexural capacities, and strain variation of the specimens were analyzed. Subsequently, a nonlinear finite element (FE) model of the UHPC-reinforced T-beam was developed using ABAQUS, and the FE model results were compared with the experimental results to validate the accuracy of the FE simulation method. The results indicated that the two UHPC-reinforced T-beams exhibited a similar flexural failure process to the undamaged T-beam. The longitudinal tensile strain distribution at the mid-span section showed that the composite section formed by the filling of UHPC in the damaged region still adhered the assumption of the planar section. Owing to the excellent bond performance between UHPC and the existing concrete, the main cracks of the UHPC-reinforced T-beams appeared in the chiseled area, and the crack widths of the UHPC-reinforced T-beams under the same load were smaller than those of the reference T-beam. Overall, the reinforcing method of filling UHPC in the damaged region can restore or even enhance the flexural performance of the damaged reinforced concrete T-beams.
Application of image processing technology based on field programmable gate array in mechanical part inspection
Authors: Lv Yi
Published: June 2024

Introduction: In the field of industrial manufacturing, accurate inspection of mechanical components such as gears and bearings is of Paramount importance. However, the traditional mechanical testing methods are often disturbed by human factors, which not only affects the stability of the test results, but also leads to low efficiency and large error. In order to solve these problems, this research focuses on developing a new edge detection model.

Methods: A novel edge detection model based on field-programmable gate array image processing technology was used in this study. The model uses adaptive threshold multi-directional edge detection technology to identify the edge features of mechanical gears and bearings, aiming at improving the precision of detection.

Results and Discussion: After performance verification, the running time of the model was controlled within 11 s, and the detection error was limited to less than 9%. Compared with the control group and the experimental group, their performance was superior. Further analysis data show that the detection accuracy of this model is as high as 0.9004, its internal resource utilization rate is 88%, and the detection rate is as high as 91%, which are better than the comparison model.

Conclusion: The proposed test model not only significantly improves the efficiency and accuracy of the test, but also fully meets the requirements of the test. This new edge detection model has potential application value in industrial manufacturing field, and provides a new solution for industrial manufacturing quality inspection.
Visualization of oil-lubrication ball bearings at high rotational speeds
Authors: Tohyama Mamoru , Ohmiya Yasuhiro , Hirose Michiru , Matsuyama Hiroki , Toda Takuya , Hasegawa Kenichi , Onizuka Takaaki , Sato Hideaki , Yokoi Masahiro , Sato Norikazu
Published: June 2024

Deep-groove ball bearings for the eAxles of electric vehicles must adapt to higher rotational speed conditions because the speed of eAxle motors have been increasing as the size and weight of the motors decrease. Therefore, understanding the oil-lubricated conditions inside ball bearings at high rotational speeds is essential for optimizing their design for eAxles. To clarify the oil-lubricated conditions inside ball bearings at these high speeds, a new test apparatus was developed. This apparatus is capable of simultaneously measuring the friction torque of deep-groove ball bearings, the oil-film thickness on the rolling balls, and observing the oil distributions inside the bearings at rotational speeds up to 20,000 min-1. The oil-film thickness was measured using three-wavelength optical interferometry, and the oil distribution was observed using fluorescence. It was found that the oil-film thickness became constant at rotational speed conditions exceeding approximately 7,700 min-1. Oil starvations were observed on the raceway around the rolling ball, and these regions increased with increasing rotational speeds. Additionally, in the deep-groove ball bearing with a crown-shaped cage, the oil was mainly supplied to the rolling balls from the inner ring side through the space between the cage claws that held the ball. Moreover, the amount of mixed air tended to increase as the rotational speed increased to approximately 7,700 min-1. Those oil starvations and increasing air in oils were considered to be factors that prevent the increase in oil-film thickness. The findings of the reported study will contribute to the development of multibody dynamic technology for high-speed ball bearings necessary in electric vehicles.
The added value of a face-to-face pan-European course—what makes it worth it?
Authors: de Leeuw Robert , Huirne Judith A. F. , Rositto Christiano , Mabrouk Mohammed , Barri Pierre , Bongers Marlies , Thurkow Andreas , El-Balat Ahmed , Vlahos Nikon , Brolmann Hans
Published: June 2024

Introduction

Over the past decade, digital education has seen widespread adoption, particularly accentuated during the COVID-19 pandemic. The post-COVID era has further emphasized the advantages of digital education in terms of cost, availability, and sustainability. However, concerns regarding the efficacy of digital education, particularly in skills-based learning and the absence of social interaction, have been raised. This paper will look at the added value of international, face-to-face, skills-based courses.

