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15 pages, 1856 KiB  
Article
Nomogram Predicting In-Hospital Mortality in Patients with Myocardial Infarction Treated with Primary Coronary Interventions Based on Logistic and Angiographic Predictors
by Lukasz Gawinski, Anna Milewska, Michal Marczak and Remigiusz Kozlowski
Biomedicines 2025, 13(3), 646; https://doi.org/10.3390/biomedicines13030646 - 6 Mar 2025
Viewed by 130
Abstract
Background: Systems developed in recent years to assess the risk of in-hospital death in patients with myocardial infarction (MI) are mainly based on angiographic, electrocardiographic, and laboratory variables. Risk systems based on contemporary angiographic data and logistic variables have not been reported. The [...] Read more.
Background: Systems developed in recent years to assess the risk of in-hospital death in patients with myocardial infarction (MI) are mainly based on angiographic, electrocardiographic, and laboratory variables. Risk systems based on contemporary angiographic data and logistic variables have not been reported. The aim of this study was to develop and validate a system to assess the risk of in-hospital death in patients across the entire clinical spectrum of MI treated with primary coronary intervention (PCI) based on modern angiographic and logistic predictors. Methods: A subgroup of patients from the observational single-centre registry of MI treated with PCIs (from 1 February 2019 until 31 January 2020) was used to develop a multivariate logistic regression model predicting in-hospital mortality. The population (603 patients) was divided, with 60% of the sample used for model derivation and the remaining 40% used for internal model validation. Results: The main findings were as follows: (1) coronary angiography results and suboptimal flow after PCI were important predictors of in-hospital mortality; (2) the time of PCI as well as the mode of presentation of patients with MI contributed to in-hospital mortality; and (3) the discrimination (C statistic = 0.848, 95% CI: [0.765, 0.857]) and calibration (χ2 = 2.78, pHL = 0.94) were good in the derivation set, while the discrimination (C statistic = 0.6438, 95% CI: [0.580, 0.703]) in the validation set was satisfactory. Conclusions: A novel clinical nomogram based on four available logistic and angiographic variables was developed and validated for in-hospital mortality after PCIs in a wide range of MIs. Full article
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<p>Patient flow diagram. The study population was from the single-centre ACS GRU registry (included a total of 663 patients). The final study group consisted of patients with MI who were treated with PCIs and had complete clinical data (<span class="html-italic">N</span> = 516). CABG—coronary artery bypass grafting, MI—myocardial infarction, MINOCA—myocardial infarction with non-obstructive coronary arteries, and PCI—primary coronary intervention.</p>
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<p>Discrimination of the in-hospital mortality score in: (<b>a</b>) derivation set; (<b>b</b>) validation set. ROC curve of the nomogram in the derivation set (<b>a</b>) and validation set (<b>b</b>). ROC = receiver operating characteristic.</p>
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<p>Calibration curves for the in-hospital mortality score in the derivation set. The Hosmer–Lemeshow test (χ<sup>2</sup> = 2.78, pHL= 0.94) was used for predictive accuracy of the model. Graphically, this test is presented using a calibration curve. Blue circle—observed, red line—predicted.</p>
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<p>The decision curve analysis of the nomogram model. The benefits observed in the treatment group were more significant than those seen in the group without treatment when the predicted risk of death in patients MI was found to range from 0.01 to 0.81. The decision curve analysis shows that the nomogram can achieve a good net benefit. Red line—none, blue line—all, green line—nomogram.</p>
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17 pages, 11610 KiB  
Article
The Methylation and Expression of LINC00511, an Important Angiogenesis-Related lncRNA in Stomach Adenocarcinoma
by Zhiying Li, Yingli Chen, Yuanyuan Zhao and Qianzhong Li
Int. J. Mol. Sci. 2025, 26(5), 2132; https://doi.org/10.3390/ijms26052132 - 27 Feb 2025
Viewed by 112
Abstract
Stomach adenocarcinoma (STAD) has high incidence and mortality rates. Long non-coding RNAs (lncRNAs) and angiogenesis are closely related to the pathogenesis and metastasis of STAD. Recently, emerging evidence demonstrated that DNA methylation plays crucial roles in the development of STAD. This study explored [...] Read more.
Stomach adenocarcinoma (STAD) has high incidence and mortality rates. Long non-coding RNAs (lncRNAs) and angiogenesis are closely related to the pathogenesis and metastasis of STAD. Recently, emerging evidence demonstrated that DNA methylation plays crucial roles in the development of STAD. This study explored the relationship between DNA methylation and the abnormal expression of angiogenesis-related lncRNAs (ARlncRNAs) in stomach adenocarcinoma, aiming to identify prognostic biomarkers. Moreover, a Cox analysis and Lasso regression were used to establish an ARlncRNA feature set related to angiogenesis. The prognostic model was evaluated by using a Kaplan–Meier (KM) analysis, ROC curves, and nomograms. Based on the identified 18 key ARlncRNAs, a prognostic predictive model was constructed. In addition, a specific ARlncRNA with abnormal methylation in the model, LINC00511, showed significant differences in expression and methylation across different subgroups. The methylation and expression of LINC00511 were analyzed by a correlation and co-expression analysis. The correlation analysis indicated that promoter methylation may improve LINC00511 expression. Further analysis found 355 mRNAs co-expressed with LINC00511 which may interact with 6 miRNAs to regulate target gene expression. The abnormal methylation of LINC00511 could significantly contribute to the progression of stomach adenocarcinoma. Full article
(This article belongs to the Section Molecular Oncology)
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<p>Flowchart of the work.</p>
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<p>Identification of ARlncRNAs in patients with STAD. (<b>A</b>) The volcano plot of 2108 differentially expressed ARlncRNAs; (<b>B</b>) the expression profiles of differentially expressed ARlncRNAs in tumor and normal; (<b>C</b>) the trajectory of the coefficient of the independent variable; and (<b>D</b>) Lasso coefficient spectrum.</p>
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<p>Prognostic characteristics of 18 ARlncRNAs in the TCGA. (<b>A</b>–<b>C</b>) Survival curves for STAD patients categorized into high-risk and low-risk groups across the training group, validation group, and overall dataset; (<b>D</b>–<b>F</b>) risk scores, survival status, and risk heatmaps of three groups of STAD patients; and (<b>G</b>–<b>I</b>) ROC curves of three groups of STAD patients.</p>
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<p>Independent prognostic value of <math display="inline"><semantics> <mrow> <msub> <mrow> <mi>R</mi> </mrow> <mrow> <mi>s</mi> </mrow> </msub> </mrow> </semantics></math>. (<b>A</b>) Results of the univariate Cox independent prognostic analysis; (<b>B</b>) results of the multivariate independent prognostic analysis; (<b>C</b>) timeROC curve; (<b>D</b>) a nomogram designed to predict overall survival (OS) in patients with STAD; and (<b>E</b>) C-index curves for predicting 1-, 2-, and 3-year survival rates (** <math display="inline"><semantics> <mrow> <mi>p</mi> <mo>&lt;</mo> <mn>0.01</mn> <mo>,</mo> <mo> </mo> </mrow> </semantics></math>*** <math display="inline"><semantics> <mrow> <mi>p</mi> <mo>&lt;</mo> <mn>0.001</mn> </mrow> </semantics></math>).</p>
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<p>Kaplan–Meier survival curve: OS curve by high and low expression of LINC00511. (<b>A</b>) TCGA-STAD Kaplan–Meier survival curve; (<b>B</b>) GSE57303 Kaplan–Meier survival curve.</p>
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<p>DNA methylation and Spearman correlation analysis. (<b>A</b>) Ranking of methylation levels at 11 CpG sites from high to low; (<b>B</b>) the relationship between the expression levels of LINC00511 and the methylation levels of CpG sites.</p>
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<p>Distribution of LINC00511 expression in clinical characteristics of stomach adenocarcinoma patients. (<b>A</b>) Grade; (<b>B</b>) tumor T-stage; (<b>C</b>) methylation; and (<b>D</b>) patient’ s gender.</p>
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<p>Relationship between LINC00511 and methylation sites in clinical characteristics of stomach adenocarcinoma patients. (<b>A</b>) Grade; (<b>B</b>) tumor T-stage; and (<b>C</b>) tumor Stage.</p>
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<p>Target gene analysis of LINC00511. (<b>A</b>) The relationship of LINC00511 and mRNA; (<b>B</b>) the relationship of LINC00511 and miRNA; (<b>C</b>) GO enrichment analysis of 355 mRNAs; and (<b>D</b>) KEGG pathway of 355 mRNAs.</p>
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17 pages, 2164 KiB  
Article
Development of Clinical-Radiomics Nomogram for Predicting Post-Surgery Functional Improvement in High-Grade Glioma Patients
by Tamara Ius, Maurizio Polano, Michele Dal Bo, Daniele Bagatto, Valeria Bertani, Davide Gentilini, Giuseppe Lombardi, Serena D’agostini, Miran Skrap and Giuseppe Toffoli
Cancers 2025, 17(5), 758; https://doi.org/10.3390/cancers17050758 - 23 Feb 2025
Viewed by 310
Abstract
Introduction: Glioma Grade 4 (GG4) tumors, which include both IDH-mutated and IDH wild-type astrocytomas, are the most prevalent and aggressive form of primary brain tumor. Radiomics is gaining ground in neuro-oncology. The integration of this data into machine learning models has the potential [...] Read more.
