bluuebunny/crossref_metadata_2025_split huggingface dataset:
T-cell exhaustion-related genes in Graves’ disease: a comprehensive genome mapping analysis
Authors: Jiang Zhengrong , Cai Huiyao , Lin Yizhao , Lin Ruhai , Chen Lijun , Huang Huibin 
Published: August 2024

BackgroundT-cell exhaustion (Tex) can be beneficial in autoimmune diseases, but its role in Graves’ disease (GD), an autoimmune disorder of the thyroid, remains unknown. This study investigated Tex-related gene expression in GD patients to discern the potential contributions of these genes to GD pathogenesis and immune regulation.MethodsThrough gene landscape analysis, a protein–protein interaction network of 40 Tex-related genes was constructed. mRNA expression levels were compared between GD patients and healthy control (HCs). Unsupervised clustering categorized GD cases into subtypes, revealing distinctions in gene expression, immune cell infiltration, and immune responses. Weighted gene co-expression network analysis and differential gene expression profiling identified potential therapeutic targets. RT-qPCR validation of candidate gene expression was performed using blood samples from 112 GD patients. Correlations between Tex-related gene expression and clinical indicators were analyzed.ResultsExtensive Tex-related gene interactions were observed, with six genes displaying aberrant expression in GD patients. This was associated with atypical immune cell infiltration and regulation. Cluster analysis delineated two GD subtypes, revealing notable variations in gene expression and immune responses. Screening efforts identified diverse drug candidates for GD treatment. The Tex-related gene CBL was identified for further validation and showed reduced mRNA expression in GD patients, especially in cases of relapse. CBL mRNA expression was significantly lower in patients with moderate-to-severe thyroid enlargement than in those without such enlargement. Additionally, CBL mRNA expression was negatively correlated with the disease-specific indicator thyrotropin receptor antibodies.ConclusionTex-related genes modulate GD pathogenesis, and their grouping aids subtype differentiation and exploration of therapeutic targets. CBL represents a potential marker for GD recurrence.
Accurate parameters identification of proton exchange membrane fuel cell using Young’s double-slit experiment optimizer
Authors: Tummala Ayyarao S. L. V. , Polumahanthi Nishanth , Khan Baseem , Ali Ahmed 
Published: August 2024

IntroductionFuel cell technology is a harbinger of the future for generating electricity due to their high efficiency and low emissions achieved through the direct conversion of chemical energy into electrical energy without combustion.MethodsTo optimize the design and performance, a fuel cell model is essential to predict its behaviour in different conditions. This technical note presents a novel physics-based approach, the Young’s Double-slit Experiment Optimizer (YDEO), for identifying parameters in Proton Exchange Membrane Fuel Cells. A performance metric is established by formulating an objective function that relies on the summation of squared errors between experimental and estimated values.Results and discussionThe effectiveness of this approach is evaluated through the analysis of four benchmark test cases: Horizon 500 W, BCS500 W, NedstackPS6, and 250 W. The corresponding objective function values for these test cases are 0.011243, 2.065557, 0.011698, and 5.250849, respectively. The simulation results demonstrate the efficacy of the proposed YDEO algorithm when compared with other existing popular and contemporary algorithms in the literature.
Risk factors and prediction model for osteonecrosis of the femoral head in female systemic lupus erythematosus
Authors: Xu Wenbo , Wang Lihe , Shi Pengbo , Liu Linfeng , Zhang Wenxin 
Published: August 2024

