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Biomedicines
Volume 12
Issue 7
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Biomedicines, Volume 12, Issue 7 (July 2024) – 249 articles

Cover Story (view full-size image): EGFR tyrosine kinase inhibitors (TKIs) are key drugs in the treatment of non-small cell lung cancer patients with EGFR-activating mutations. First-, second-, and third-generation (abbreviated as 1G, 2G, and 3G) EGFR-TKIs have been applied in clinical use, and osimertinib (3G-TKI) is now the standard-of-care as front-line treatment in many countries. In this study, we searched for an optimal TKI after front-line osimertinib failure using in vitro models harboring EGFR-activating mutation plus osimertinib-resistant secondary mutation by comparing erlotinib (1G-TKI), novel 3G-TKIs, and BI4020 (4G-TKI). We also explored acquired resistance mechanisms to BI4020 assuming that it may be used as a front-line TKI in the near future. View this paper
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20 pages, 7728 KiB  
Article
Unveiling the Potential of Migrasomes: A Machine-Learning-Driven Signature for Diagnosing Acute Myocardial Infarction
by Yihao Zhu, Yuxi Chen, Jiajin Xu and Yao Zu
Biomedicines 2024, 12(7), 1626; https://doi.org/10.3390/biomedicines12071626 - 22 Jul 2024
Viewed by 1766
Abstract
Background: Recent studies have demonstrated that the migrasome, a newly functional extracellular vesicle, is potentially significant in the occurrence, progression, and diagnosis of cardiovascular diseases. Nonetheless, its diagnostic significance and biological mechanism in acute myocardial infarction (AMI) have yet to be fully explored. [...] Read more.
Background: Recent studies have demonstrated that the migrasome, a newly functional extracellular vesicle, is potentially significant in the occurrence, progression, and diagnosis of cardiovascular diseases. Nonetheless, its diagnostic significance and biological mechanism in acute myocardial infarction (AMI) have yet to be fully explored. Methods: To remedy this gap, we employed an integrative machine learning (ML) framework composed of 113 ML combinations within five independent AMI cohorts to establish a predictive migrasome-related signature (MS). To further elucidate the biological mechanism underlying MS, we implemented single-cell RNA sequencing (scRNA-seq) of cardiac Cd45+ cells from AMI-induced mice. Ultimately, we conducted mendelian randomization (MR) and molecular docking to unveil the therapeutic effectiveness of MS. Results: MS demonstrated robust predictive performance and superior generalization, driven by the optimal combination of Stepglm and Lasso, on the expression of nine migrasome genes (BMP1, ITGB1, NDST1, TSPAN1, TSPAN18, TSPAN2, TSPAN4, TSPAN7, TSPAN9, and WNT8A). Notably, ITGB1 was found to be predominantly expressed in cardiac macrophages in AMI-induced mice, mechanically regulating macrophage transformation between anti-inflammatory and pro-inflammatory. Furthermore, we showed a positive causality between genetic predisposition towards ITGB1 expression and AMI risk, positioning it as a causative gene. Finally, we showed that ginsenoside Rh1, which interacts closely with ITGB1, could represent a novel therapeutic approach for repressing ITGB1. Conclusions: Our MS has implications in forecasting and curving AMI to inform future diagnostic and therapeutic strategies for AMI. Full article
(This article belongs to the Special Issue Integrative Genomic Analysis, Big Data Processing and Programming, and Pharmaco-Informatics in Biomedicine)
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<p>Schematic overview of the study. This study can be divided into three parts: signature development, mechanism exploration, and target analysis.</p> Full article ">Figure 2