Introduction: Glioma Grade 4 (GG4) tumors, which include both IDH-mutated and IDH wild-type astrocytomas, are the most prevalent and aggressive form of primary brain tumor. Radiomics is gaining ground in neuro-oncology. The integration of this data into machine learning models has the potential to improve the accuracy of prognostic models for GG4 patients. Karnofsky Performance Status (KPS), an established preoperative prognostic factor for survival, is commonly used in these patients. In this study, we developed a nomogram to identify patients with improved functional performance as indicated by an increase in KPS after surgery by analyzing radiomic features from preoperative 3D MRI scans. Methods: Quantitative imaging features were extracted from the -3D T1 GRE sequence of 157 patients from a single center and were used to develop the machine learning (ML) model. To improve applicability and create a nomogram, multivariable logistic regression analysis was performed to build a model incorporating clinical characteristics and radiomics features. Results: We labeled 55 cases in which KPS was improved after surgery (35%, KPS-flag = 1). The resulting model was evaluated according to test series results. The best model was obtained by XGBoost using the features extracted by pyradiomics, with a Matthew coefficient score (MCC) of 0.339 (95% CI: 0.330–0.3483) in cross-validation. The out-of-sample evaluation on the test set yielded an MCC of 0.302. A nomogram evaluating the improvement of KPS post-surgery was built based on statistically significant variables from multivariate logistic regression including clinical and radiomics data (c-index = 0.760, test set). Conclusions: MRI radiomic analysis represents a powerful tool to predict postoperative functional outcomes, as evaluated by KPS. Full article
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<p>A Sankey diagram to visualize the flow and relationships between categorical variables created based on the relationship among localization, EOR, and flag to predict KPS improvement. The width of the flow represents the proportion of patients moving from one category to another. Of note, GG4 cases labeled with a KPS-flag = 1 showed an improvement of performance status by a heterogeneity of localization, side, and different rates of EOR. For these reasons, we evaluate the informative effect of radiomics data to classify that condition (<a href="#cancers-17-00758-f001" class="html-fig">Figure 1</a>).</p>
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<p>A unsupervised clustering heatmap of the radiomic features extracted from 157 GG4 cases using PyRadiomics. Each row represents a radiomic feature, while each column corresponds to a patient case. The features are standardized using z-score normalization, and hierarchical clustering was performed using Euclidean distance and Ward’s linkage method. The top annotation bar includes key clinical and molecular features such as FLAG status, IDH mutation status, MGMT methylation status, tumor laterality, location, and additional clinical data. This visualization highlights potential patterns and subgroup structures within the radiological landscape of the GG4 cases.</p>
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<p>The top 20 feature variables and their importance in the FLAG-KPS model. The figure illustrates the top 20 most influential features identified by the FLAG-KPS model, ranked by their importance scores. The importance was determined using the average SHAP (Shapley Additive Explanations) values over 1000 bootstrap model iterations. Higher SHAP values indicate greater influence on model predictions and provide insight into the key factors driving the model’s decision-making process.</p>
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<p>A comparison of the top 20 radiomic features selected by the XGBoost model with the Wilcoxon signed-rank test between the GG4 patient cohort and the IDH wild-type (IDHwt) patient subgroup classified according to the 2021 WHO guidelines. The Wilcoxon signed-rank test is used to detect statistically significant differences in the distribution of radiomic features between these groups identified by the xgboost model. The results are presented in a log10-transformed <span class="html-italic">p</span>-value plot highlighting the most important features based on their statistical significance. This analysis sheds light on the radiomic features that differentiate the GG4 cases from the IDHwt subgroup and can thus contribute to classification and prognostic assessment.</p>
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<p>Receiver Operating Characteristic (ROC) curve of the clinical-radiomics nomogram model. The ROC curve illustrates the model’s ability to distinguish between outcome classes by plotting the true positive rate (sensitivity) against the false positive rate (1—specificity) across different probability thresholds. The area under the curve (AUC) was 0.823 (95% CI: 66.1–96.41%), computed using 100 stratified bootstrap iterations. A higher AUC indicates stronger discriminative performance, highlighting the model’s effectiveness in clinical decision-making and predictive accuracy.</p>
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<p>A clinical-radiomics nomogram. The clinical-radiomics nomogram developed for the GG4 cohort by integrating a multivariate logistic regression model constructed using the rms package. This nomogram combines both clinical and radiomic features to provide a quantitative tool for individual risk assessment and outcome prediction. By assigning a weighted contribution to each predictor, the model facilitates the intuitive interpretation of complex relationships among the variables. The use of the rms package ensures robust model calibration, validation, and visualization and increases the reliability and clinical applicability of the nomogram.</p>
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11 pages, 2431 KiB  
Article
A Simple Nomogram to Predict Clinically Significant Prostate Cancer at MRI-Guided Biopsy in Patients with Mild PSA Elevation and Normal DRE
by Hubert Kamecki, Andrzej Tokarczyk, Małgorzata Dębowska, Urszula Białończyk, Wojciech Malewski, Przemysław Szostek, Omar Tayara, Stefan Gonczar, Sławomir Poletajew, Łukasz Nyk, Piotr Kryst and Stanisław Szempliński
Cancers 2025, 17(5), 753; https://doi.org/10.3390/cancers17050753 - 23 Feb 2025
Viewed by 316
Abstract
Background: Evidence to help avoid unnecessary prostate biopsies is being actively pursued. Our goal was to develop and internally validate a nomogram for predicting clinically significant prostate cancer (csPC) in men with low suspicion of disease (prostate specific antigen [PSA] < 10 ng/mL, [...] Read more.
Background: Evidence to help avoid unnecessary prostate biopsies is being actively pursued. Our goal was to develop and internally validate a nomogram for predicting clinically significant prostate cancer (csPC) in men with low suspicion of disease (prostate specific antigen [PSA] < 10 ng/mL, normal digital rectal examination [DRE]), in whom magnetic resonance imaging (MRI) findings are positive. Methods: Patients with no prior prostate cancer diagnosis who underwent MRI–ultrasound fusion biopsy of the prostate were retrospectively analyzed. Inclusion criteria were PSA < 10 ng/mL, normal DRE, Prostate Imaging Reporting And Data System (PIRADS) category ≥ 3, and no extraprostatic extension or seminal vesicle invasion reported on MRI. Associations between csPC diagnosis and patient or lesion characteristics were analyzed, and a multivariable model was developed. Internal validation of the model with 5-fold cross-validation and bootstrapping methods was performed. Results: Among 209 patients, 67 were diagnosed with csPC. Factors incorporated into the model for predicting csPC were age, 5-alpha reductase inhibitor use, PSA, prostate volume, PIRADS > 3, and lesion location in the peripheral zone. The model’s ROC AUC was 0.86, with consistent performance at internal validation (0.84 with cross-validation, 0.82 with bootstrapping). With an empirical threshold of <10% csPC probability to omit biopsy, 72 (50.7%) unnecessary biopsies would have been avoided, at the cost of missing 2 (3.0%) csPC cases. Conclusions: Our nomogram might serve as a valuable tool in refining selection criteria in men considered for prostate biopsy. The major limitation of the study is its retrospective character. Prospective, external validation of the model is warranted. Full article
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<p>Flowchart depicting the process of patient inclusion.</p>
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<p>The nomogram based on the predictive model of clinically significant prostate cancer probability.</p>
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<p>Receiver-operating curves for the model fitted on the whole training set (<b>left image</b>) and for the models fitted during the validation process (<b>right image</b>).</p>
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<p>Calibration curves for the model fitted on the whole training set (<b>left image</b>) and for the models fitted during the validation process (<b>right image</b>).</p>
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<p>Decision curves for the model fitted on the whole training set (<b>left image</b>) and for the models fitted during the validation process (<b>right image</b>), compared with curves for individual risk factors.</p>
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26 pages, 13288 KiB  
Article
MGST1 Protects Pancreatic Ductal Cells from Inflammatory Damage in Acute Pancreatitis by Inhibiting Ferroptosis: Bioinformatics Analysis with Experimental Validation
by Ruoyi Zhang, Xin Ling, Xianwen Guo and Zhen Ding
Int. J. Mol. Sci. 2025, 26(5), 1899; https://doi.org/10.3390/ijms26051899 - 22 Feb 2025
Viewed by 217
Abstract
Numerous animal experiments have implicated ferroptosis in the pathogenesis of acute pancreatitis (AP). Nonetheless, due to sampling constraints, the precise role of ferroptosis in the human body during AP remains elusive. Method: Peripheral blood sequencing data of patients with acute pancreatitis (GSE194331) were [...] Read more.