BackgroundOsteonecrosis of the femoral head (ONFH) is a severe complication of systemic lupus erythematosus (SLE) and occurs more frequently in SLE patients than in other autoimmune diseases, which can influence patients’ life quality. The objective of this research was to analyze risk factors for the occurrence of ONFH in female SLE patients, construct and validate a risk nomogram model.MethodsClinical records of SLE patients who fulfilled the 1997 American College of Rheumatology SLE classification criteria were retrospectively analyzed. The Least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis were used to summarize the independent risk factors of ONFH in female SLE patients, which were used to develop a nomogram. The predictive performance of the nomogram was assessed using the receiver characteristic (ROC) curve, calibration curves and decision curve analysis (DCA).Results793 female SLE patients were ultimately included in this study, of which 87 patients (10.9%) developed ONFH. Ten independent risk factors including disease duration, respiratory involvement, menstrual abnormalities, Sjögren's syndrome, osteoporosis, anti-RNP, mycophenolate mofetil, cyclophosphamide, biologics, and the largest daily glucocorticoid (GC) were identified to construct the nomogram. The area under the ROC curve of the nomogram model was 0.826 (95% CI: 0.780–0.872) and its calibration for forecasting the occurrence of ONFH was good (χ2= 5.589, P = 0.693). DCA showed that the use of nomogram prediction model had certain application in clinical practice when the threshold was 0.05 to 0.95. In subgroup analysis, we found that the risk of ONFH was significantly increased in age at SLE onset of ≤ 50 years old, largest daily GC dose of ≥50 mg and the therapy of GC combined with immunosuppressant patients with menstrual abnormalities.ConclusionMenstrual abnormalities were the first time reported for the risk factors of ONFH in female SLE patients, which remind that clinicians should pay more attention on female SLE patients with menstrual abnormalities and take early interventions to prevent or slow the progression of ONFH. Besides, the nomogram prediction model could provide an insightful and applicable tool for physicians to predict the risk of ONFH.
Dynamics and implications of anti-drug antibodies against adalimumab using ultra-sensitive and highly drug-tolerant assays
Authors: Ding Xiaoliang , Xue Ling , Wang Mingjun , Zhu Shengxiong , Zhu Kouzhu , Jiang Sheng , Wu Jian , Miao Liyan 
Published: August 2024

BackgroundAdalimumab induces the production of anti-drug antibodies (ADA) that may lead to reduced drug concentration and loss-of-response, posing significant clinical challenges. However, traditional immunoassays have limitations in terms of sensitivity and drug-tolerance, hindering the insights of ADA response.MethodsHerein, we developed an integrated immunoassay platform combining the electrochemiluminescence immunoassay with immunomagnetic separation strategy. A longitudinal cohort study involving 49 patients with ankylosing spondylitis was carried out to analyze the dynamic profiles of ADA and to investigate the impact of ADA on adalimumab pharmacokinetics using a population pharmacokinetic model. Additionally, cross-sectional data from 12 patients were collected to validate the correlation between ADA levels and disease relapse.ResultsThe ADA assay demonstrated high sensitivity (0.4 ng/mL) and drug-tolerance (100 μg/mL), while the neutralizing antibodies (NAB) assay showed a sensitivity of 100 ng/mL and drug-tolerance of 20 μg/mL. Analysis of the longitudinal cohort revealed that a majority of patients (44/49, 90%) developed persistent ADA within the first 24 weeks of treatment. ADA levels tended to plateau over time after an initial increase during the early immune response phase. Further, nearly all of the tested patients (26/27, 96%) were classified as NAB positive, with a strong correlation between ADA levels and neutralization capacity (R2 = 0.83, P &lt; 0.001). Population pharmacokinetic modeling revealed a significant positive association between model-estimated individual clearance and observed ADA levels. Higher ADA levels were associated with adalimumab clearance and disease relapse in a cross-sectional cohort, suggesting a promising ADA threshold of 10 for potential clinical application. Moreover, the IgG class was the primary contributor to ADA against adalimumab and the apparent affinity exhibited an increasing trend over time, indicating a T-cell dependent mechanism for ADA elicitation by adalimumab.ConclusionIn summary, this integrated immunoassay platform shows promise for in-depth analysis of ADA against biologics, offering fresh insights into immunogenicity and its clinical implications.
Circulating cell adhesion molecules in systemic sclerosis: a systematic review and meta-analysis
Authors: Mangoni Arduino A. , Zinellu Angelo 
Published: August 2024