<p>Development of an MS for predicting AMI. (<b>A</b>) ML-based integrative framework for establishing the MS. (<b>B</b>) AUC scores of 113 ML combinations within the training and testing cohorts. The best-performing ML combination (first-ranked) is highlighted in the blue box. (<b>C</b>) Coefficient profiles of ten genes were obtained in the Stepglm algorithm. (<b>D</b>) Lasso further selected nine genes with non-zero coefficients under the optimal lambda. (<b>E</b>) The optimal lambda was obtained when the minimum deviation was reached. (<b>F</b>) Overview of the control and AMI cases within the training and testing cohorts (left). MS-derived confusion matrix and predictive indicators (right). (<b>G</b>) Expressions of nine genes between the control and AMI in the training cohort. (<b>H</b>) Expressions of nine genes between the control and AMI in the testing cohort.</p> Full article ">Figure 3
<p>Comparison of predictive performance between the MS and published signatures. The AUC scores of the MS model within five cohorts and the meta-cohort are highlighted in red boxes. An unpaired student’s test was performed; * <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> Full article ">Figure 4
<p>Expression patterns of MS at single-cell resolution in AMI progression. (<b>A</b>) t-SNE visualization of immune cells from control and infracted murine hearts, with annotated time points and cell type. (<b>B</b>) Dot plot of marker genes for five cell types. The scale colors represent the average expression levels of marker genes. The dot size represents the percentage of cells expressed within the cell types. The box with different colors stands for a panel of specific gene markers for four cell populations. (<b>C</b>) The numbers of each cell type in control (Day 0) and different time points after AMI (Days 1, 3, 5, and 7). Expression distribution of <span class="html-italic">Ndst1</span> (<b>D</b>), <span class="html-italic">Itgb1</span> (<b>E</b>), <span class="html-italic">Tspan2</span> (<b>F</b>), <span class="html-italic">Tspan7</span> (<b>G</b>), <span class="html-italic">Tspan9</span> (<b>H</b>), and <span class="html-italic">Tspan18</span> (<b>I</b>) in five cell types. <span class="html-italic">Itgb1</span> was more highly expressed in macrophages than in the other four cell types.</p> Full article ">Figure 5
<p>Pseudo-time analysis reveals the dynamics of MS during macrophage transition. (<b>A</b>) t-SNE visualization of macrophages from control and infracted murine hearts, with annotated time points and macrophage type. (<b>B</b>) The numbers of each macrophage type in control (Day 0) and different time points after AMI (Day 1, Day 3, Day 5, Day 7). (<b>C</b>) Violin plot of marker genes of five macrophage types. (<b>D</b>) Heatmap of dynamic genes during the macrophage transition (left). Significant GO and KEGG enrichment terms for dynamic genes (right). (<b>E</b>) Trajectory plots showing the dynamics of <span class="html-italic">Itgb1</span>, <span class="html-italic">Ssp1</span>, and <span class="html-italic">Tspan9</span> in macrophage differentiation ordered by pseudo-time.</p> Full article ">Figure 6
<p>The causal association and potential druggability of <span class="html-italic">ITGB1</span> and AMI risk. (<b>A</b>) Two-sample Mendelian randomization analysis of the positive association between the SNP effect on <span class="html-italic">ITGB1</span> (x-axis) and AMI (y-axis). (<b>B</b>) Bayesian weighted Mendelian randomization analysis of the positive association between the SNP effect on <span class="html-italic">ITGB1</span> (x-axis) and AMI (y-axis). (<b>C</b>) Forest plot displaying the OR effects (95% confidence intervals) and <span class="html-italic">p</span>-values of <span class="html-italic">ITGB1</span> expression on AMI risk. (<b>D</b>) Molecular docking visualization of ginsenoside Rh1 and ITGB1.</p> Full article ">
14 pages, 3233 KiB  
Article
CRISPR-Cas System, Antimicrobial Resistance, and Enterococcus Genus—A Complicated Relationship
by Carmen Costache, Ioana Colosi, Dan-Alexandru Toc, Karla Daian, David Damacus, Alexandru Botan, Adelina Toc, Adrian Gabriel Pana, Paul Panaitescu, Vlad Neculicioiu, Pavel Schiopu, Dumitrana Iordache and Anca Butiuc-Keul
Biomedicines 2024, 12(7), 1625; https://doi.org/10.3390/biomedicines12071625 - 22 Jul 2024
Viewed by 1339
Abstract
(1) Background: The rise in antibiotic resistant bacteria poses a significant threat to public health worldwide, necessitating innovative solutions. This study explores the role of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) in the context of antibiotic resistance among different species from the [...] Read more.