Method

This study evaluates the potential added value of face-to-face international skills courses using the European “Gynecology Experts Training for Upcoming Professionals” (GET-UP) course. Focus group discussions were conducted with participants and faculty members to explore beliefs, attitudes, and perceptions regarding face-to-face learning. Qualitative analysis was performed using thematic analysis to identify domains of added value.

Results

The GET-UP course, conducted over 4 days with a diverse European faculty and participants, highlighted several added-value domains. Themes including diversity, role models, preparation, live interaction, and community emerged from the analysis, emphasizing the significance of face-to-face interaction in enriching the learning experience beyond attaining learning goals.

Discussion

The study underscores the importance of face-to-face interaction in educational settings, offering insights into diverse teaching methods, role modeling opportunities, enhanced preparation, live interactions, and fostering a sense of community. While digital education continues to evolve with interactive features, this study suggests that the inherent pressure and dynamics of face-to-face learning provide unique benefits that may not be easily replicated in digital environments. Future research should investigate and validate these findings further to inform educational practices effectively.
Navigating the landscape of PD-1/PD-L1 imaging tracers: from challenges to opportunities
Authors: Badenhorst Melinda , Windhorst Albert D. , Beaino Wissam
Published: June 2024

Immunotherapy targeted to immune checkpoint inhibitors, such as the program cell death receptor (PD-1) and its ligand (PD-L1), has revolutionized cancer treatment. However, it is now well-known that PD-1/PD-L1 immunotherapy response is inconsistent among patients. The current challenge is to customize treatment regimens per patient, which could be possible if the PD-1/PD-L1 expression and dynamic landscape are known. With positron emission tomography (PET) imaging, it is possible to image these immune targets non-invasively and system-wide during therapy. A successful PET imaging tracer should meet specific criteria concerning target affinity, specificity, clearance rate and target-specific uptake, to name a few. The structural profile of such a tracer will define its properties and can be used to optimize tracers in development and design new ones. Currently, a range of PD-1/PD-L1-targeting PET tracers are available from different molecular categories that have shown impressive preclinical and clinical results, each with its own advantages and disadvantages. This review will provide an overview of current PET tracers targeting the PD-1/PD-L1 axis. Antibody, peptide, and antibody fragment tracers will be discussed with respect to their molecular characteristics and binding properties and ways to optimize them.
Identification of an inflammatory response-related gene prognostic signature and immune microenvironment for cervical cancer
Authors: Wu Zhuna , Zhuang Xuanxuan , Liang Meili , Sheng Liying , Huang Li , Li Yanting , Ke Yumin
Published: June 2024

Background: Cervical cancer (CC) is the fourth most common cancer among women worldwide. As part of the brisk cross-talk between the host and the tumor, prognosis can be affected through inflammatory responses or the tumor microenvironment. However, further exploration of the inflammatory response-related genes that have prognostic value, microenvironment infiltration, and chemotherapeutic therapies in CC is needed.

Methods: The clinical data and mRNA expression profiles of CC patients were downloaded from a public database for this study. In the TCGA cohort, a multigene prognostic signature was constructed by least absolute shrinkage and selection operator (LASSO) and Cox analyses. CC patients from the GEO cohort were used for validation. K‒M analysis was used to compare overall survival (OS) between the high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors of OS. The immune cell infiltration and immune-related functional score were calculated by single-sample gene set enrichment analysis (GSEA). Immunohistochemistry was utilized to validate the protein expression of prognostic genes in CC tissues.

Results: A genetic signature model associated with the inflammatory response was built by LASSO Cox regression analysis. Patients in the high-risk group had a significantly lower OS rate. The predictive ability of the prognostic genes was evaluated by means of receiver operating characteristic (ROC) curve analysis. The risk score was confirmed to be an independent predictor of OS by univariate and multivariate Cox analyses. The immune status differed between the high-risk and low-risk groups, and the cancer-related pathways were enriched in the high-risk group according to functional analysis. The risk score was significantly related to tumor stage and immune infiltration type. The expression levels of five prognostic genes (LCK, GCH1, TNFRSF9, ITGA5, and SLC7A1) were positively related to sensitivity to antitumor drugs. Additionally, the expression of prognostic genes was significantly different between CC tissues and myoma patient cervix (non-tumorous) tissues in the separate sample cohort.