Numerous animal experiments have implicated ferroptosis in the pathogenesis of acute pancreatitis (AP). Nonetheless, due to sampling constraints, the precise role of ferroptosis in the human body during AP remains elusive. Method: Peripheral blood sequencing data of patients with acute pancreatitis (GSE194331) were obtained from the Gene Expression Omnibus (GEO) database. We analyzed differentially expressed genes whose expression increased or decreased with increasing disease severity and intersected them with the ferroptosis gene set to identify ferroptosis-related driver genes for the disease. The hub genes were selected using machine learning algorithms, and a nomogram diagnosis model was constructed. Clinical samples, animal models, and an in vitro experiment were also used for validation. The investigation unveiled 22 ferroptosis-related driver genes, and we identified three hub genes, AQP3, TRIB2, and MGST1, by employing two machine learning algorithms. AQP3 and TRIB2 exhibit robust correlations with various immune cells. The disease diagnosis model constructed utilizing these three genes demonstrated high sensitivity and specificity (AUC = 0.889). In the in vitro experiments, we discovered for the first time that ferroptosis occurs in pancreatic duct cells during acute pancreatitis, and that MGST1 is significantly upregulated in duct cells, where it plays a crucial role in negatively regulating ferroptosis via the ACSL4/GPX4 axis. In addition, overexpression of MGST1 protects ductal cells from inflammatory damage. In our investigation, we explored the mechanisms of ferroptosis in immune cells and pancreatic duct cells in patients with AP. These results highlight a potential pathway for the early diagnosis and treatment of acute pancreatitis. Full article
(This article belongs to the Section Molecular Immunology)
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<p>The flow chart of this study.</p>
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<p>Identification of DEGs and Ferroptosis-Related Driving Genes in Acute Pancreatitis. (<b>A</b>) PCA plot showing the distribution of samples from four groups, including healthy controls, mild AP, moderately severe AP, and severe AP. The first principal component (PC1) accounts for 11.38% of the variance, while the second principal component (PC2) explains 5.7%. (<b>B</b>) PCA plot showing the distribution of samples from three groups, including healthy controls, mild to moderately severe AP, and severe AP. The first principal component (PC1) accounts for 11.38% of the variance, while the second principal component (PC2) explains 5.7%. (<b>C</b>) The heatmap of the top 50 most differentially expressed genes, including the 25 most upregulated and 25 most downregulated genes, along with the volcano plot depicting all differentially expressed genes between the healthy control and mild to moderately severe AP groups. (<b>D</b>) The heatmap of the top 50 most differentially expressed genes, including the 25 most upregulated and 25 most downregulated genes, along with the volcano plot depicting all differentially expressed genes between the mild to moderately severe AP and severe AP groups. (<b>E</b>) The Venn diagram illustrates that by intersecting 410 DEGs that were upregulated with increasing disease severity and the ferroptosis gene set, 20 ferroptosis-related genes were identified. (<b>F</b>) The Venn diagram illustrates that by intersecting 159 DEGs that were downregulated with increasing disease severity and the ferroptosis gene set, 2 ferroptosis-related genes were identified.</p>
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<p>Enrichment Analysis of Ferroptosis-Related Driving Genes and Correlation Analysis. (<b>A</b>) KEGG pathway analysis of 22 ferroptosis-related driver genes. (<b>B</b>–<b>D</b>) GO enrichment analysis identified the top 10 significantly enriched pathways in BP, CC, and MF for the 22 ferroptosis-related driver genes. For all enriched GO and KEGG terms, <span class="html-italic">p</span> &lt; 0.05. (<b>E</b>) The correlation heatmap of the 22 ferroptosis driver genes, * <span class="html-italic">p</span> &lt; 0.05. (<b>F</b>) Heatmap of the expression levels of the 22 ferroptosis driver genes across the healthy control group, the mild to moderately severe AP group, and the severe AP group.</p>
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<p>Identification of Hub Genes Using Machine Learning Methods and Construction of a Diagnostic Model. (<b>A</b>) The LASSO regression cross-validation curve illustrates the selection of optimal λ values using 10-fold cross-validation. (<b>B</b>) The SVM analysis demonstrated effective classification of samples based on ferroptosis-related gene expression profiles. (<b>C</b>) The Venn diagram shows the intersection of genes selected by Lasso and SVM algorithms, identifying three hub genes: <span class="html-italic">AQP3</span>, <span class="html-italic">TRIB2,</span> and <span class="html-italic">MGST1</span>. (<b>D</b>–<b>F</b>) The expression levels of <span class="html-italic">AQP3</span>, <span class="html-italic">TRIB2</span>, and <span class="html-italic">MGST1</span> across different groups, including healthy controls, mild to moderately severe AP, and severe AP. ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001. (<b>G</b>–<b>I</b>) The GSEA of the three hub genes revealed the top 10 significantly enriched pathways. (<b>J</b>) The ROC curve analysis of three hub genes. (<b>K</b>) The nomogram integrating the hub genes. (<b>L</b>,<b>M</b>) The calibration curve illustrates the connection between predicted and observed probabilities. The ideal dashed line represents perfect prediction accuracy. The visible dashed line corresponds to the whole dataset, and the bias-corrected solid line, derived through bootstrapping, reflects the actual performance of the nomogram.</p>
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<p>Association between Hub Genes and Immune Cell Infiltration. (<b>A</b>) The proportion distribution of 22 immune cell subtypes between the AP patients and the healthy control group. (<b>B</b>) The alterations in 16 types of immune cells across varying disease severities were assessed using the CIBERSORT algorithm. ns: not significant, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001. (<b>C</b>–<b>E</b>) Lollipop plots were used to visualize the correlation between the three hub genes and various immune cell types. (<b>F</b>) The correlation heatmap displaying the relationships between the three hub genes and various immune cells, * <span class="html-italic">p</span> &lt; 0.05. (<b>G</b>) The correlation coefficients and corresponding <span class="html-italic">p</span>-values between the three hub genes (<span class="html-italic">AQP3</span>, <span class="html-italic">TRIB2</span>, and <span class="html-italic">MGST1</span>) and various immune cells.</p>
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<p>Potential Roles of the Three hub Genes in Pancreatic Tissue Inferred Through Single-Cell Analysis. (<b>A</b>) Network analysis was used to gather interactions between miRNAs, lincRNAs, TFs, and the three hub genes. The purple icons represent transcription factors, the blue icons represent lncRNAs, the green icons represent miRNAs, and the red icons represent the three hub genes. (<b>B</b>) The Drug Gene Interaction Database was used to identify drugs with strong interaction scores associated with <span class="html-italic">AQP3</span>, <span class="html-italic">TRIB2</span>, and <span class="html-italic">MGST1</span>. (<b>C</b>) After t-SNE processing of single-cell data from the Control and AP mouse groups, the distribution of the three hub genes across 12 different cell types within the tissue is illustrated. (<b>D</b>–<b>F</b>) The bubble plot illustrates the expression enrichment of the three hub genes across different cell types in mouse pancreatic tissue.</p>
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<p>Validation of Hub Genes through Clinical Samples and Animal Models. (<b>A</b>) Clinical baseline data of 12 healthy controls, 24 mild to moderate AP patients, and 16 severe AP patients who were included in this study. (<b>B</b>–<b>D</b>) RT-qPCR results of the three hub genes in PBMCs from the patients included in this study. (<b>E</b>) HE staining of mouse pancreatic tissue within NC and AP groups. (<b>F</b>–<b>H</b>) The differential expression of hub genes in mouse pancreatic tissues between NC and AP groups was analyzed using RT-qPCR. (<b>I</b>) WB results show the changes in MGST1 expression in pancreatic tissue from NC and AP mice. (<b>J</b>,<b>K</b>) Immunofluorescence and immunohistochemistry results display the expression changes of MGST1 in pancreatic tissue from NC and AP mice. N = 4, means ± SD, * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>MGST1 is Upregulated during Ferroptosis in Human Pancreatic Duct Cells. (<b>A</b>) MGST1 was upregulated in response to RSL3 (10 µM; 24 h) along with activation of the ferroptosis pathway in CFPAC-1 cells. (<b>B</b>) The effects were reversed following a 24 h pretreatment with ferroptosis inhibitors (10 µM liproxstatin-1). (<b>C</b>) MGST1 protein levels were significantly elevated in H6C7 cells in response to TCS stimulation (400 µM; 24 h), along with activation of the ferroptosis pathway. (<b>D</b>) MGST1 levels also significantly increased in H6C7 cells stimulated by RSL3 (10 µM; 24 h). (<b>E</b>) ELISA results show a significant increase in MGST1 protein expression in the cell supernatant from the TCS group compared to the NC group. (<b>F</b>) The effects were reversed following 24 h pretreatment with ferroptosis inhibitors (1 µM liproxstatin-1). (<b>G</b>) After a 24 h pretreatment with a ferroptosis inhibitor (1 µM liproxstatin-1), cell viability in the TCS group significantly improved. (<b>H</b>–<b>J</b>) After 24 h pretreatment with a ferroptosis inhibitor, the expression levels of IL-6, IL-1β, IL-8, and IL-18 were significantly reduced. N = 3, means ± SD, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>MGST1 Negatively Regulates Ferroptosis and Protects Human pancreatic Ductal Cells from Inflammatory Damage. (<b>A</b>) WB analysis showed that MGST1 protein levels in H6C7 cells were significantly decreased following transfection with siRNA. (<b>B</b>) ACSL4 expression was upregulated while GPX4 expression was downregulated in the disease group following MGST1 knockdown using siRNA; (<b>C</b>–<b>E</b>) Protein quantitative analysis of MGST1, ACSL4, and GPX4; (<b>F</b>,<b>G</b>) Cell viability and GSH/GSSG levels significantly decreased after MGST1 knockdown; (<b>H</b>–<b>K</b>) The mRNA levels of various inflammatory factors, including <span class="html-italic">IL-6</span>, <span class="html-italic">IL-1β</span>, <span class="html-italic">IL-8</span>, and <span class="html-italic">IL-18</span>, were significantly increased in the disease group following MGST1 knockdown; (<b>L</b>,<b>M</b>) ROS fluorescence intensity increased markedly after MGST1 knockdown. N = 3, means ± SD, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>MGST1 Overexpression Alleviates Ferroptosis and Inflammatory Damage in Ductal Cells. (<b>A</b>,<b>B</b>) The protein level of MGST1 was significantly increased after transfection with the overexpressed plasmid. (<b>C</b>) MGST1 overexpression via plasmid transfection led to downregulation of ACSL4 expression and upregulation of GPX4 expression in the disease group. (<b>D</b>,<b>E</b>) Protein quantitative analysis of MGST1, ACSL4, and GPX4. (<b>F</b>,<b>G</b>) Cell viability and GSH/GSSG levels significantly increased after MGST1 overexpression. (<b>H</b>–<b>K</b>) The mRNA levels of various inflammatory factors, including <span class="html-italic">IL-6</span>, <span class="html-italic">IL-1β</span>, <span class="html-italic">IL-8</span>, and <span class="html-italic">IL-18</span>, were significantly decreased in the disease group following MGST1 overexpression. N = 3, means ± SD, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p>
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36 pages, 18292 KiB  
Article
Identification of Prognostic Genes Related to Cell Senescence and Lipid Metabolism in Glioblastoma Based on Transcriptome and Single-Cell RNA-Seq Data
by Qiong Li and Hongde Liu
Int. J. Mol. Sci. 2025, 26(5), 1875; https://doi.org/10.3390/ijms26051875 - 21 Feb 2025
Viewed by 308
Abstract
Glioblastoma (GBM) is the most aggressive primary brain cancer, with poor prognosis due to its aggressive behavior and high heterogeneity. This study aimed to identify cellular senescence (CS) and lipid metabolism (LM)-related prognostic genes to improve GBM prognosis and treatment. Transcriptome and scRNA-seq [...] Read more.