(1) Background: The rise in antibiotic resistant bacteria poses a significant threat to public health worldwide, necessitating innovative solutions. This study explores the role of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) in the context of antibiotic resistance among different species from the Enterococcus genus. (2) Methods: The genomes of Enterococcus included in the study were analyzed using CRISPRCasFinder to distinguish between CRISPR-positive (level 4 CRISPR) and CRISPR-negative genomes. Antibiotic resistance genes were identified, and a comparative analysis explored potential associations between CRISPR presence and antibiotic resistance profiles in Enterococcus species. (3) Results: Out of ten antibiotic resistance genes found in Enterococcus species, only one, the efmA gene, showed a strong association with CRISPR-negative isolates, while the others did not significantly differ between CRISPR-positive and CRISPR-negative Enterococcus genomes. (4) Conclusion: These findings indicate that the efmA gene may be more prevalent in CRISPR-negative Enterococcus genomes, and they may contribute to a better understanding of the molecular mechanisms underlying the acquisition of antibiotic resistance genes in Enterococcus species. Full article
(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Therapeutics of Infectious Diseases (2nd Edition))
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<p>Visual presentation of processing <span class="html-italic">Enterococcus</span> genomic data using CRISPRCasdb. The CRISPRCasdb interface shows <span class="html-italic">Enterococcus</span> genomes with identified CRISPR-Cas elements, allowing data download.</p> Full article ">Figure 2
<p>The distribution of the CRISPR-positive and CRISPR-negative isolates among the <span class="html-italic">Enterococcus</span> species strains. Each group, CRISPR-positive and CRISPR-negative, contains different <span class="html-italic">Enterococcus</span> species (horizontal axis), and for each species, a different number of strains (noted on the columns).</p> Full article ">Figure 3
<p>The distribution of the CRISPR-Cas types among the CRISPR-positive and CRISPR-negative isolates. Each group, CRISPR-positive and CRISPR-negative, contains a different number of <span class="html-italic">Enterococcus</span> isolates (noted on the columns) for each type (horizontal axis).</p> Full article ">Figure 4
<p>Heatmap showing the relationship between the <span class="html-italic">Enterococcus</span> isolates and the presence of genes and plasmids. The vertical axis represents the <span class="html-italic">Enterococcus</span> isolates, while the horizontal axis denotes the genes and plasmids. Each cell within the heatmap is color-coded to indicate the presence or absence of the respective genes and plasmids in each isolate. A green color signifies the presence of a gene/plasmid, whereas a red color indicates its absence. The varying patterns of green and red across the heatmap highlight the differences in gene presence among the isolates.</p> Full article ">Figure 5
<p>Heatmap showing the relationship between the <span class="html-italic">Enterococcus</span> isolates and types of CRISPR-Cas. The vertical axis represents the <span class="html-italic">Enterococcus</span> isolates, while the horizontal axis denotes the CRISPR-Cas types. Each cell within the heatmap is color-coded to indicate the presence or absence of the respective types in each isolate (a different color for each type). A red color indicates the absence of the respective type.</p> Full article ">
31 pages, 4261 KiB  
Review
Preclinical Models of Hepatocellular Carcinoma: Current Utility, Limitations, and Challenges
by Antonio Cigliano, Weiting Liao, Giovanni A. Deiana, Davide Rizzo, Xin Chen and Diego F. Calvisi
Biomedicines 2024, 12(7), 1624; https://doi.org/10.3390/biomedicines12071624 - 22 Jul 2024
Cited by 1 | Viewed by 2341
Abstract
Hepatocellular carcinoma (HCC), the predominant primary liver tumor, remains one of the most lethal cancers worldwide, despite the advances in therapy in recent years. In addition to the traditional chemically and dietary-induced HCC models, a broad spectrum of novel preclinical tools have been [...] Read more.
