bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two ferroptosis-specific expressed genes NOX4 and PARP14 are considered as potential biomarkers for the diagnosis and treatment of diabetic retinopathy and atherosclerosis
Authors: Li Chen , Cai QinHua 
Published: March 2024

Abstract
Objectives
Both Diabetic retinopathy (DR) and Atherosclerosis (AS) are common complications in patients with diabetes, and they share major pathophysiological similarities and have a common pathogenesis. Studies performed to date have demonstrated that ferroptosis plays a vital part in the occurrence and development of DR and AS, but its mechanism in the two diseases remains poorly understood.

Methods
DR Chip data (GSE60436 and GSE102485) and AS chip data (GSE100927 and GSE57691) were obtained from the Gene Expression Omnibus (GEO) database. The screening of the differential expression genes (DEGs) was analyzed using the limma package, and the genes related to ferroptosis were obtained from the FerrDb V2 database. Two key genes (NOX4 and PARP14) were identified through external datasets validation and receiver operating characteristic (ROC) curve analysis. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to conduct a functional enrichment analysis, and miRNA-mRNA networks were established. The CIBERSORT algorithm was applied to identify the immune cell infiltration between the disease group and control group. Next, the correlations between key genes and infiltrating immune cells were investigated by the Spearman method. Finally, the correlation between 2 key genes and ferroptosis markers was confirmed.

Results
Nine ferroptosis differentially expressed genes (DE-FRGs) between DR and AS were identified in this study. NOX4 and PARP14 were selected as key genes for further analysis by external datasets and ROC curve analysis. The key genes NOX4, PARP14 and their correlated genes (such as CYBA, NOX1, NOX3, CYBB, PARP9, PARP10, and PARP15) are mainly enriched in oxidoreductase activity, protein ADP-ribosylation, superoxide metabolic process, reactive oxygen species metabolic process, PID pathway, and VEGFA-VEGFR2 pathway. A miRNA-mRNA network was constructed, and we got 12 miRNAs correlated with the target gene NOX4, 38 miRNAs correlated with the target gene PARP14. Three common miRNAs (hsa-miR-1-3p, hsa-miR-129-2-3p, and hsa-miR-155-5p) were observed in the network. Immune infiltration analysis displayed that activated B cell, MDSC, and Type 17 T helper cell are the common immune cells involved in the immune infiltration process of DR and AS. The results revealed that there are significant correlations between two key genes and most ferroptosis marker genes no matter in DR or AS.

Conclusion
Ferroptosis-related genes NOX4 and PARP14 may be common biomarkers of DR and AS. Both were associated with immune infiltration in patients with DR and AS. Our data provide a theoretical basis for the early diagnosis and immunotherapy of the two diseases.
Pediatric malignant pheochromocytoma with atypical presentation as vision changes, lung metastasis, and recurrence: a case report
Authors: Zhang Kaijun , Yang Penghui , Li Mi , Xiang Ping , Cheng Zhenli , Zhou Xue 
Published: March 2024

Abstract
Background
This case report documents a case of malignant pheochromocytoma manifested as vision changes with lung metastasis and recurrence.

Case presentation
A 10-year-old Han Chinese girl presented with vision changes and was eventually diagnosed with pheochromocytoma by contrast-enhanced computed tomography, urine vanillylmandelic acid. After medication for hypertension and surgery, clinical symptoms disappeared. Malignant pheochromocytoma with lung metastasis was confirmed histologically using the Pheochromocytoma of the Adrenal Gland Scaled Score scoring system and genetically with succinate dehydrogenase complex iron sulfur subunit B mutation, and 3 months later, unplanned surgery was performed because of the high risks and signs of recurrence. She is asymptomatic as of the writing of this case report. Our patient’s case highlights the importance of considering a diagnosis of malignant pheochromocytoma, and long-term follow-up for possible recurrence.

Conclusion
Although there are well-recognized classic clinical manifestations associated with pheochromocytoma, atypical presentation, such as vision changes in children, should be considered. In addition, malignant pheochromocytoma children with a high Pheochromocytoma of the Adrenal Gland Scaled Score and succinate dehydrogenase complex iron sulfur subunit B mutation require a long-term follow-up or even unplanned surgery because of the higher risk of recurrence.
Successful management of massive digoxin overdose using DIGIFab and therapeutic plasma exchange: a case report
Authors: Alhussein Reema M. , Alamri Nawaf A. , Alhashem Hussain M. , Alarifi Mohammed I. , Alyahya Bader 
Published: March 2024

Abstract
Background
Despite the efficacy and safety of DIGIFab, it is relatively expensive and has limited availability. In addition, alternative interventions, such as therapeutic plasma exchange, may need to be considered in massive digoxin overdoses. Although few case reports describe its efficacy.