Glioblastoma (GBM) is the most aggressive primary brain cancer, with poor prognosis due to its aggressive behavior and high heterogeneity. This study aimed to identify cellular senescence (CS) and lipid metabolism (LM)-related prognostic genes to improve GBM prognosis and treatment. Transcriptome and scRNA-seq data, CS-associated genes (CSAGs), and LM-related genes (LMRGs) were acquired from public databases. Prognostic genes were identified by intersecting CSAGs, LMRGs, and differentially expressed genes (DEGs), followed by WGCNA and univariate Cox regression. A risk model and nomogram were constructed. Analyses covered clinicopathological features, immune microenvironment, somatic mutations, and drug sensitivity. GBM scRNA-seq data identified key cells and prognostic gene expression. SOCS1 and PHB2 were identified as prognostic markers, contributing to the construction of a robust risk model with excellent predictive ability. High-risk group (HRG) patients had poorer survival, higher immune and stromal scores, and distinct somatic mutation profiles. Drug sensitivity analysis revealed significant differences in IC50 values. In microglia differentiation, SOCS1 and PHB2 showed dynamic expression patterns. These findings provide new strategies for GBM prognosis and treatment. Full article
(This article belongs to the Special Issue Glioblastoma: From Molecular Mechanisms to Therapies)
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<p>Identification of WGCNA-related genes and key modules in glioblastoma. (<b>a</b>) Sample-level clustering. Each branch in the clustering tree represents a sample, and the vertical coordinate represents the sample expression Euclidean distance. (<b>b</b>) Soft threshold screening. (<b>c</b>) Co-expression module identification. (<b>d</b>) Heatmap of correlations between key modules and non-tumor control samples, GBM samples. (<b>e</b>) The scatter plot between Gene Significance (GS) and Module Membership (MM). Meanwhile, |MM| &gt; 0.6 and |GS| &gt; 0.2 were used as thresholds to further screen the genes in the significant modules, in which 1816 genes were obtained from the turquoise color module, 554 genes from the yellow module, and 2098 genes from the blue module. Combined, 4468 genes were obtained.</p>
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<p>Functional enrichment and PPI network analysis of 15 candidate genes. (<b>a</b>) Differential gene volcano plots. The labeled genes in the figure are the top 10 upregulated genes and the top 10 downregulated genes with the largest log2 (Fold Change). (<b>b</b>) Heatmap of ring expression density of differential genes. Grouping bars at the end of the ring heatmap, light yellow indicates normal samples, and light green indicates GBM samples; in the heatmap, the redder the color, the higher the expression. (<b>c</b>) Upset plot of candidate selections. Colors and markers are used to highlight overlapping relationships between methods. (<b>d</b>) GO and KEGG enrichment results (top10). (<b>e</b>,<b>f</b>) Network diagram of STRING analysis of candidate genes. The PPI network showed that after removing one isolated gene, there were 14 nodes and 30 edges in the network diagram. Among these genes, AKR1B1, SP1, ACLY, and CAV1 had relatively strong interactions with other genes.</p>
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<p>Identification of SOCS1 and PHB2 as prognostic genes and development of a risk prediction model. (<b>a</b>) Forest plot of one-factor Cox regression analysis. HR is abbreviated as risk ratio; when HR &gt; 1, the cue factor is a facilitator of the occurrence of a positive event; when HR &lt; 1, the cue factor is a deterrent to the occurrence of a positive event; and when HR = 1, the cue factor has no effect on the occurrence of a positive event. (<b>b</b>) Distribution of risk scores and survival status of primary tumor samples in TCGA-GBM sets. (<b>c</b>) KM curve analysis. The horizontal axis is the total survival time (days), and the vertical axis is the probability of survival; the high-risk group is shown in red, and the low-risk group is shown in blue. (<b>d</b>) ROC curve of training set. (<b>e</b>) Prognostic gene expression analysis.</p>
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<p>Validation of risk prediction model. (<b>a</b>) Distribution of risk scores and survival status of primary tumor samples in the validation set. (<b>b</b>) KM curve of high- and low-risk groups. (<b>c</b>) ROC curve of the validation set. (<b>d</b>) Prognostic gene expression analysis.</p>
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<p>Differences in clinicopathological features between the high-risk group (HRG) and low-risk group (LRG). (<b>a</b>) Heatmap of clinical features and molecular pathology characteristics of GBM samples. The top annotations of the samples include the following clinical features: risk group (red for the high-risk group, blue for the low-risk group), sex (orange for female, blue for male), age (light green for age 60 and below, dark blue for age 60 and above), IDH1 mutation status (light yellow for wild-type, red for mutant, and dark blue for unknown), and MGMT promoter methylation status (dark blue for methylated, orange for unmethylated, and yellow for unknown). (<b>b</b>–<b>e</b>) Distribution of risk status among subgroups of different clinicopathological features (age (<b>b</b>), gender (<b>c</b>), MGMT methylation (<b>d</b>), IDH1 status (<b>e</b>)) in the HRG and LRG (<span class="html-italic">p</span> &gt; 0.05). Different color codes in the figure denote low-risk (blue) and high-risk (red) samples, with the number and proportion of samples in each group and the significance <span class="html-italic">p</span>-value. (<b>f</b>) Correlation of Risk Scores with Clinical Characteristics. *** represented <span class="html-italic">p</span> &lt; 0.001, * represented <span class="html-italic">p</span> &lt; 0.05, and NS represented <span class="html-italic">p</span> &gt; 0.05.</p>
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<p>KM curve analysis. age (<b>a</b>), gender (<b>b</b>), MGMT methylation (<b>c</b>), IDH1 status (<b>d</b>). The horizontal axis is the overall survival time (days), and the vertical axis is the survival probability, with the high-risk group in red and the low-risk group in blue. The <span class="html-italic">p</span>-value was used to assess the statistically significant difference in survival time between the high- and low-risk groups.</p>
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<p>Prognostic analysis of the risk model in glioblastoma. (<b>a</b>) Results of one-way Cox analysis. (<b>b</b>) Results of multifactorial Cox analysis.</p>
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<p>Construction and validation of the nomogram. (<b>a</b>) Nomogram. The upper half of the column line graph allows for the calculation of scores for individual factors; the lower half allows for the speculation of the probability of survival for GBM patients based on the total score obtained. (<b>b</b>) Column line graphs 1-, 2-, and 3-year calibration curves. Horizontal coordinates are predicted event rates, and vertical coordinates are observed actual event rates, both ranging from 0 to 1. (<b>c</b>) ROC curve analysis. (<b>d</b>) DCA Curve. The diagonal line (All) represents all samples with all interventions; the horizontal line (None) represents all samples with no intervention.</p>
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<p>Functional prognostic genes and risk model in glioblastoma. (<b>a</b>) GSEA enrichment pathway (top5). (<b>b</b>) Results of GSVA in the high- and low-risk groups. t &gt; 0 represents pathways that were significantly upregulated in the high-risk group, and t &lt; 0 represents pathways that were significantly downregulated in the high-risk group.</p>
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<p>Immune infiltration analysis for high- and low-risk groups. (<b>a</b>) Immune cell abundance in samples from the high-risk and low-risk groups. The heat map colors reflect the level of immune infiltration, with higher levels of immune infiltration tending to be more red and lower levels tending to be bluer. (<b>b</b>) Differential infiltration of immune cells between the high- and low-risk groups, yellow represents the low-risk group, and red represents the high-risk group. (<b>c</b>) Differential immune infiltrating cell correlation heat map, red represents positive correlation, blue represents negative correlation, a darker color means higher correlation; * reflects the significance level, and the numbers in the boxes are correlation values. *** represented <span class="html-italic">p</span> &lt; 0.001, ** represented <span class="html-italic">p</span> &lt; 0.01, * represented <span class="html-italic">p</span> &lt; 0.05. (<b>d</b>) Heatmap of prognostic genes, risk scores, and differential immune cell correlations; the lower left corner shows the relationship between immune cells with differential infiltration, and the magnitude of the correlation is reflected in the size and color of the squares in the matrix. The upper right line color and thickness reflect the range of <span class="html-italic">p</span>-values and the range of correlations, respectively.</p>
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<p>Immune landscape in high and low-risk groups in glioblastoma. (<b>a</b>) Expression of immune checkpoints with differences between the high- and low-risk groups, with the high-risk group in red and the low-risk group in blue. Vertical coordinates are immune checkpoint gene expression levels. (<b>b</b>) Correlation Analysis Between Prognostic Genes, Risk Scores, and Differential Immune Checkpoints. The larger the positive correlation, the closer the color converges to red. The larger the negative correlation, the more the color converges to blue, and * reflects significance. **** represented <span class="html-italic">p</span> &lt; 0.0001, *** represented <span class="html-italic">p</span> &lt; 0.001, ** represented <span class="html-italic">p</span> &lt; 0.01, * represented <span class="html-italic">p</span> &lt; 0.05, and ns represented <span class="html-italic">p</span> &gt; 0.05. (<b>c</b>) ESTIMATE Analysis. The distribution of Stromal Score, Immune Score, and ESTIMATE Score in the samples of the high- and low-risk groups is presented in the figure. Statistical significance was assessed by the Wilcoxon rank sum test and is shown as a <span class="html-italic">p</span>-value in the figure. (<b>d</b>) TIDE Analysis. The distribution of TIDE scores and MIS scores in the samples of the high- and low-risk groups is presented in the figure. Statistical significance was assessed by the Wilcoxon rank sum test and is shown as a <span class="html-italic">p</span>-value in the figure.</p>
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<p>Analysis of tumor mutations in the high-risk and low-risk groups (<b>a</b>) Mutation analysis of the high-risk group: for each figure, the middle-left panel depicts the mutation pattern of the gene for each sample, the numbers on the right are the mutation frequency for each gene, the right bar is the proportion of each mutation type for the gene, and the upper bar is the total mutation load for each sample. (<b>b</b>) Mutation analysis of the low-risk group.</p>
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<p>Drug sensitivity analysis in the high and low-risk groups. Each letter (<b>a</b>–<b>e</b>) represents a different drug ((<b>a</b>) Vorinostat; (<b>b</b>) AZD6244; (<b>c</b>) AZD8055; (<b>d</b>) PF.02341066; (<b>e</b>) QS11.), and it shows the drug sensitivity analysis based on the IC<sub>50</sub> values and their correlation with risk scores. The left side highlights the linear relationship between risk scores and IC<sub>50</sub> values, while the right side compares the IC<sub>50</sub> values between the high-risk and low-risk groups, showing significant differences in drug sensitivity. *** represented <span class="html-italic">p</span> &lt; 0.001, ** represented <span class="html-italic">p</span> &lt; 0.01, * represented <span class="html-italic">p</span> &lt; 0.05.</p>
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<p>Molecular regulatory networks of prognostic genes. (<b>a</b>) Key miRNA-mRNA interaction network. (<b>b</b>) lncRNA-miRNA-mRNA interaction network; only key miRNA results that are predictive of lncRNAs are plotted.</p>
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<p>The cellular interactions and functions of microglia. (<b>a</b>) Selection plot of highly variable genes. The top 10 highly variable genes are labeled in the graph to highlight their importance in the cell population. (<b>b</b>) Confirmed optimal number of clusters. The following figure demonstrates the percentage of cumulative variance for the first 50 principal components. (<b>c</b>,<b>d</b>) UMAP cell distribution and source classification. (<b>e</b>) Cell annotation results. (<b>f</b>) Heatmap of GSVA. The heatmap shows the top 10 most differentiated biological pathways identified by GSVA in different cell types.</p>
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<p>Identification of key cell clusters. (<b>a</b>) Plot of cell type proportions. Different colored bars indicate different cell types. (<b>b</b>) Violin plots of differences in prognostic gene expression. *** represented <span class="html-italic">p</span> &lt; 0.001, * represented <span class="html-italic">p</span> &lt; 0.05, and ns represented <span class="html-italic">p</span> &gt; 0.05.</p>
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<p>Pseudo-temporal dynamics and communication networks of microglia. (<b>a</b>) Simulation analysis of trajectory differentiation. The distribution of cells in pseudo time is indicated by different colors, demonstrating the dynamic changes in cell state. The darker the blue color, the earlier the cells have differentiated. Cells differentiate over time from left to right, with the lightest blue color representing the most recently differentiated cell. (<b>b</b>) State Trajectory Analysis. Cell trajectories in different states are identified using colors to identify the different states. (<b>c</b>) Population cell type trajectory analysis. The movement trajectories of two groups of cells (normal, tumor) in the pseudo-time dimension are shown. (<b>d</b>) Heat map of ligand-receptor pair interactions between key cells. The vertical axis is the cell that sends the signal, the horizontal axis is the cell that receives the signal, and the color depth of the heatmap represents the signal strength. The bars on the top and right are the accumulation of the number of vertical and horizontal axes.</p>
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12 pages, 4079 KiB  
Article
Development of a Clinical and Laboratory-Based Predictive Nomogram Model for Unfavorable Functional Outcomes Among Patients Who Undergo Interventions for Aneurysmal Subarachnoid Hemorrhage
by Zhongxiao Wang, Ting Liu, Yue An, An Xu, Kangxu An, Ying Zhang, Jian Liu, Kun Wang, Wenqiang Li, Guangshuo Li, Xingquan Zhao, Weixin Si, Yisen Zhang and Xinjian Yang
J. Clin. Med. 2025, 14(5), 1443; https://doi.org/10.3390/jcm14051443 - 21 Feb 2025
Viewed by 173
Abstract
Objective: This study elucidates the prognostic significance of perioperative changes in laboratory indicators for aneurysmal SAH and develops a nomogram model for outcome prediction. Methods: Aneurysmal SAH patients who received clipping or coiling at our institution between January 2016 and December 2022 were [...] Read more.