Hepatocellular carcinoma (HCC), the predominant primary liver tumor, remains one of the most lethal cancers worldwide, despite the advances in therapy in recent years. In addition to the traditional chemically and dietary-induced HCC models, a broad spectrum of novel preclinical tools have been generated following the advent of transgenic, transposon, organoid, and in silico technologies to overcome this gloomy scenario. These models have become rapidly robust preclinical instruments to unravel the molecular pathogenesis of liver cancer and establish new therapeutic approaches against this deadly disease. The present review article aims to summarize and discuss the commonly used preclinical models for HCC, evaluating their strengths and weaknesses. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements (3rd Edition))
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<p>The multistep process leading to HCC development. This image was modified using the BioRender online tool (<a href="http://www.biorender.com" target="_blank">www.biorender.com</a>, accessed on 10 June 2024). Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; TERT, telomerase reverse transcriptase; TP53, tumor protein 53; CTNNB1, catenin beta 1; ARID1A, AT-rich interaction domain 1A; HDAC, histone deacetylase; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; VEGFR, vascular endothelial growth factor receptor; EGFR, epidermal growth factor receptor.</p> Full article ">Figure 2
<p>Overview of the in vitro models to study HCC. This image was created using the BioRender online tool (<a href="http://www.biorender.com" target="_blank">www.biorender.com</a>, accessed on 10 June 2024).</p> Full article ">Figure 3
<p>Classification and potential application of HCC mouse models. Abbreviations: CCl4, carbon tetrachloride; CD, choline-deficient; DEN, diethylnitrosamine; GEM, genetically engineered mouse; HCC, hepatocellular carcinoma; HFD, high-fat diet; HTVI, hydrodynamic tail vein injection; MAFLD, metabolic-associated fatty liver disease; PDX, patient-derived xenograft; PLC, primary liver cancer; SW, sugar water; TME, tumor microenvironment. Created with the BioRender tool (<a href="http://www.biorender.com" target="_blank">www.biorender.com</a>, accessed on 10 June 2024).</p> Full article ">Figure 4
<p>Inducible and conditional GEM models used for spatial and/or temporal control of gene expression. (<b>A</b>) Tetracycline (tet)-regulated expression system. Briefly, the tet transactivator acts as a constitutive repressor that is inducibly inhibited by ligands to allow expression from the tet operon (tTA). Alternatively, it functions as an inducible activator of the tet operon upon ligand addition (rtTA). (<b>B</b>) Tamoxifen-regulated Cre-loxP system. The Cre-lox tool is primarily used to generate knockout alleles and activate gene expression. The correct insertion of a loxP-flanked “stop” sequence (transcriptional termination element) between the promoter and transgene coding sequence hinders the expression of the gene. In the tamoxifen-inducible Cre-lox model, the system is induced upon tamoxifen administration, and the cells expressing Cre-ER undergo gene inactivation due to the Cre-mediated recombination of the loxP sites, excising the STOP codon in the reporter transgene. Provided by Biorender (<a href="http://www.biorender.com" target="_blank">www.biorender.com</a>, accessed on 11 June 2024), modified from <a href="https://doi.org/10.3389/fphar.2019.00724" target="_blank">https://doi.org/10.3389/fphar.2019.00724</a>.</p> Full article ">Figure 5
<p>Representative steps in performing the hydrodynamic tail vein injection technique. Modified with Biorender software online (<a href="http://www.biorender.com" target="_blank">www.biorender.com</a>).</p> Full article ">Figure 6
<p>Schematic diagram of CAM assay. CAM, chorioallantoic membrane assay. Modified with Biorender software (<a href="http://www.biorender.com" target="_blank">www.biorender.com</a>, accessed on 12 June 2024).</p> Full article ">
10 pages, 2457 KiB  
Article
Inhibition of Protease-Activated Receptor-2 Activation in Parkinson’s Disease Using 1-Piperidin Propionic Acid
by Santina Quarta, Michele Sandre, Mariagrazia Ruvoletto, Marta Campagnolo, Aron Emmi, Alessandra Biasiolo, Patrizia Pontisso and Angelo Antonini
Biomedicines 2024, 12(7), 1623; https://doi.org/10.3390/biomedicines12071623 - 22 Jul 2024
Viewed by 1514
Abstract
In Parkinson’s disease, neuroinflammation is a double-edged sword; when inflammation occurs it can have harmful effects, despite its important role in battling infections and healing tissue. Once triggered by microglia, astrocytes acquire a reactive state and shift from supporting the survival of neurons [...] Read more.