IntroductionPatients with systemic sclerosis (SSc) have an increased risk of endothelial dysfunction, atherosclerosis, and cardiovascular events compared to the general population. Therefore, the availability of robust circulating biomarkers of endothelial dysfunction and atherogenesis may facilitate early recognition and management of cardiovascular risk in SSc. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating various types of circulating cell adhesion molecules involved in endothelial dysfunction and atherogenesis (i.e., immunoglobulin-like vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, Down syndrome cell, DSCAM, and endothelial cell-selective, ESAM, adhesion molecules, E-, L-, and P-selectin, integrins, and cadherins) in SSc patients and healthy controls.MethodsWe searched PubMed, Scopus, and Web of Science from inception to 1 May 2024. Risk of bias and certainty of evidence were assessed using validated tools.ResultsIn 43 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum concentrations of ICAM-1 (standard mean difference, SMD=1.16, 95% CI 0.88 to 1.44, p&lt;0.001; moderate certainty), VCAM-1 (SMD=1.09, 95% CI 0.72 to 1.46, p&lt;0.001; moderate certainty), PECAM-1 (SMD=1.65, 95% CI 0.33 to 2.98, p=0.014; very low certainty), E-selectin (SMD=1.17, 95% CI 0.72 to 1.62, p&lt;0.001; moderate certainty), and P-selectin (SMD=1.10, 95% CI 0.31 to 1.90, p=0.007; low certainty). There were no significant between-group differences in L-selectin concentrations (SMD=-0.35, 95% CI -1.03 to 0.32, p=0.31; very low certainty), whereas minimal/no evidence was available for cadherins, NCAM, DSCAM, ESAM, or integrins. Overall, no significant associations were observed between the effect size and various patient and study characteristics in meta-regression and subgroup analyses.DiscussionThe results of this systematic review and meta-analysis suggest that specific circulating cell adhesion molecules, i.e., ICAM-1, VCAM-1, PECAM-1, E-selectin, and P-selectin, can be helpful as biomarkers of endothelial dysfunction and atherogenesis in the assessment of cardiovascular risk in SSc patients.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024549710.
TP63 transcriptionally regulates SLC7A5 to suppress ferroptosis in head and neck squamous cell carcinoma
Authors: Chen Zilong , Cai Haoxi , Ye Weiwei , Wu Junming , Liu Jing , Xie Yun , Feng Shiqiang , Jin Yuanpei , Lv Yunxia , Ye Hui , Cai Chengfu , Cai Gengming 
Published: August 2024

BackgroundMost head and neck squamous cell carcinoma (HNSCC) patients are diagnosed at an advanced local stage. While immunotherapy has improved survival rates, only a minority of patients respond durably to targeted immunotherapies, posing substantial clinical challenges. We investigated the heterogeneity of the tumor microenvironment in HNSCC cohorts before and after immunotherapy by analyzing single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing datasets retrieved from public databases.MethodsWe constructed a single-cell transcriptome landscape of HNSCC patients before and after immunotherapy and analyzed the cellular composition, developmental trajectories, gene regulatory networks, and communication patterns of different cell type subpopulations. Additionally, we assessed the expression levels of relevant indicators in HNSCC cells via western blot, ELISA, and fluorescent probe techniques.ResultsAt the single-cell level, we identified a subpopulation of TP63+ SLC7A5+ HNSCC that exhibited a ferroptosis-resistant phenotype. This subpopulation suppresses ferroptosis in malignant cells through the transcriptional upregulation of SLC7A5 mediated by high TP63 expression, thereby promoting tumor growth and resistance to immunotherapy. The experimental results demonstrated that the overexpression of TP63 upregulated the expression of SLC7A5 and suppressed the concentrations of Fe2+ and ROS in HNSCC cells. By integrating bulk transcriptome data, we developed a clinical scoring model based on TP63 and SLC7A5, which are closely associated with tumor stage, revealing the significant prognostic efficacy of the TP63+ SLC7A5+ HNSCC-mediated ferroptosis mechanism in HNSCC patients.ConclusionOur research elucidates the TME in HNSCC before and after immunotherapy, revealing a novel mechanism by which TP63+ SLC7A5+ HNSCC inhibits ferroptosis and enhances tumor resistance via TP63-induced SLC7A5 upregulation. These insights lay the foundation for the development of more effective treatments for HNSCC.
The landscape of miRNA-mRNA regulatory network and cellular sources in inflammatory bowel diseases: insights from text mining and single cell RNA sequencing analysis
Authors: Li Yuan , Wang Yao , Chen Simeng , Liu Lijia 
Published: August 2024