Conclusion: A model consisting of 5 inflammation-related genes can be used to predict prognosis and influence immune status in CC patients. Furthermore, the inhibition or enhancement of these genes may become a novel alternative therapy.
Impact of butorphanol versus sufentanil on postoperative cognition and inflammation in elderly: a pilot study
Authors: Wen Qiannan , Sun Defeng , Yang Lin , Li Yuexian
Published: June 2024

Background

This randomized controlled trial aimed to compare the effects of butorphanol and sufentanil on early post-operative cognitive dysfunction (POCD) and systemic inflammation in older surgical patients.

Methods

Patients (aged 65 years or above) undergoing surgeries with general anesthesia were randomized to either the butorphanol group (40 μg/kg during anesthesia induction) or the sufentanil group (0.4 μg/kg). Cognitive function changes during the perioperative period were assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) scale up to 3 days after surgery. POCD was defined as a Z-score or composite Z-score greater than 1.96 for both MMSE and MoCA scores. Circulating inflammatory factors, including tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 10 (IL-10), were measured using enzyme-linked immunosorbent assay.

Results

The study included 114 patients (median age: 71 years, 57.7% male). Compared to sufentanil, butorphanol significantly reduced the incidence of POCD on the first (11.5% versus 32.7%, p = 0.017) and third day (3.8% versus 15.4%, p = 0.046) after surgery. Additionally, patients receiving butorphanol had significantly lower circulating levels of TNF-α and IL-1β at the time of discharge from the post-anesthesia care unit and on the first and third day after surgery (p < 0.05 for all comparisons). Furthermore, circulating IL-10 levels were significantly higher in patients receiving butorphanol (p < 0.05 for all comparisons).

Conclusion

Administration of butorphanol during anesthesia induction, as opposed to sufentanil, was associated with a significant reduction in the early incidence of POCD in older surgical patients, possibly attributed to its impact on systemic inflammation.

Clinical trial registration: The present study was registered in the China Clinical Trial Center (ChiCTR2300070805, 24/04/2023).
A convenient model of serum-induced reactivity of human astrocytes to investigate astrocyte-derived extracellular vesicles
Authors: White Katherine E. , Bailey Hannah L. , Shaw Barry S. , Geiszler Philippine C. , Mesquita-Ribeiro Raquel , Scott Daniel , Layfield Robert , Serres Sébastien
Published: June 2024

Extracellular vesicles (EVs) are secreted by all cells in the CNS, including neurons and astrocytes. EVs are lipid membrane enclosed particles loaded with various bioactive cargoes reflecting the dynamic activities of cells of origin. In contrast to neurons, the specific role of EVs released by astrocytes is less well understood, partly due to the difficulty in maintaining primary astrocyte cultures in a quiescent state. The aim of this study was to establish a human serum-free astrocyte culture system that maintains primary astrocytes in a quiescent state to study the morphology, function, and protein cargoes of astrocyte-derived EVs. Serum-free medium with G5 supplement and serum-supplemented medium with 2% FBS were compared for the culture of commercially available human primary fetal astrocytes. Serum-free astrocytes displayed morphologies similar to in vivo astrocytes, and surprisingly, higher levels of astrocyte markers compared to astrocytes chronically cultured in FBS. In contrast, astrocyte and inflammatory markers in serum-free astrocytes were upregulated 24 h after either acute 2% FBS or cytokine exposure, confirming their capacity to become reactive. Importantly, this suggests that distinct signaling pathways are involved in acute and chronic astrocyte reactivity. Despite having a similar morphology, chronically serum-cultured astrocyte-derived EVs (ADEVs) were smaller in size compared to serum-free ADEVs and could reactivate serum-free astrocytes. Proteomic analysis identified distinct protein datasets for both types of ADEVs with enrichment of complement and coagulation cascades for chronically serum-cultured astrocyte-derived EVs, offering insights into their roles in the CNS. Collectively, these results suggest that human primary astrocytes cultured in serum-free medium bear similarities with in vivo quiescent astrocytes and the addition of serum induces multiple morphological and transcriptional changes that are specific to human reactive astrocytes and their ADEVs. Thus, more emphasis should be made on using multiple structural, molecular, and functional parameters when evaluating ADEVs as biomarkers of astrocyte health.
Pathological cell assembly dynamics in a striatal MSN network model
Authors: Correa Astrid , Ponzi Adam , Calderón Vladimir M. , Migliore Rosanna
Published: June 2024