Objective: This study elucidates the prognostic significance of perioperative changes in laboratory indicators for aneurysmal SAH and develops a nomogram model for outcome prediction. Methods: Aneurysmal SAH patients who received clipping or coiling at our institution between January 2016 and December 2022 were included. All patients were randomly assigned to derivation and validation cohorts. Independent predictors of unfavorable outcomes were identified by multivariate analyses. Three models were conducted to evaluate whether perioperative laboratory changes improve prediction performance. A nomogram including all independent predictors was developed in the derivation cohort and verified in both cohorts. Results: Diabetes mellitus [OR (95% CI) = 2.84 (1.44–5.59)], WFNS grade 3–5 [OR: (95% CI), 9.17 (5.49–15.33)], clipping [OR (95% CI) = 1.71 (1.03–2.85)], perioperative changes in white blood cell count [OR (95% CI) = 2.15 (1.17–3.96)], and concentrations of ALT [OR (95% CI) = 1.41 (1.04–1.91)], sodium [OR (95% CI) = 5.40 (3.01–9.71)], and glucose [OR (95% CI) = 2.18 (1.05–4.53)] were independent predictors of an unfavorable outcome. The predictive nomogram incorporated the aforementioned predictors and performed well in the derivation cohort (AUC, 0.839; 95% CI: 0.810–0.866) and the validation cohort (AUC, 0.797; 95% CI: 0.734–0.850). Conclusions: Perioperative changes in laboratory indicators can be predictors of unfavorable outcomes in aneurysmal SAH patients. The nomogram based on clinical and laboratory risk factors can be used as a convenient tool to facilitate individualized decision making. Full article
(This article belongs to the Section Clinical Neurology)
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<p>Baseline comparison between the training set and the validation set.</p>
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<p>Receiver operating characteristic curve analysis comparing Model 1 (AUC = 0.715), Model 2 (AUC = 0.767), and Model 3 (AUC = 0.839) for predicting unfavorable outcomes at 6 months.</p>
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<p>Nomogram based on Model 3.</p>
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<p>(<b>A</b>) Calibration curve of Model 3 in the derivation cohort. (<b>B</b>) DCA curve of Model 3 in the derivation cohort, with reference lines representing the net benefit of the default strategy, which is the net benefit obtained when no predictions are made. “None” represents the scenario where all patients are considered negative, and no interventions are applied. “All” represents the scenario where all patients are considered positive, and interventions are always applied.</p>
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<p>(<b>A</b>) ROC curve of Model 3 in the validation set. (<b>B</b>) Calibration curve of Model 3 in the validation set. (<b>C</b>) The DCA curve of Model 3 in the validation set, with reference lines representing the net benefit of the default strategy, which is the net benefit obtained when no predictions are made. “None” represents the scenario where all patients are considered negative, and no interventions are applied. “All” represents the scenario where all patients are considered positive, and interventions are always applied.</p>
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18 pages, 11624 KiB  
Article
The Impact of Tertiary Lymphoid Structures on Tumor Prognosis and the Immune Microenvironment in Colorectal Cancer
by Leyi Zhao, Lingze Xi, Yani Liu, Guoliang Wang, Mingtong Zong, Peng Xue and Shijie Zhu
Biomedicines 2025, 13(3), 539; https://doi.org/10.3390/biomedicines13030539 - 21 Feb 2025
Viewed by 275
Abstract
Background: Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Tertiary lymphoid structures (TLSs), organized immune cell aggregates in non-lymphoid tissues, are linked to chronic inflammation and tumorigenesis. However, the precise relationship between TLSs and CRC prognosis remains unclear. This study [...] Read more.
Background: Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Tertiary lymphoid structures (TLSs), organized immune cell aggregates in non-lymphoid tissues, are linked to chronic inflammation and tumorigenesis. However, the precise relationship between TLSs and CRC prognosis remains unclear. This study aimed to develop a TLS-associated genetic signature to predict CRC prognosis and support clinical applications. Methods: Utilizing the TCGA database, we analyzed TLS-related gene expression in CRC versus normal tissues. Prognostic models were constructed using Cox and Kaplan-Meier analyses. CRC samples were stratified into high and low TLS groups via ssGSEA, with validation in the GSE75500 dataset. We identified clinical characteristics associated with TLS scores, created prognostic nomograms, analyzed the top 50 differential genes, assessed tumor mutations, estimated immune infiltration using CIBERSORT, and examined correlations between TLS scores and immune checkpoints. Results: A 13-gene TLS-associated prognostic model for CRC was developed, emphasizing immune response genes. Survival analysis indicated significantly better outcomes for the TLS-high group. Cox regression identified stage IV and M1 as independent factors influencing TLS scores. Nomogram analysis demonstrated that combining TLS scores with clinical features enhances prognostic accuracy. TLS scores were closely associated with immune checkpoint genes, suggesting potential immunotherapy benefits for TLS-high patients. Conclusions: This study developed and validated a TLS-based prognostic model for CRC, exploring relevant immune cells. The model holds promise for predicting clinical prognosis and treatment responsiveness in CRC patients. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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<p>Flow chart of this study.</p>
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<p>(<b>A</b>) Volcano plot of 13 differently expressed genes; (<b>B</b>) heatmap of 13 differently expressed genes; (<b>C</b>) boxplot of 13 differently expressed genes; (<b>D</b>) correlation dot plot of 13 differently expressed genes. (“*”: <span class="html-italic">p</span> &lt; 0.05, “**”: <span class="html-italic">p</span> &lt; 0.01, “***”: <span class="html-italic">p</span> &lt; 0.001).</p>
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<p>(<b>A</b>) <span class="html-italic">CCL2</span>-OS curves; (<b>B</b>) <span class="html-italic">CCL3</span>-OS curves; (<b>C</b>) <span class="html-italic">CCL8</span>-OS curves; (<b>D</b>) <span class="html-italic">CCL19</span>-OS curves; (<b>E</b>) <span class="html-italic">CCL20</span>-OS curves; (<b>F</b>) <span class="html-italic">CXCL8</span>-OS curves; (<b>G</b>) <span class="html-italic">CXCL11</span>-OS curves; (<b>H</b>) <span class="html-italic">CXCL13</span>-OS curves; (<b>I</b>) <span class="html-italic">IRF4</span>-OS curves; (<b>J</b>) <span class="html-italic">MS4A1</span>-OS curves; (<b>K</b>) <span class="html-italic">TNFRSF17</span>-OS curves.</p>
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<p>(<b>A</b>) GO enrichment analysis (BP) of 11 TLS-related differential genes; (<b>B</b>) GO enrichment analysis (MF) of 11 TLS-related differential genes; (<b>C</b>) KEGG enrichment analysis of 11 TLS-related differential genes.</p>
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<p>(<b>A</b>) Cutpoint for TLS in TCGA samples calculated by ssGSEA enrichment analysis, TLS-high in orange, TLS-low in sky blue; (<b>B</b>) scatter plot of survival time for TLS-high and TLS-low groups; (<b>C</b>) K-M curve of survival status for TLS-high and TLS-low groups.</p>
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<p>(<b>A</b>) Cutpoint for TLS in GEO samples calculated by ssGSEA enrichment analysis, TLS-high in orange, TLS-low in sky blue; (<b>B</b>) scatter plot of survival time for TLS-high and TLS-low groups; (<b>C</b>) K-M curve of survival status for TLS-high and TLS-low groups.</p>
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<p>(<b>A</b>) Heatmap of top 50 differential genes; (<b>B</b>) volcano plot of top 50 differential genes; (<b>C</b>) Circular plot of Go enrichment analysis based on related differential genes; (<b>D</b>) bar chart of GO enrichment analysis based on related differential genes; (<b>E</b>) KEGG enrichment analysis based on related differential genes.</p>
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<p>(<b>A</b>) Heatmap of top 50 differential genes; (<b>B</b>) volcano plot of top 50 differential genes; (<b>C</b>) Circular plot of Go enrichment analysis based on related differential genes; (<b>D</b>) bar chart of GO enrichment analysis based on related differential genes; (<b>E</b>) KEGG enrichment analysis based on related differential genes.</p>
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<p>(<b>A</b>) Influence of age on TLS score; (<b>B</b>) influence of gender on TLS score; (<b>C</b>) influence of stage on TLS score; (<b>D</b>) influence of T on TLS score; (<b>E</b>) influence of N on TLS score; (<b>F</b>) influence of M on TLS score. (“*”: <span class="html-italic">p</span> &lt; 0.05, “**”: <span class="html-italic">p</span> &lt; 0.01, “***”: <span class="html-italic">p</span> &lt; 0.001, “ns”: no significant).</p>
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<p>(<b>A</b>) Univariate cox prognostic analysis of clinical characteristics and TLS scores; (<b>B</b>) univariate and multifactorial cox prognostic analysis of clinical characteristics and TLS scores; (<b>C</b>) nomogram of clinical characteristics and TLS score; (<b>D</b>) calibration curves of clinical characteristics and TLS score. (“**”: <span class="html-italic">p</span> &lt; 0.01, “***”: <span class="html-italic">p</span> &lt; 0.001).</p>
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<p>(<b>A</b>) The difference of TMB between the two groups in the TCGA cohort; (<b>B</b>) a correlation study between TMB and TLS score; (<b>C</b>) top 20 genes of genetic alterations landscape related to TLS in 380 of 408 samples; (<b>D</b>) top 20 genes of genetic alterations landscape related to TLS in 131 of 132 samples.</p>