Case presentation
We report a case of a 17-year-old white male patient brought by family members to our emergency department in Riyadh, Saudi Arabia. After intentionally ingesting 48 mg of digoxin tablets to commit suicide, the patient’s initial digoxin serum level was 8.04 ng/mL. The patient was resuscitated in the emergency department. After admission to the intensive care unit, the patient underwent therapeutic plasma exchange, because of insufficient DIGIFab doses. Afterward, the serum digoxin levels drastically decreased, and his symptoms reverted. The patient was successfully managed and discharged 7 days after admission.

Conclusion
Despite insufficient evidence and a limited number of case reports describing the use of extracorporeal treatment in digoxin overdose, we noted the significant impact of therapeutic plasma exchange on our patient. However, therapeutic plasma exchange’s use in routine treatment requires stronger evidence to confirm its benefits.
Mesenchymal stem/stromal cells from human pluripotent stem cell-derived brain organoid enhance the ex vivo expansion and maintenance of hematopoietic stem/progenitor cells
Authors: Zhou Ya , Cai Xinping , Zhang Xiuxiu , Dong Yong , Pan Xu , Lai Mowen , Zhang Yimeng , Chen Yijin , Li Xiaohong , Li Xia , Liu Jiaxin , Zhang Yonggang , Ma Feng 
Published: March 2024

Abstract
Background
Mesenchymal stem/stromal cells (MSCs) are of great therapeutic value due to their role in maintaining the function of hematopoietic stem/progenitor cells (HSPCs). MSCs derived from human pluripotent stem cells represent an ideal alternative because of their unlimited supply. However, the role of MSCs with neural crest origin derived from HPSCs on the maintenance of HSPCs has not been reported.

Methods
Flow cytometric analysis, RNA sequencing and differentiation ability were applied to detect the characteristics of stromal cells from 3D human brain organoids. Human umbilical cord blood CD34+ (UCB-CD34+) cells were cultured in different coculture conditions composed of stromal cells and umbilical cord MSCs (UC-MSCs) with or without a cytokine cocktail. The hematopoietic stroma capacity of stromal cells was tested in vitro with the LTC-IC assay and in vivo by cotransplantation of cord blood nucleated cells and stroma cells into immunodeficient mice. RNA and proteomic sequencing were used to detect the role of MSCs on HSPCs.

Results
The stromal cells, derived from both H1-hESCs and human induced pluripotent stem cells forebrain organoids, were capable of differentiating into the classical mesenchymal-derived cells (osteoblasts, chondrocytes, and adipocytes). These cells expressed MSC markers, thus named pluripotent stem cell-derived MSCs (pMSCs). The pMSCs showed neural crest origin with CD271 expression in the early stage. When human UCB-CD34+ HSPCs were cocultured on UC-MSCs or pMSCs, the latter resulted in robust expansion of UCB-CD34+ HSPCs in long-term culture and efficient maintenance of their transplantability. Comparison by RNA sequencing indicated that coculture of human UCB-CD34+ HSPCs with pMSCs provided an improved microenvironment for HSC maintenance. The pMSCs highly expressed the Wnt signaling inhibitors SFRP1 and SFRP2, indicating that they may help to modulate the cell cycle to promote the maintenance of UCB-CD34+ HSPCs by antagonizing Wnt activation.

Conclusions
A novel method for harvesting MSCs with neural crest origin from 3D human brain organoids under serum-free culture conditions was reported. We demonstrate that the pMSCs support human UCB-HSPC expansion in vitro in a long-term culture and the maintenance of their transplantable ability. RNA and proteomic sequencing indicated that pMSCs provided an improved microenvironment for HSC maintenance via mechanisms involving cell–cell contact and secreted factors and suppression of Wnt signaling. This represents a novel method for large-scale production of MSCs of neural crest origin and provides a potential approach for development of human hematopoietic stromal cell therapy for treatment of dyshematopoiesis.
Transplantation of the LRP1high subpopulation of human umbilical cord-derived mesenchymal stem cells improves ovarian function in mice with premature ovarian failure and aged mice
Authors: Shen Jiacheng , Wu Li , Shi Xiaoying , Chen Gang , Liu Tingwei , Xu Fangfang , Xu Xiaocui , Kou Xiaochen , Zhao Yanhong , Wang Hong , Wang Chenfei , Gao Shaorong , Xu Shaohua 
Published: March 2024

Abstract
Background
Premature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF.