Under normal conditions the principal cells of the striatum, medium spiny neurons (MSNs), show structured cell assembly activity patterns which alternate sequentially over exceedingly long timescales of many minutes. It is important to understand this activity since it is characteristically disrupted in multiple pathologies, such as Parkinson's disease and dyskinesia, and thought to be caused by alterations in the MSN to MSN lateral inhibitory connections and in the strength and distribution of cortical excitation to MSNs. To understand how these long timescales arise we extended a previous network model of MSN cells to include synapses with short-term plasticity, with parameters taken from a recent detailed striatal connectome study. We first confirmed the presence of sequentially switching cell clusters using the non-linear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP). We found that the network could generate non-stationary activity patterns varying extremely slowly on the order of minutes under biologically realistic conditions. Next we used Simulation Based Inference (SBI) to train a deep net to map features of the MSN network generated cell assembly activity to MSN network parameters. We used the trained SBI model to estimate MSN network parameters from ex-vivo brain slice calcium imaging data. We found that best fit network parameters were very close to their physiologically observed values. On the other hand network parameters estimated from Parkinsonian, decorticated and dyskinetic ex-vivo slice preparations were different. Our work may provide a pipeline for diagnosis of basal ganglia pathology from spiking data as well as for the design pharmacological treatments.
Development of a predictive model for 1-year postoperative recovery in patients with lumbar disk herniation based on deep learning and machine learning
Authors: Chen Yan , Lin Fabin , Wang Kaifeng , Chen Feng , Wang Ruxian , Lai Minyun , Chen Chunmei , Wang Rui
Published: June 2024

Background

The aim of this study is to develop a predictive model utilizing deep learning and machine learning techniques that will inform clinical decision-making by predicting the 1-year postoperative recovery of patients with lumbar disk herniation.

Methods

The clinical data of 470 inpatients who underwent tubular microdiscectomy (TMD) between January 2018 and January 2021 were retrospectively analyzed as variables. The dataset was randomly divided into a training set (n = 329) and a test set (n = 141) using a 10-fold cross-validation technique. Various deep learning and machine learning algorithms including Random Forests, Extreme Gradient Boosting, Support Vector Machines, Extra Trees, K-Nearest Neighbors, Logistic Regression, Light Gradient Boosting Machine, and MLP (Artificial Neural Networks) were employed to develop predictive models for the recovery of patients with lumbar disk herniation 1 year after surgery. The cure rate score of lumbar JOA score 1 year after TMD was used as an outcome indicator. The primary evaluation metric was the area under the receiver operating characteristic curve (AUC), with additional measures including decision curve analysis (DCA), accuracy, sensitivity, specificity, and others.

Results

The heat map of the correlation matrix revealed low inter-feature correlation. The predictive model employing both machine learning and deep learning algorithms was constructed using 15 variables after feature engineering. Among the eight algorithms utilized, the MLP algorithm demonstrated the best performance.

Conclusion

Our study findings demonstrate that the MLP algorithm provides superior predictive performance for the recovery of patients with lumbar disk herniation 1 year after surgery.
Early poststroke clinically significant fatigue predicts functional independence: a prospective longitudinal study
Authors: Juárez-Belaúnde Alan , Soto-León Vanesa , Dileone Michele , Orcajo Elena , León-Álvarez Natacha , Muñoz Alberto , Tornero Jesus , Oliviero Antonio
Published: June 2024

Background

Poststroke fatigue is a prevalent issue among stroke survivors, significantly impeding functional recovery and diminishing their quality of life.

Aim

This prospective cohort study aims to investigate the association between poststroke fatigue and the extent of functional recovery in survivors of ischemic and hemorrhagic strokes. Additionally, it seeks to delineate the temporal progression of poststroke fatigue in these two stroke subtypes.

Methods

We assessed a cohort of 79 patients recovering from acute ischemic or hemorrhagic strokes. Poststroke fatigue was quantified using the Fatigue Severity Scale (FSS) and the Numeric Rating Scale (NRSfatigue). Patients’ condition was evaluated using the National Institute of Health Stroke Scale (NIHSS), and functional independence levels were determined using the Barthel Index for Activities of Daily Living (BIADL) and the Modified Rankin Scale (MRS). Depressive mood and pain were measured using the Beck Depression Inventory (BDI) and the Numeric Rating Scale for pain (NRSpain), respectively.