In Parkinson’s disease, neuroinflammation is a double-edged sword; when inflammation occurs it can have harmful effects, despite its important role in battling infections and healing tissue. Once triggered by microglia, astrocytes acquire a reactive state and shift from supporting the survival of neurons to causing their destruction. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson’s disease. Protein aggregates and PAR2 expression were analyzed using Thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson’s patients, treated or untreated with 1-PPA. A significant decrease in amyloid aggregates was observed after 1-PPA treatment in all patients. A parallel decrease in PAR2 expression, which was higher in sporadic Parkinson’s patients, was also observed both at the transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease in IL-1β, IL-6, and TNF-α, together with a decreased expression of PAR2. In conclusion, 1-PPA determines the reduction in neuroglia inflammation and amyloid aggregates formation, suggesting that the pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Amyloid aggregates in skin fibroblasts of patients with Parkinson’s disease. (<b>A</b>) Representative examples of amyloid aggregates detected using Thioflavine-S staining in human skin fibroblasts from a control (CTR) and from patients with Parkinson’s disease (genetic, #1 and sporadic, #7), untreated or treated with 10 ng/mL of 1-PPA for 48 h. (<b>B</b>) Quantification of immunofluorescence intensity of amyloid aggregates, obtained with the Zeiss AxioVision<sup>®</sup> software (version 4.8), in the control (CTR) and in patients with genetic (#1–#6) and sporadic (#7 and #8) patients. Each value is expressed as the mean ± SEM of at least 5 measurements.</p> Full article ">Figure 2
<p>PAR-2 and SerpinB3 expression in skin fibroblasts of patients with sporadic Parkinson’s disease. (<b>A</b>) Immunofluorescence analysis of skin fibroblast of sporadic patients (#7 and #8) and of a representative control (CTR) untreated or incubated with 1-PPA (10 ng/mL) for 24 h. (<b>B</b>) Quantification of immunofluorescence intensity of PAR2 and SerpinB3, obtained using Zeiss AxioVision<sup>®</sup> software, in skin fibroblasts untreated or treated with 1-PPA. Each value is expressed as the mean ± SEM of at least 5 measurements and the <span class="html-italic">p</span>-values were considered significant if <span class="html-italic">p</span> ≤ 0.05. Scale bar: 50 µm.</p> Full article ">Figure 3
<p>PAR2 and SerpinB3 expression in skin fibroblasts of patients with genetic Parkinson’s disease. (<b>A</b>) Representative examples of immunofluorescence analysis in patients with genetic Parkinson’s disease (#3 and #6) and in a control (CTR) in presence or not of 1-PPA (10 ng/mL) for 24 h. (<b>B</b>) Quantification of immunofluorescence intensity of PAR-2 and SerpinB3 expression after treatment with medium (CTR) or with 1-PPA, using Zeiss AxioVision<sup>®</sup> software. Each value is expressed as the mean ± SEM of 5 measurements and the <span class="html-italic">p</span>-values were considered significant if <span class="html-italic">p</span> ≤ 0.05. Scale bar: 50 µm.</p> Full article ">Figure 4
<p>Gene expression of PAR2 and of SerpinB3 in skin fibroblasts of patients with Parkinson’s disease. Distribution of quantitative real-time PCR results of PAR2 (<b>A</b>) and of SerpinB3 (SB3) (<b>B</b>) mRNA in skin fibroblasts of all patients and of the controls, treated or untreated for 24 h with 10 ng/mL of 1-PPA. Results are expressed as 2<sup>-ΔCT</sup> values; central bar represents mean ± SEM.</p> Full article ">Figure 5
<p>Effect of 1-PPA on cytokine expression in activated mouse microglia. Quantitative real-time PCR of inflammatory cytokine genes (IL-1β, TNF-α, IL-6) in primary mouse microglia activated with LPS 100 ng/mL for 24 h and treated or not with 1-PPA at 10 ng/mL concentration. Results are expressed as the mean ± SEM of 2<sup>-ΔCT</sup> values of three different experiments.</p> Full article ">Figure 6
<p>PAR2 expression in mouse microglia. (<b>A</b>) Representative examples of immunofluorescence analysis of PAR2 in primary mouse microglia cells (CTR) and in LPS-activated microglia in presence or in no presence of 1-PPA. (<b>B</b>) Quantification of immunofluorescence intensity of PAR2 expression in control cells and in LPS-activated cells untreated or treated with 1-PPA. Each value is expressed as the mean ± SEM of at least 5 measurements, using Zeiss AxioVision<sup>®</sup> software. (<b>C</b>) Parallel analysis of quantitative real-time PCR of PAR2 mRNA in microglial cells and in LPS-activated cells untreated or treated with 10 ng/mL of 1-PPA for 24 h. Results are expressed 2<sup>-ΔCT</sup>. The <span class="html-italic">p</span>-values were considered significant if <span class="html-italic">p</span> ≤ 0.05.</p> Full article ">
11 pages, 1542 KiB  
Article
The Kinetics of Inflammation-Related Proteins and Cytokines in Children Undergoing CAR-T Cell Therapy—Are They Biomarkers of Therapy-Related Toxicities?