Methods
10 × Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1high and LRP1low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1high subpopulation on mouse oocytes and granulosa cells.

Results
We identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells.

Conclusion
Through exploration of the heterogeneity of UC-MSCs, we identified the LRP1high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF.

Graphical abstract
Small molecule autoencoders: architecture engineering to optimize latent space utility and sustainability
Authors: Oestreich Marie , Ewert Iva , Becker Matthias 
Published: March 2024

AbstractAutoencoders are frequently used to embed molecules for training of downstream deep learning models. However, evaluation of the chemical information quality in the latent spaces is lacking and the model architectures are often arbitrarily chosen. Unoptimized architectures may not only negatively affect latent space quality but also increase energy consumption during training, making the models unsustainable. We conducted systematic experiments to better understand how the autoencoder architecture affects the reconstruction and latent space quality and how it can be optimized towards the encoding task as well as energy consumption. We can show that optimizing the architecture allows us to maintain the quality of a generic architecture but using 97% less data and reducing energy consumption by around 36%. We additionally observed that representing the molecules as SELFIES reduced the reconstruction performance compared to SMILES and that training with enumerated SMILES drastically improved latent space quality. Scientific Contribution: This work provides the first comprehensive systematic analysis of how choosing the autoencoder architecture affects the reconstruction performance of small molecules, the chemical information content of the latent space as well as the energy required for training. Demonstrated on the MOSES benchmarking dataset it provides first valuable insights into how autoencoders for the embedding of small molecules can be designed to optimize their utility and simultaneously become more sustainable, both in terms of energy consumption as well as the required amount of training data. All code, data and model checkpoints are made available on Zenodo (Oestreich et al. Small molecule autoencoders: architecture engineering to optimize latent space utility and sustainability. Zenodo, 2024). Furthermore, the top models can be found on GitHub with scripts to encode custom molecules: https://github.com/MarieOestreich/small-molecule-autoencoders.
Graphical Abstract
Cytokine-based models for efficient differentiation between infection and cytokine release syndrome in patients with hematological malignancies
Authors: Wang Linqin , Lv Yuqi , Zhou Linghui , Wu Shenghao , Zhu Yuanyuan , Fu Shan , Ding Shuyi , Hong Ruimin , Zhang Mingming , Yu Hanjing , Chang Alex H. , Wei Guoqing , Hu Yongxian , Huang He 
Published: March 2024

AbstractAlthough the efficacy of chimeric antigen receptor (CAR)-T cell therapy has been widely demonstrated, its clinical application is hampered by the complexity and fatality of its side effects. Cytokine release syndrome (CRS) is the most common toxicity following CAR-T cell infusion, and its symptoms substantially overlap with those of infection. Whereas, current diagnostic techniques for infections are time-consuming and not highly sensitive. Thus, we are aiming to develop feasible and efficient models to optimize the differential diagnosis in clinical practice. This study included 191 febrile patients from our center, including 85 with CRS-related fever and 106 with infectious fever. By leveraging the serum cytokine profile at the peak of fever, we generated differential models using a classification tree algorithm and a stepwise logistic regression analysis, respectively. The first model utilized three cytokines (IFN-β, CXCL1, and CXCL10) and demonstrated high sensitivity (90% training, 100% validation) and specificity (98.44% training, 90.48% validation) levels. The five-cytokine model (CXCL10, CCL19, IL-4, VEGF, and CCL20) also showed high sensitivity (91.67% training, 95.65% validation) and specificity (98.44% training, 100% validation). These feasible and accurate differentiation models may prompt early diagnosis of infections during immune therapy, allowing for early and appropriate intervention.
Bold techno competence in language learning: a study on the effects of efficacy of workshops in decreasing technostress and boosting academic enjoyment, autonomy, and language achievement
Authors: Ahmed Abdel-Al Ibrahim Khaled , Hashemifardnia Arash 
Published: March 2024