Results

Our primary findings indicate that the early manifestation of clinically significant fatigue (CSF) is predictive of a poorer trajectory in functional independence levels during recovery. Furthermore, we observed differing patterns of fatigue progression between ischemic and hemorrhagic strokes. Fatigue tends to ameliorate over time in hemorrhagic stroke cases, paralleling functional recovery, while it remains stable over time in ischemic stroke cases.

Conclusion

Our results underscore the detrimental impact of early poststroke fatigue on long-term outcomes. Furthermore, they highlight the imperative of managing poststroke fatigue, particularly during the subacute phase of stroke recovery.
The current landscape of machine learning-based radiomics in arteriovenous malformations: a systematic review and radiomics quality score assessment
Authors: Grossen Audrey A. , Evans Alexander R. , Ernst Griffin L. , Behnen Connor C. , Zhao Xiaochun , Bauer Andrew M.
Published: June 2024

Background

Arteriovenous malformations (AVMs) are rare vascular anomalies involving a disorganization of arteries and veins with no intervening capillaries. In the past 10 years, radiomics and machine learning (ML) models became increasingly popular for analyzing diagnostic medical images. The goal of this review was to provide a comprehensive summary of current radiomic models being employed for the diagnostic, therapeutic, prognostic, and predictive outcomes in AVM management.

Methods

A systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, in which the PubMed and Embase databases were searched using the following terms: (cerebral OR brain OR intracranial OR central nervous system OR spine OR spinal) AND (AVM OR arteriovenous malformation OR arteriovenous malformations) AND (radiomics OR radiogenomics OR machine learning OR artificial intelligence OR deep learning OR computer-aided detection OR computer-aided prediction OR computer-aided treatment decision). A radiomics quality score (RQS) was calculated for all included studies.

Results

Thirteen studies were included, which were all retrospective in nature. Three studies (23%) dealt with AVM diagnosis and grading, 1 study (8%) gauged treatment response, 8 (62%) predicted outcomes, and the last one (8%) addressed prognosis. No radiomics model had undergone external validation. The mean RQS was 15.92 (range: 10–18).

Conclusion

We demonstrated that radiomics is currently being studied in different facets of AVM management. While not ready for clinical use, radiomics is a rapidly emerging field expected to play a significant future role in medical imaging. More prospective studies are warranted to determine the role of radiomics in the diagnosis, prediction of comorbidities, and treatment selection in AVM management.
Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies
Authors: Domínguez Carral Jana , Reinhard Carola , Ebrahimi-Fakhari Darius , Dorison Nathalie , Galosi Serena , Garone Giacomo , Malenica Masa , Ravelli Claudia , Serdaroglu Esra , van de Pol Laura A. , Koy Anne , Leuzzi Vincenzo , Roubertie Agathe , Lin Jean-Pierre , Doummar Diane , Cif Laura , Ortigoza-Escobar Juan Darío
Published: June 2024

Background

GNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD.

Objectives

This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies.

Methods

A Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise.

Results

Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis.

Conclusion

This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.
Prophylactic management of cerebral vasospasm with clazosentan in real clinical practice: a single-center retrospective cohort study
Authors: Sakata Hiroyuki , Kanoke Atsushi , Uchida Hiroki , Haryu Shinya , Omodaka Shunsuke , Kimura Naoto , Yoshida Masahiro , Niizuma Kuniyasu , Tominaga Teiji , Endo Hidenori
Published: June 2024

Introduction

Clazosentan, a selective endothelin receptor subtype A antagonist, reduces vasospasm-related morbidity and all-cause mortality following aneurysmal subarachnoid hemorrhage (SAH) in the Japanese population, as demonstrated by a recent randomized phase 3 trial. However, evidence to suggest clazosentan should be prioritized over the current standard of care to prevent cerebral vasospasm is still lacking. Therefore, we investigated the efficacy and safety of clazosentan in comparison with conventional postoperative management in real-world clinical practice.

Methods

We conducted a single-center, retrospective, observational cohort study using prospectively collected data from consecutive patients with aneurysmal SAH. After clazosentan was approved for use in Japan, the conventional postoperative management protocol, composed of intravenous fasudil chloride and oral cilostazol (control group, April 2021 to March 2022), was changed to the clazosentan protocol (clazosentan group, April 2022 to March 2023). The primary endpoint was the incidence of vasospasm-related symptomatic infarction. The secondary endpoints were favorable functional outcomes (modified Rankin scale score < 3) at discharge, angiographic vasospasm, and the need for rescue therapy for delayed cerebral ischemia.