by Paweł Marschollek, Karolina Liszka, Monika Mielcarek-Siedziuk, Iwona Dachowska-Kałwak, Natalia Haze, Anna Panasiuk, Igor Olejnik, Tomasz Jarmoliński, Jowita Frączkiewicz, Zuzanna Gamrot, Anna Radajewska, Iwona Bil-Lula and Krzysztof Kałwak
Biomedicines 2024, 12(7), 1622; https://doi.org/10.3390/biomedicines12071622 - 21 Jul 2024
Cited by 2 | Viewed by 1135
Abstract
CD19-targeted CAR-T cell therapy has revolutionized the treatment of relapsed/refractory (r/r) pre-B acute lymphoblastic leukemia (ALL). However, it can be associated with acute toxicities related to immune activation, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokines released from [...] Read more.
CD19-targeted CAR-T cell therapy has revolutionized the treatment of relapsed/refractory (r/r) pre-B acute lymphoblastic leukemia (ALL). However, it can be associated with acute toxicities related to immune activation, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokines released from activated immune cells play a key role in their pathophysiology. This study was a prospective analysis of proinflammatory proteins and cytokines in children treated with tisagenlecleucel. Serial measurements of C-reactive protein, fibrinogen, ferritin, IL-6, IL-8, IL-10, IFNγ, and TNFα were taken before treatment and on consecutive days after infusion. The incidence of CRS was 77.8%, and the incidence of ICANS was 11.1%. No CRS of grade ≥ 3 was observed. All complications occurred within 14 days following infusion. Higher biomarker concentrations were found in children with CRS grade ≥ 2. Their levels were correlated with disease burden and CAR-T cell dose. While cytokine release syndrome was common, most cases were mild, primarily due to low disease burden before lymphodepleting chemotherapy (LDC). ICANS occurred less frequently but exhibited various clinical courses. None of the toxicities were fatal. All of the analyzed biomarkers rose within 14 days after CAR-T infusion, with most reaching their maximum around the third day following the procedure. Full article
(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)
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<p>Cytokine release following CAR-T cell activation cascade.</p> Full article ">Figure 2
<p>Representative flow cytometry plot for CAR-positive CD3+ lymphocytes detection.</p> Full article ">Figure 3
<p>The distribution of maximum biomarker concentrations is shown as boxplots. The kinetics of the analyzed biomarkers over the 14 days following infusion (horizontal axis). The values presented are the medians for each timepoint measurement.</p> Full article ">Figure 4
<p>Dot plots for significant correlations. Abbreviations: MRD—minimal residual disease; LDC—lymphodepleting chemotherapy.</p> Full article ">
18 pages, 3364 KiB  
Article
Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives
by Jingyi Ma, Dileepkumar Veeragoni, Hindole Ghosh, Nicole Mutter, Gisele Barbosa, Lauren Webster, Rainer Schobert, Wendy van de Sande, Prasad Dandawate and Bernhard Biersack
Biomedicines 2024, 12(7), 1621; https://doi.org/10.3390/biomedicines12071621 - 21 Jul 2024
Viewed by 1195
Abstract
The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested [...] Read more.