AbstractThis study investigated the impact of techno-competence workshops on English as a Foreign Language (EFL) learners’ language achievement, technostress, academic enjoyment, and autonomy in a large university in Iran. A concurrent mixed-methods approach was employed, with qualitative data collected through structured interviews and quantitative data gathered using a teacher-made test validated through a known-group procedure. Ninety-six upper-intermediate EFL learners were randomly assigned to an Experimental Group (EG) and a Control Group (CG). Results revealed a significant decrease in technostress, an increase in academic enjoyment, and heightened autonomy among participants attending the techno-competence workshops. The quantitative analysis demonstrated a substantial improvement in language achievement for the EG compared to the CG. Findings contribute to the understanding of the multifaceted impacts of techno-competence on language learning outcomes and offer practical insights for educators, curriculum developers, and policymakers in fostering effective language education in technologically enriched environments. Despite certain limitations, this study lays the groundwork for future research endeavors exploring the intricate dynamics between techno-competence and language learning outcomes across diverse contexts.
Shallow and deep learning classifiers in medical image analysis
Authors: Prinzi Francesco , Currieri Tiziana , Gaglio Salvatore , Vitabile Salvatore 
Published: March 2024

AbstractAn increasingly strong connection between artificial intelligence and medicine has enabled the development of predictive models capable of supporting physicians’ decision-making. Artificial intelligence encompasses much more than machine learning, which nevertheless is its most cited and used sub-branch in the last decade. Since most clinical problems can be modeled through machine learning classifiers, it is essential to discuss their main elements. This review aims to give primary educational insights on the most accessible and widely employed classifiers in radiology field, distinguishing between “shallow” learning (i.e., traditional machine learning) algorithms, including support vector machines, random forest and XGBoost, and “deep” learning architectures including convolutional neural networks and vision transformers. In addition, the paper outlines the key steps for classifiers training and highlights the differences between the most common algorithms and architectures. Although the choice of an algorithm depends on the task and dataset dealing with, general guidelines for classifier selection are proposed in relation to task analysis, dataset size, explainability requirements, and available computing resources. Considering the enormous interest in these innovative models and architectures, the problem of machine learning algorithms interpretability is finally discussed, providing a future perspective on trustworthy artificial intelligence.Relevance statement The growing synergy between artificial intelligence and medicine fosters predictive models aiding physicians. Machine learning classifiers, from shallow learning to deep learning, are offering crucial insights for the development of clinical decision support systems in healthcare. Explainability is a key feature of models that leads systems toward integration into clinical practice.Key points• Training a shallow classifier requires extracting disease-related features from region of interests (e.g., radiomics).• Deep classifiers implement automatic feature extraction and classification.• The classifier selection is based on data and computational resources availability, task, and explanation needs.
Graphical Abstract
Methotrexate treatment strategies for rheumatoid arthritis: a scoping review on doses and administration routes
Authors: Rubio-Romero Esteban , Díaz-Torné César , Moreno-Martínez María José , De-Luz Julen 
Published: March 2024

Abstract
Background
To describe the evidence of methotrexate (MTX) initiation strategies in patients with rheumatoid arthritis (RA) and, in the case of non-responders, analyse the efficacy and safety of route and dose optimisation.

Methods
We conducted a comprehensive scoping review of randomised controlled trials according to PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O’Malley. PubMed, EMBASE, and Cochrane were searched without language restriction, and hand searches of relevant articles were examined.

Results
We identified 1,367 potentially eligible studies, of which 12 were selected based on the titles and abstracts and then on the full-length articles. In naïve-MTX patients, a linear dose-response relationship for starting dose was found between 5 mg/m2/week (7.5–10 mg/week) and 10 mg/m2/week (15–22 mg/week), without toxicity correlation. A higher initial dose of MTX (25 mg vs. 15 mg) was more effective, resulting in fewer dose increases due to ineffectiveness and more dose reductions due to higher remission rates. There was also a trend towards increased gastrointestinal toxicity. Comparing different routes of administration of MTX, subcutaneous MTX showed a statistically higher ACR20 response (85%) in comparison with oral MTX (77%) (p < 0.05). The clinical efficacy and safety of accelerated and conventional start MTX regimens were comparable between 7.5 and 15 mg with a 2,5 mg dose increase every two weeks. In RA patients who have failed the initial treatment with MTX, the stepwise increase in MTX doses is associated with a higher ACR20 response and sustained remission rate than other strategies. In MTX non-responders, optimisation to SC MTX was associated with improvements in ACR20 and ACR50 rates with similar toxicity between groups. In the early RA patients subgroup, SC MTX showed higher ACR20 response rates than oral MTX, and intensive oral methods have a much higher sustained remission rate, shorter mean time to remission, and better clinical disease activity measures than conventional treatments.

Conclusions
Higher starting doses of MTX and initial subcutaneous MTX made better performance in improving the ACR20 response, although the clinical effectiveness and safety of other MTX start regimens are comparable. This scoping review provides evidence in support of optimising MTX treatment in terms of route and dose prior to concluding that MTX treatment in RA patients has failed.