BackgroundInflammatory Bowel Diseases (IBDs), encompassing Ulcerative Colitis (UC) and Crohn’s Disease (CD), are chronic, recurrent inflammatory conditions of the gastrointestinal tract. The microRNA (miRNA) -mRNA regulatory network is pivotal in the initiation and progression of IBDs. Although individual studies provide valuable insights into miRNA mechanisms in IBDs, they often have limited scope due to constraints in population diversity, sample size, sequencing platform variability, batch effects, and potential researcher bias. Our study aimed to construct comprehensive miRNA-mRNA regulatory networks and determine the cellular sources and functions of key miRNAs in IBD pathogenesis.MethodsTo minimize potential bias from individual studies, we utilized a text mining-based approach on published scientific literature from PubMed and PMC databases to identify miRNAs and mRNAs associated with IBDs and their subtypes. We constructed miRNA-mRNA regulatory networks by integrating both predicted and experimentally validated results from DIANA, Targetscan, PicTar, Miranda, miRDB, and miRTarBase (all of which are databases for miRNA target annotation). The functions of miRNAs were determined through gene enrichment analysis of their target mRNAs. Additionally, we used two large-scale single-cell RNA sequencing datasets to identify the cellular sources of miRNAs and the association of their expression levels with clinical status, molecular and functional alternation in CD and UC.ResultsOur analysis systematically summarized IBD-related genes using text-mining methodologies. We constructed three comprehensive miRNA-mRNA regulatory networks specific to IBD, CD, and UC. Through cross-analysis with two large-scale scRNA-seq datasets, we determined the cellular sources of the identified miRNAs. Despite originating from different cell types, hsa-miR-142, hsa-miR-145, and hsa-miR-146a were common to both CD and UC. Notably, hsa-miR-145 was identified as myofibroblast-specific in both CD and UC. Furthermore, we found that higher tissue repair and enhanced glucose and lipid metabolism were associated with hsa-miR-145 in myofibroblasts in both CD and UC contexts.ConclusionThis comprehensive approach revealed common and distinct miRNA-mRNA regulatory networks in CD and UC, identified cell-specific miRNA expressions (notably hsa-miR-145 in myofibroblasts), and linked miRNA expression to functional alterations in IBD. These findings not only enhance our understanding of IBD pathogenesis but also offer promising diagnostic biomarkers and therapeutic targets for clinical practice in managing IBDs.
Prevalence of skin manifestations in patients with COVID-19: a systematic review and meta-analysis
Authors: Aguiar Beatriz Regina Lima de , Ferreira Elaine Barros , De Luca Canto Graziela , Guerra Eliete Neves Silva , Reis Paula Elaine Diniz dos 
Published: August 2024

BackgroundCOVID-19 presents extrapulmonary manifestations that can aid in the diagnosis. Skin manifestations have been reported but their characteristics are not yet clear. Health professionals need information about its prevalence and main characteristics.MethodsThis systematic review followed the PRISMA criteria. The protocol was registered in the PROSPERO (number CRD42020193173). Seven electronic databases and the gray literature were searched independently by two researchers. Observational analytical studies that presented data on the prevalence of skin manifestations in patients aged 19 or older with COVID-19 were included. Prevalence estimates were synthesized through a meta-analysis using random-effects models. Association meta-analysis and comparisons were performed for individual characteristics.ResultsWe included 31 studies with 10,934 patients, of which 10,121 tested positive for COVID-19. The general prevalence of skin manifestations was 29% (95% CI: 17.0–43.0; I2: 99%), the most in Africa, with a mean duration between 7 and 9 days and the most frequently affecting feet+hands (75%) and the trunk (71%). Patients with mild/moderate COVID-19 had more of chilblain-like+pernio-like lesions (97%) and inflammatory lesions (86%) than patients with severe or critical COVID-19. Manifestations of vascular origin were only in elderly patients and were significant with the severity of COVID-19 (p = 0).ConclusionThe global prevalence of skin manifestations is similar to other signs and symptoms of COVID-19. Skin assessment should be considered when investigating and diagnosing COVID-19 in adult and elderly patients.Systematic review registration: PROSPERO, identifier CRD42020193173, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020193173.
Is there a duration-characteristic relationship for trypsin exposure on tendon? A study on anterior cruciate ligament reconstruction in a rabbit model
Authors: Ma Rongxing , Gao Xiaokang , Jin Yangyang , Wang Xiaolong , Li Ruifeng , Qiao Ruiqi , Wang Xinliang , Liu Dayong , Xie Zhitao , Wang Limin , Zhang Jingyu , Xu Weiguo , Hu Yongcheng 
Published: August 2024