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<p>(<b>A</b>) Bar plot of immune cells infiltration profile; (<b>B</b>) boxplot of immune cell infiltration profile; (<b>C</b>) correlation between immune cells and TLS score. (“*”: <span class="html-italic">p</span> &lt; 0.05, “**”: <span class="html-italic">p</span> &lt; 0.01, “***”: <span class="html-italic">p</span> &lt; 0.001).</p>
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<p>(<b>A</b>) Association of high and low TLS scores with 10 immune checkpoint-associated genes; (<b>B</b>) chord diagram of the association of high and low TLS scores with 10 immune checkpoint-associated genes. (“***”: <span class="html-italic">p</span> &lt; 0.001).</p>
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11 pages, 1515 KiB  
Article
RAS-Beppu Classification: A New Recurrence Risk Classification System Incorporating the Beppu Score and RAS Status for Colorectal Liver Metastases
by Takuya Tajiri, Kosuke Mima, Toru Beppu, Hiromitsu Hayashi, Taichi Horino, Yuki Adachi, Katsunori Imai, Toshiro Masuda, Yuji Miyamoto and Masaaki Iwatsuki
Cancers 2025, 17(4), 640; https://doi.org/10.3390/cancers17040640 - 14 Feb 2025
Viewed by 292
Abstract
Background: Preoperative recurrence risk stratification for colorectal liver metastases (CRLM) undergoing hepatectomy is essential when designing a treatment strategy. We developed a Beppu classification system consisting of three risk groups and found that the RAS mutation increased risk in low- and moderate-risk [...] Read more.
Background: Preoperative recurrence risk stratification for colorectal liver metastases (CRLM) undergoing hepatectomy is essential when designing a treatment strategy. We developed a Beppu classification system consisting of three risk groups and found that the RAS mutation increased risk in low- and moderate-risk patients. Methods: A total of 173 patients undergoing initial hepatectomy for CRLM between 2004 and 2020 were analyzed. Disease-free survival (DFS) and overall survival (OS) were assessed. Patients in the low- and moderate-risk groups of the Beppu classification with RAS mutations were moved into the moderate- and high-risk groups, respectively, in the RAS-Beppu classification. Results: The DFS curves of the three risk groups in the Beppu and RAS-Beppu classification were significantly different. Five-year DFS rates were 57%, 31%, and 16% in the RAS-Beppu classification of low-, moderate-, and high-risk groups, respectively. With multivariate analysis, Beppu classifications (p = 0.0017) and RAS-Beppu classifications (p = 0.0002) were independent prognostic factors for DFS. The RAS-Beppu classification showed higher hazard ratios than the Beppu classification, as well as the genetic and morphological evaluation score and the modified clinical risk score, which include the RAS status. The hazard ratios in the RAS-Beppu classification were significant in all two-group comparisons (2.22 for moderate vs. low, 3.48 for high vs. low, and 1.70 for high vs. moderate). The multivariate analysis of OS showed benefits of the RAS-Beppu classification in the high- vs. low-risk and high- vs. moderate-risk comparisons. Conclusions: The RAS-Beppu classification using standard parameters is a novel suitable tool for predicting recurrence risk before liver resection. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis (Volume II))
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<p>Recurrence risk stratification by the <span class="html-italic">RAS</span>-Beppu classification.</p>
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<p>Disease-free survival based on the Beppu (<b>a</b>) and <span class="html-italic">RAS</span>-Beppu classification (<b>b</b>) (n = 173). 3Y: 3-year disease-free survival. 5Y: 5-year disease-free survival. HR: hazard ratio. Beppu classification: low, Beppu score ≤ 6; moderate, 7–10; high, ≥11.</p>
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<p>Overall survival based on the Beppu (<b>a</b>) and <span class="html-italic">RAS</span>-Beppu classification (<b>b</b>) (n = 173). 3Y: 3-year disease-free survival. 5Y: 5-year disease-free survival. HR: hazard ratio. Beppu classification: low, Beppu score ≤ 6; moderate, 7–10; high, ≥11.</p>
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15 pages, 3452 KiB  
Article
Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Pathologic T3a Upstaging in Clinical T1 RCC
by Di Yin, Keruo Wang, Hongyi Xu, Yunfei Guo, Baoxin Qian, Dengyi Duan, Yiming Li, Wenyi Zhang, Zhengyang Li and Yang Zhao
Diagnostics 2025, 15(4), 443; https://doi.org/10.3390/diagnostics15040443 - 12 Feb 2025
Viewed by 432
Abstract
Background/Objectives: To develop a nomogram for the preoperative prediction of pathologic T3a (pT3a) upstaging in patients with clinical T1(cT1) renal cell carcinoma (RCC). Methods: A total of 169 cT1 patients with RCC with preoperative contrast-enhanced CT (CECT) and clinical data were [...] Read more.
Background/Objectives: To develop a nomogram for the preoperative prediction of pathologic T3a (pT3a) upstaging in patients with clinical T1(cT1) renal cell carcinoma (RCC). Methods: A total of 169 cT1 patients with RCC with preoperative contrast-enhanced CT (CECT) and clinical data were enrolled in this study. Afterwards, the sample was split randomly into training and testing sets in a 7:3 ratio. Radiomics features were extracted and selected from the whole primary tumor on CECT images to develop radiomics signatures. The nomogram was constructed using the obtained radiomics signature and clinical risk factors. The predictive performance of different models was evaluated and visualized using receiver operator characteristic (ROC) curves. Results: In total, 26 radiomics features were selected for the radiomics signature construction. The radiomics signature yielded area under the curve (AUC) values of 0.945 and 0.873 in the training and testing sets, respectively. The nomogram integrating radiomics signature and predictive clinical factors, including tumor size and neutrophil–lymphocyte ratio (NLR), achieved higher predictive performance in the training [AUC, 0.958; 95% confidence interval (CI): 0.921, 0.995] and testing (AUC, 0.913; 95% CI: 0.814, 1.000) sets. Good calibration was achieved for the nomogram in both the training and testing sets (Brier score = 0.082 and 0.098). Decision curve analysis (DCA) demonstrated that the nomogram was clinically useful in predicting pT3a upstaging, with a corresponding net benefit of 0.378. Conclusions: The proposed nomogram can preoperatively predict pT3a upstaging in cT1 RCC and serve as a non-invasive imaging marker to guide individualized treatment. Full article
(This article belongs to the Section Medical Imaging and Theranostics)
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<p>Overview of the workflow and patient recruitment in our study.</p>
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<p>Twenty-six selected radiomics features and their respective contribution coefficients.</p>
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<p>The receiving operating characteristics (ROC) curves of the radiomics signature, the clinical model, and clinical–radiomics combined model in the (<b>a</b>) training and (<b>b</b>) testing sets, respectively.</p>
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<p>(<b>a</b>) The nomogram obtained by integrating the clinical risk factors and rad-combined signature. In the radiomics nomogram, one of the non-upstaging cT1 patients with RCC was presented as an example to illustrate the application of the nomogram. The distributions of the radiomics signature, NLR, and tumor size are shown on each scale. To utilize the nomogram, each variable of individual patients is positioned on the corresponding axis. The red dots and vertical red lines are drawn to the top point scale to determine the points assigned to each variable. The total points of this patient are 130, corresponding to a probability of 10% on the bottom axis for predicting pT3a upstaging. Calibration curves of the nomogram in the training (<b>b</b>) and testing (<b>c</b>) sets.</p>
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<p>Decision curve analysis (DCA) for the nomogram in the testing set. The <span class="html-italic">y</span>-axis represents the net benefit, and the <span class="html-italic">x</span>-axis represents the threshold probability. In the current study, the threshold probability was 2%, and the corresponding net benefit is 0.378.</p>
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<p>Representative CECT and pathologic images of two cases with upstaging (<b>a</b>–<b>d</b>) and non-upstaging RCC (<b>e</b>–<b>h</b>). CECT images (<b>a</b>–<b>c</b>) depicting a 61-year-old male patient presenting with a soft mass in the right kidney (red circles). The hematoxylin and eosin (HE)-stained image (<b>d</b>) revealed that the renal mass has invaded the renal vein, resulting in thrombosis (black arrows). CECT images (<b>e</b>–<b>g</b>) depicting a 58-year-old male patient presenting with a soft mass on the left kidney (red circles). The hematoxylin and eosin (HE)-stained image (<b>d</b>) revealed that the renal mass maintains a clear boundary (black arrows).</p>
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15 pages, 1545 KiB  
Article
Clinical Characteristics and a Novel Prediction Nomogram (EASTAR) for Patients with Hemorrhagic Fever with Renal Syndrome: A Multicenter Retrospective Study
by Ke Ma, Ting Wu, Wei Guo, Jun Wang, Quan Ming, Jun Zhu, Hongwu Wang, Guang Chen, Xiaojing Wang, Weiming Yan, Xiaoping Luo, Tao Chen and Qin Ning
Trop. Med. Infect. Dis. 2025, 10(2), 51; https://doi.org/10.3390/tropicalmed10020051 - 8 Feb 2025
Viewed by 687
Abstract
Background: The fatality rate of hemorrhagic fever with renal syndrome (HFRS), due to hantavirus transmitted by rodents, ranges from 1% to 12%. This study aims to delineate the clinical and laboratory characteristics of HFRS, identify factors associated with disease severity, and construct and [...] Read more.