Results

The analysis included 100 and 81 patients in the control and clazosentan groups, respectively. The incidence of vasospasm-related symptomatic infarction was significantly lower in the clazosentan group than in the control group (6.2% vs. 16%, p = 0.032). Multiple logistic analyses demonstrated that the use of clazosentan was independently associated with fewer incidence of vasospasm-related symptomatic infarct (23.8% vs. 47.5%, odds ratio 0.34 [0.12–0.97], p = 0.032). Clazosentan was significantly associated with favorable outcomes at discharge (79% vs. 66%, p = 0.037). Moreover, both the incidence of angiographic vasospasm (25.9% vs. 44%, p = 0.013) and the need for rescue therapy (16.1% vs. 34%, p = 0.006) was lower in the clazosentan group. The occurrence of pulmonary edema was significantly higher with clazosentan use (19.8% vs. 5%, p = 0.002), which did not result in morbidity.

Conclusion

A postoperative management protocol centering on clazosentan was associated with the reduced vasospasm-related symptomatic infarction and improved clinical outcomes compared to the conventional management protocol in Japanese clinical practice. Clazosentan might be a promising treatment option for counteracting cerebral vasospasm after aneurysmal SAH.
Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin
Authors: Galatolo Daniele , Rocchiccioli Silvia , Di Giorgi Nicoletta , Dal Canto Flavio , Signore Giovanni , Morani Federica , Ceccherini Elisa , Doccini Stefano , Santorelli Filippo Maria
Published: June 2024

Introduction

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the SACS gene, which codes for sacsin, a large protein involved in protein homeostasis, mitochondrial function, cytoskeletal dynamics, autophagy, cell adhesion and vesicle trafficking. However, the pathogenic mechanisms underlying sacsin dysfunction are still largely uncharacterized, and so attempts to develop therapies are still in the early stages.

Methods

To achieve further understanding of how processes are altered by loss of sacsin, we used untargeted proteomics to compare protein profiles in ARSACS fibroblasts versus controls.

Results

Our analyses confirmed the involvement of known biological pathways and also implicated calcium and lipid homeostasis in ARSACS skin fibroblasts, a finding further verified in SH-SY5Y SACS–/– cells. Validation through mass spectrometry-based analysis and comparative quantification of lipids by LC-MS in fibroblasts revealed increased levels of ceramides coupled with a reduction of diacylglycerols.

Discussion

In addition to confirming aberrant Ca2+ homeostasis in ARSACS, this study described abnormal lipid levels associated with loss of sacsin.
Mapping intracellular NAD content in entire human brain using phosphorus-31 MR spectroscopic imaging at 7 Tesla
Authors: Guo Rong , Yang Shaolin , Wiesner Hannes M. , Li Yudu , Zhao Yibo , Liang Zhi-Pei , Chen Wei , Zhu Xiao-Hong
Published: June 2024

Introduction

Nicotinamide adenine dinucleotide (NAD) is a crucial molecule in cellular metabolism and signaling. Mapping intracellular NAD content of human brain has long been of interest. However, the sub-millimolar level of cerebral NAD concentration poses significant challenges for in vivo measurement and imaging.

Methods

In this study, we demonstrated the feasibility of non-invasively mapping NAD contents in entire human brain by employing a phosphorus-31 magnetic resonance spectroscopic imaging (31P-MRSI)-based NAD assay at ultrahigh field (7 Tesla), in combination with a probabilistic subspace-based processing method.

Results

The processing method achieved about a 10-fold reduction in noise over raw measurements, resulting in remarkably reduced estimation errors of NAD. Quantified NAD levels, observed at approximately 0.4 mM, exhibited good reproducibility within repeated scans on the same subject and good consistency across subjects in group data (2.3 cc nominal resolution). One set of higher-resolution data (1.0 cc nominal resolution) unveiled potential for assessing tissue metabolic heterogeneity, showing similar NAD distributions in white and gray matter. Preliminary analysis of age dependence suggested that the NAD level decreases with age.

Discussion

These results illustrate favorable outcomes of our first attempt to use ultrahigh field 31P-MRSI and advanced processing techniques to generate a whole-brain map of low-concentration intracellular NAD content in the human brain.