BackgroundDecellularized allograft tendons are highly regarded for their accessibility and the reduced risk of immune rejection, making them a promising choice for grafting due to their favorable characteristics. However, effectively integrating reconstructed tendons with host bone remains a significant clinical challenge.PurposeThis study aims to investigate the relationship between the duration of tendon exposure to trypsin and its impact on tendon biomechanical properties and healing capacity.MethodsMorphological assessments and biochemical quantifications were conducted. Allograft tendons underwent heterotopic transplantation into the anterior cruciate ligament (ACL) in a rabbit model, with specimens harvested 6 weeks post-surgery for a comparative analysis of cell adhesion strength and mechanical performance. Duration-response curves were constructed using maximum stress and cell adhesion quantity as primary indicators.ResultsThe trypsin treatment enhanced cell adhesion on the tendon surface. Adhesion rates in the control group vs. the experimental groups were as follows: 3.10 ± 0.56% vs. 4.59 ± 1.51%, 5.36 ± 1.24%, 6.12 ± 1.98%, and 8.27 ± 2.34% (F = 6.755, p = 0.001). However, increasing treatment duration led to a decline in mechanical properties, with the ultimate load (N) in the control vs. experimental groups reported as 103.30 ± 10.51 vs. 99.59 ± 4.37, 93.15 ± 12.38, 90.42 ± 7.87, and 82.68 ± 6.89, F = 4.125 (p = 0.013).ConclusionThe findings reveal an increasing trend in adhesion effectiveness with prolonged exposure duration, while mechanical strength declines. The selection of the optimal processing duration should involve careful consideration of the benefits derived from both outcomes.
Deep learning model shows pathologist-level detection of sentinel node metastasis of melanoma and intra-nodal nevi on whole slide images
Authors: Siarov Jan , Siarov Angelica , Kumar Darshan , Paoli John , Mölne Johan , Neittaanmäki Noora 
Published: August 2024

IntroductionNodal metastasis (NM) in sentinel node biopsies (SNB) is crucial for melanoma staging. However, an intra-nodal nevus (INN) may often be misclassified as NM, leading to potential misdiagnosis and incorrect staging. There is high discordance among pathologists in assessing SNB positivity, which may lead to false staging. Digital whole slide imaging offers the potential for implementing artificial intelligence (AI) in digital pathology. In this study, we assessed the capability of AI to detect NM and INN in SNBs.MethodsA total of 485 hematoxylin and eosin whole slide images (WSIs), including NM and INN from 196 SNBs, were collected and divided into training (279 WSIs), validation (89 WSIs), and test sets (117 WSIs). A deep learning model was trained with 5,956 manual pixel-wise annotations. The AI and three blinded dermatopathologists assessed the test set, with immunohistochemistry serving as the reference standard.ResultsThe AI model showed excellent performance with an area under the curve receiver operating characteristic (AUC) of 0.965 for detecting NM. In comparison, the AUC for NM detection among dermatopathologists ranged between 0.94 and 0.98. For the detection of INN, the AUC was lower for both AI (0.781) and dermatopathologists (range of 0.63–0.79).DiscussionIn conclusion, the deep learning AI model showed excellent accuracy in detecting NM, achieving dermatopathologist-level performance in detecting both NM and INN. Importantly, the AI model showed the potential to differentiate between these two entities. However, further validation is warranted.