Background: The fatality rate of hemorrhagic fever with renal syndrome (HFRS), due to hantavirus transmitted by rodents, ranges from 1% to 12%. This study aims to delineate the clinical and laboratory characteristics of HFRS, identify factors associated with disease severity, and construct and validate a nomogram for prognosis prediction of HFRS in the central part of China. Methods: Out of 598 HFRS patients diagnosed via serology tests from four hospitals in Hubei Province, 551 were included. Clinical data were gathered and analyzed, followed by logistic univariate and multivariate analyses to identify independent prognostic factors. A nomogram was developed and validated to forecast the patient’s prognosis. Results: Vaccination led to a notable drop in HFRS incidence from 2018 to 2019, and seasonal trends exhibited bimodal changes with peaks from May to July and November to January. The 30-day mortality rate was 4.17% (23/551). Red blood cell count (RBC), age, two-stage overlap, qSOFA ≥ 2, aspartate aminotransferase (AST), and three-stage overlap were identified as independent prognostic factors. A predictive risk classification system using a nomogram chart was developed, and Kaplan–Meier curves indicated that the new system accurately distinguished 30-day mortality among the three risk groups. Conclusions: The risk score (EASTAR) system demonstrated good predictive performance for prognostic prediction, and it can be applied to quickly screen patients who require ICU admission. Full article
(This article belongs to the Section Infectious Diseases)
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<p>Flowchart of retrospective, multicenter cohort study.</p>
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<p>Nomogram (EASTAR) for predicting 30−day mortality of HFRS. Low-risk group (total score ≤ 100), medium-risk group (101–220), and high-risk group (total score ≥ 221).</p>
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<p>ROC curve and precision–recall (PR) curve analysis of the nomogram for predicting 30−day mortality (<b>A</b>) ROC curve analysis in the training cohort and (<b>B</b>) in the validation cohort. (<b>C</b>) PR curve analysis is in the training cohort, and (<b>D</b>) is in the validation cohort.</p>
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<p>Calibration curve and decision curve analysis (DCA) curve analysis of the nomogram for predicting 30−day mortality (<b>A</b>) Calibration curve analysis in the training cohort and (<b>B</b>) in the validation cohort. (<b>C</b>) DCA curve analysis is in the training cohort, and (<b>D</b>) is in the validation cohort.</p>
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15 pages, 677 KiB  
Review
Normal Values for Speckle-Tracking Echocardiography in Children: A Review, Update, and Guide for Clinical Use of Speckle-Tracking Echocardiography in Pediatric Patients
by Massimiliano Cantinotti, Guglielmo Capponi, Pietro Marchese, Eliana Franchi, Giuseppe Santoro, Nadia Assanta, Kritika Gowda, Shelby Kutty and Raffaele Giordano
J. Clin. Med. 2025, 14(4), 1090; https://doi.org/10.3390/jcm14041090 - 8 Feb 2025
Viewed by 356
Abstract
Background/Objectives: While speckle-tracking echocardiography (STE) is increasingly gaining acceptance in the medical community, establishing normal pediatric values and interpreting data derived from software provided by various vendors can pose significant challenges. This review aims to present an updated compilation of nomograms pertinent to [...] Read more.
Background/Objectives: While speckle-tracking echocardiography (STE) is increasingly gaining acceptance in the medical community, establishing normal pediatric values and interpreting data derived from software provided by various vendors can pose significant challenges. This review aims to present an updated compilation of nomograms pertinent to speckle-tracking echocardiography. Methods: A review of research using three medical engine searches (National Library of Medicine, Science Direct, and Cochrane Library) for Medical Subject Headings (MeSH) and the free text terms “echocardiography”, “STE”, “normal values”, and ”children” was performed and refined by adding the keywords “nomograms”, “z-scores”, and “healthy children”. Results: A total of twenty-five studies were selected for the final analysis. Our research indicated that current nomograms provide adequate coverage of most strain parameters; however, those pertaining to the right ventricle and the atria are less numerous than those for the left ventricle. A noted trend suggests a decrease in strain values with advancing age and increasing body surface area; nevertheless, the relationships observed were weak and nonlinear. The absence of robust correlations between strain values and age and body size parameters hindered the generation of a Z-score possessing sufficient statistical power. Consequently, normal values are primarily represented as mean values accompanied by standard deviation. A comparative analysis of vendors demonstrated good agreement between different versions of the same platform for Philips (except for QLAB 5) and, similarly, between General Electric (GE) and TomTec. The limited data available regarding the comparison between GE and Philips revealed significant findings that warrant further investigation of differences. Conclusions: A comprehensive review and an updated list of current pediatric nomograms for STE measurements have been presented. This may serve as a valuable guide for accurately interpreting STE in pediatric patients with congenital and acquired heart disease. Full article
(This article belongs to the Special Issue Thoracic Imaging in Cardiovascular and Pulmonary Disease Diagnosis)
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<p>Selection diagram according to PRISMA guidelines.</p>
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Article
Development of a Comprehensive Model for Drying Optimization and Moisture Management in Power Transformer Manufacturing
by Youssouf Brahami, Amidou Betie, Fethi Meghnefi, Issouf Fofana and Zié Yeo
Energies 2025, 18(4), 789; https://doi.org/10.3390/en18040789 - 8 Feb 2025
Viewed by 399
Abstract
The presence of moisture in the insulation of power transformers accelerates the degradation of both paper and oil, thereby increasing the risk of unexpected failures. Due to the hygroscopic nature of cellulose, the insulation can retain up to 8% moisture after the transformer [...] Read more.
The presence of moisture in the insulation of power transformers accelerates the degradation of both paper and oil, thereby increasing the risk of unexpected failures. Due to the hygroscopic nature of cellulose, the insulation can retain up to 8% moisture after the transformer manufacturing process. Reducing this moisture content is crucial in extending the operational lifespan of transformers. The drying cycle of paper insulation is a critical step in power transformer manufacturing, directly influencing the insulation’s longevity and overall performance. This paper introduces a nomogram that combines degradation and drying models, enabling the precise optimization of the drying process based on various parameters such as the temperature, paper mass, and extraction rate. The results of this study demonstrate that for a given extraction rate threshold, the required drying time can be determined based on the mass of paper to be dried, the drying temperature, and the degree of paper degradation (degree of polymerization). These predictive tools are essential for engineers and researchers aiming to enhance transformer reliability. Full article
(This article belongs to the Special Issue Emerging Trends in Enhancing Power Grid Performance)
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<p>Variation in DP as a function of temperature and environment.</p>
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<p>Measured and estimated curves of DP evolution as a function of time and temperature for vacuum drying.</p>
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<p>Evolution of the degree of polymerization as a function of time and temperature according to the established mathematical model.</p>
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<p>Evolution of the degree of polymerization as a function of temperature for different drying durations according to the established mathematical model.</p>
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<p>Maximum exposure time at a given drying temperature as a function of the degradation threshold not to be exceeded.</p>
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<p>Influence of paper mass on drying time (130 °C).</p>
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<p>Influence of temperature on the drying time of a 10 g mass.</p>
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<p>Measured and estimated extracted moisture curves.</p>
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<p>Variation in the time constant as a function of mass.</p>
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<p>Approximation function of the slopes as a function of drying temperature.</p>
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<p>Degree of polymerization and drying time as a function of temperature and paper mass.</p>
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Article
Integrating Hypoxia Signatures from scRNA-seq and Bulk Transcriptomes for Prognosis Prediction and Precision Therapy in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma
by Kexin Yu, Shibo Zhang, Jiali Shen, Meini Yu, Yangguang Su, Ying Wang, Kun Zhou, Lei Liu and Xiujie Chen
Int. J. Mol. Sci. 2025, 26(3), 1362; https://doi.org/10.3390/ijms26031362 - 6 Feb 2025
Viewed by 663
Abstract
Hypoxia, a common feature in many malignancies, is particularly prominent in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Investigating the mechanisms underlying hypoxia is essential for understanding the heterogeneity of CESC and developing personalized therapeutic regimens. Firstly, the CESC-specific hypoxia gene sets [...] Read more.
Hypoxia, a common feature in many malignancies, is particularly prominent in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Investigating the mechanisms underlying hypoxia is essential for understanding the heterogeneity of CESC and developing personalized therapeutic regimens. Firstly, the CESC-specific hypoxia gene sets shared between single-cell RNA sequencing (scRNA-seq) and bulk data were identified through Weighted Gene Correlation Network Analysis (WGCNA)and FindMarkers analyses. A CESC-specific hypoxia-related score (CSHRS) risk model was constructed using the least absolute shrinkage and selection operator (LASSO)and Cox regression analyses based on these genes. The prognostic differences were analyzed in terms of immune infiltration, mutations, and drug resistance. Finally, a nomogram model was constructed by integrating clinicopathological features to facilitate precision treatment for CESC. This study constructed a CSHRS risk model that divides patients into two groups, and this model can comprehensively evaluate the tumor microenvironment characteristics of CESC, provide accurate prognostic predictions, and offer rational treatment options for patients. Full article
(This article belongs to the Section Molecular Informatics)
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<p>Hypoxia is a primary prognosis risk factor in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). (<b>A</b>) Correlation analysis between hallmarks and clinicopathological features. (<b>B</b>) Univariate Cox regression analysis among various hallmarks of cancer. (<b>C</b>) Multivariate Cox regression analysis among various hallmarks of cancer. (<b>D</b>) Multivariate Cox regression analysis between hypoxia hallmark and clinicopathological features. (<b>E</b>) Somatic mutation analysis of 282 hypoxia hallmark genes. (<b>F</b>) Co-mutation analysis among hypoxia hallmark genes. The [XX] represents the number of samples with gene mutations.</p>
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<p>Identification of CESC-specific hypoxia-related genes. (<b>A</b>) The nature of the network topology constructed with unique power values. (<b>B</b>) The correlation between different modules and hypoxia. (<b>C</b>) UMAP plot showing the annotation for five cell types. (<b>D</b>) Grouping of cells by hypoxia-related genes. (<b>E</b>) Volcano plot of differentially expressed genes. (<b>F</b>) Venn plot showing the hub genes intersected by WGCNA and DEGs. (<b>G</b>) KEGG functional enrichment analysis of CSHRGs.</p>
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<p>Construction and validation of the CESC-specific hypoxia-related score (CSHRS)risk model. (<b>A</b>) Univariate Cox regression analysis of CSHRGs. (<b>B</b>) Coefficient distribution plots of log (lambda) sequences. (<b>C</b>) Multivariate Cox regression analysis of CSHRGs. (<b>D</b>) C-index of CSHRS model and model genes. (<b>E</b>,<b>F</b>) TCGA: (<b>E</b>) GSE44001, (<b>F</b>) Kaplan–Meier survival curves. (<b>G</b>,<b>H</b>) TCGA: (<b>G</b>) GSE44001 (<b>H</b>) CSHRS distribution, survival status, and gene expression patterns for patients in high- and low-CSHRS groups. (<b>I</b>,<b>J</b>) TCGA: (<b>I</b>) GSE44001, (<b>J</b>) time-dependent ROC analysis.</p>
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<p>Patients with high-CSHRS are less immune-infiltrated. (<b>A</b>) Immune infiltrates analysis for CSHRS groups. (<b>B</b>) Correlation analysis between CSHRS and immune checkpoints. (<b>C</b>) Difference analysis for CSHRS groups in immune score. (<b>D</b>) Differences analysis for CSHRS groups in ESTIMATE score. <span class="html-italic">p</span> &lt; 0.05 *, <span class="html-italic">p</span> &lt; 0.01 **, <span class="html-italic">p</span> &lt; 0.001 ***, <span class="html-italic">p</span> &lt; 0.0001 ****.</p>
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<p>CSHRS reveals the differentiation process of CAFs cells. (<b>A</b>) Grouping cells by CSHRS. (<b>B</b>) Differences analysis of CSHRS in cell types. (<b>C</b>) UMAP plot showing the CAFs re-clustered. (<b>D</b>) Differences analysis of CSHRS in CAFs subtypes. (<b>E</b>) CAFs trajectory analysis colored by cluster. (<b>F</b>) CAFs trajectory analysis colored by Pseudotime. (<b>G</b>) CAFs trajectory analysis facet by cluster. (<b>H</b>) Heat map visualizing branching cell trajectories and gene dynamics in CAFs. <span class="html-italic">p</span> &gt; 0.05 ns. <span class="html-italic">p</span> &lt; 0.0001 ****.</p>
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<p>Patients with high-CSHRS have increased genomic instability. (<b>A</b>) CNV for the high-CSHRS group (top) and low-CSHRS group (bottom). (<b>B</b>) Difference analysis of copy number amplification in CSHRS groups. (<b>C</b>) Difference analysis of copy number deletion in CSHRS groups. (<b>D</b>) Difference analysis of MSI in CSHRS groups. <span class="html-italic">p</span> &lt; 0.05 *. <span class="html-italic">p</span> &lt; 0.0001 ****.</p>
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<p>Patients with high-CSHRS benefited less from chemoradiotherapy. (<b>A</b>) Kaplan–Meier survival curves. (<b>B</b>) Time-dependent ROC curves analysis. (<b>C</b>) Correlation analysis between CSHRS, model genes, and drugs. (<b>D</b>) Correlation analysis and differences analysis of drug IC50 values in the low-CSHRS and high-CSHRS groups. <span class="html-italic">p</span> &lt; 0.05 *. <span class="html-italic">p</span> &lt; 0.01 **.</p>
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<p>Construction and validation of the nomogram model. (<b>A</b>) Correlation analysis between CSHRS and clinicopathological features. (<b>B</b>) Univariate Cox regression analysis in clinicopathological features. (<b>C</b>) Nomogram for predicting the 1-, 5-, and 7-year OS. (<b>D</b>) DCA curve of the nomogram. (<b>E</b>) Calibration curves of the nomogram for predicting 1-, 5-, and 7-year OS. (<b>F</b>–<b>H</b>) ROC curves from 1 year (<b>F</b>), 5 years (<b>G</b>), and 7 years. (<b>H</b>) Nomogram diagram compared with individual factors accuracy.</p>
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Article
Ketone Bodies Are Potential Prognostic Biomarkers in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results from the R2-GDP-GOTEL Trial
by Sara Fernández-Castillejo, Joan Badia, Luís de la Cruz-Merino, Alejandro Martín Garcia-Sáncho, Fernando Carnicero-González, Natalia Palazón-Carrión, Eduardo Ríos-Herranz, Fátima de la Cruz-Vicente, Antonio Rueda-Domínguez, Natividad Martínez-Banaclocha, José Gómez-Codina, Jorge Labrador, Francisca Martínez-Madueño, Núria Amigó, Antonio Salar-Silvestre, Delvys Rodríguez-Abreu, Laura Gálvez-Carvajal, Margarita Sánchez-Beato, Mariano Provencio-Pulla, Maria Guirado-Risueño, Esteban Nogales, Víctor Sánchez-Margalet, Carlos Jiménez-Cortegana, Guillermo Rodríguez-García, Raquel Cumeras and Josep Gumàadd Show full author list remove Hide full author list
Cancers 2025, 17(3), 532; https://doi.org/10.3390/cancers17030532 - 5 Feb 2025
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Abstract
Background: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for high-dose chemotherapy have limited treatment options and poor life expectancy. The purpose of this study is to identify a serum metabolomic profile that may be predictive of [...] Read more.
Background: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for high-dose chemotherapy have limited treatment options and poor life expectancy. The purpose of this study is to identify a serum metabolomic profile that may be predictive of outcome in patients with R/R-DLBCL. Methods: This study included 69 R/R DLBCL patients from the R2-GDP-GOTEL trial (EudraCT 2014-001620-299). Serum samples were collected at baseline, and the mean length of follow-up was 41 months. Serum metabolites were analyzed by nuclear magnetic resonance (NMR). Metabolites were correlated with treatment response, progression-free survival (PFS), and overall survival (OS). Results: Serum levels of 3-hydroxybutyrate (3OHB) and acetone were significantly (p < 0.001) associated with PFS (3OHB: hazard ratio [HR] 7.7, 95% confidence interval [CI] 2.5–24.1; acetone: HR 9.32, 95% CI 2.75–31.6) and OS (3OHB: HR 9.32, 95% CI 2.75–31.6; acetone: HR 1.92, 95% CI 1.36–2.69). Serum values of 141 µM for 3OHB and 40 µM for acetone were the optimal cutoffs associated with the survival outcomes. Elevated 3OHB levels (>141 μM) were specific to the ABC subtype of DLBCL, while acetone levels were elevated in both types of DLCBL but more pronounced in ABC cases. In a multivariate survival analysis, including the International Prognostic Index (IPI) score and refractoriness status (R/R), 3OHB and acetone remained significant. To aid oncologists employing the R2-GDP regime, we constructed PFS and OS nomograms for R/R-DLBCL risk stratification, incorporating 3OHB levels or acetone levels, IPI score, and refractoriness status. The nomogram with 3OHB and refractoriness status showed a time-dependent AUC of 0.86 for 6-month PFS and 0.84 for 12-month OS. These nomograms provide a comprehensive tool for individualized risk assessment and treatment optimization. Conclusions: The ketone bodies 3OHB and acetone are potential prognostic biomarkers of poor outcome in R/R DLBCL patients treated with the R2-GDP regimen, independently of IPI score and chemorefractoriness status. Full article
(This article belongs to the Section Cancer Biomarkers)
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<p>3-Hydroxybutyrate and acetone as prognostic metabolites in the Cox univariate analysis (<b>A</b>,<b>B</b>) and multivariate regressions models (<b>C</b>–<b>F</b>) for progression-free survival (PFS) (<b>A</b>,<b>C</b>,<b>E</b>) and overall survival (OS) (<b>B</b>,<b>D</b>,<b>F</b>).</p>
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<p>Kaplan–Meier survival curves. (<b>A</b>,<b>B</b>), progression-free survival (PFS) and overall survival (OS) for the cutoff of 3-hydroxybutyrate (3OHB); (<b>C</b>,<b>D</b>) PFS and OS for the cutoff of acetone.</p>
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<p>Nomograms for R/R DLBCL risk stratification based on single metabolites and their respective time-dependent ROCs. (<b>A</b>,<b>B</b>) 3-Hydroxybutyrate (3OHB) nomogram for progression-free survival (PFS) and its ROC; (<b>C</b>,<b>D</b>) 3OHB nomogram for overall survival (OS) and its ROC; (<b>E</b>,<b>F</b>) acetone nomogram for PFS and its ROC; (<b>G</b>,<b>H</b>) acetone nomogram for OS and its ROC.</p>
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<p>Ketone bodies of a poor prognosis per cell-of-origin (CoO) subtypes: germinal center B-cell-like (GBC) and activated B-cell-like (ABC) lymphomas. (<b>A</b>) 3-Hydroxybutyrate (3OHB) boxplot per concentration cutoff values (141 μM) and CoO. (<b>B</b>) Acetone boxplot per concentration cutoff values (40 μM) and CoO.</p>
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