The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most active compound against EAC cells (IC50 = 0.8–1.0 µM), and its anticancer effects were mediated by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of β-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity against M. mycetomatis (IC50 = 0.2–0.3 µM) and were not toxic to Galleria mellonella larvae. Slight improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed. Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs. Full article
(This article belongs to the Special Issue Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties)
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Figure 1

Figure 1
<p>The structures of the antifungal salicylanilides niclosamide and MMV665807.</p> Full article ">Figure 2
<p>Time- and dose-dependent activity of niclosamide (upper row) and <b>3a</b> (bottom row) against EAC cell lines (SK-GT-4 and FLO-1) and THP-1 monocytes. * <span class="html-italic">p</span> &lt; 0.05 and ** <span class="html-italic">p</span> &lt; 0.01 as analyzed by one-way ANOVA test.</p> Full article ">Figure 3
<p>(<b>A</b>) Niclosamide and <b>3a</b> (1.5 and 0.8 µM for SK-GT-4 and FLO-1, respectively) inhibit colony formation by EAC cells at 48 h time point. (<b>B</b>) Niclosamide and <b>3a</b> (1.5 µM) inhibit spheroid formation by SK-GT-4 cells.</p> Full article ">Figure 4
<p>Effects of niclosamide and <b>3a</b> (1.5 and 0.8 µM for SK-GT-4 and FLO-1, respectively) on PARP cleavage, and expression of pro-apoptotic BAX and anti-apoptotic BCL2 and MCL1 in EAC cell lines. GAPDH (glyceraldehyde 3-phosphate dehydrogenase) served as control.</p> Full article ">Figure 5
<p>Molecular docking of niclosamide and <b>2a</b> (<b>A</b>) in the protein cavity of STAT3 and (<b>B</b>) in the protein cavity of β-catenin at the TCF4 binding site using the Autodock vina software program. Surface view of the binding mode. White: protein; pink: interacting amino acid; green: compound; black dotted line: H bond.</p> Full article ">Figure 6
<p>Effects of niclosamide and <b>3a</b> (1.5 and 0.8 µM for SK-GT-4 and FLO-1, respectively) on levels of p-STAT3<sup>Tyr705</sup>, STAT3, and (active) non-phospho-β-catenin in EAC cell lines. GAPDH (glyceraldehyde 3-phosphate dehydrogenase) served as control.</p> Full article ">Figure 7
<p>Evaluation of compounds <b>2a–c</b> and <b>2e</b> (20 µM) in <span class="html-italic">Galleria mellonella</span> larvae. (<b>A</b>) Toxicity evaluation of test compounds for 10 days indicated by larval survival (in %). (<b>B</b>) Activity of test compounds in <span class="html-italic">M. mycetomatis</span> MM55-infected <span class="html-italic">G. mellonella</span> larvae indicated by larval survival (in %).</p> Full article ">Scheme 1
<p>Reagents and conditions: (i) subst. aniline, EDCI, CH<sub>2</sub>Cl<sub>2</sub>, r.t., 24 h, 33–50%; (ii) ethanolamine, EtOH, r.t., 1 h, 66–93%.</p> Full article ">
19 pages, 2164 KiB  
Article
Effect of Palmitoylethanolamide Compared to a Placebo on the Gut Microbiome and Biochemistry in an Overweight Adult Population: A Randomised, Placebo Controlled, Double-Blind Study
by Romeo Batacan, Jr., David Briskey, Yadav Sharma Bajagai, Chelsie Smith, Dana Stanley and Amanda Rao
Biomedicines 2024, 12(7), 1620; https://doi.org/10.3390/biomedicines12071620 - 20 Jul 2024
Viewed by 1665
Abstract
This study investigates the effects of palmitoylethanolamide (PEA) on the gut microbiome of overweight adults. Fifty-eight participants (twenty males, thirty-eight females) aged 18–65 years with a BMI range of 30–40 kg/m2 were recruited. Participants were randomised to receive PEA (n = [...] Read more.
This study investigates the effects of palmitoylethanolamide (PEA) on the gut microbiome of overweight adults. Fifty-eight participants (twenty males, thirty-eight females) aged 18–65 years with a BMI range of 30–40 kg/m2 were recruited. Participants were randomised to receive PEA (n = 36) or a placebo (n = 22) for 12 weeks. Microbiota composition, richness, diversity, and metabolic functions, faecal short chain fatty acids and calprotectin, pathology markers, and health-related questionnaires were analysed throughout the 12 weeks of supplementation. PEA supplementation significantly reduced triglyceride levels and IL-2 concentrations. No significant differences were found in the overall microbiota composition between the groups, and microbiota richness and diversity remained consistent for both groups. Functional analysis demonstrated no differences in functional richness and diversity, but specific pathways were modified. PEA supplementation resulted in a decrease in the abundance of pathways related to aromatic compound degradation, NAD interconversion, and L-glutamate degradation, while pathways associated with molybdopterin biosynthesis and O-antigen building blocks exhibited increased abundance. Increased production of O-antigen results in smooth LPS associated with reduced pathogenic stealth and persistence. PEA supplementation may influence specific microbial species, metabolic pathways, and reduce serum triglyceride and IL-2 concentration, shedding light on the intricate relationship between PEA, the microbiome, and host health. Full article
(This article belongs to the Section Microbiology in Human Health and Disease)
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<p>Relative abundances: The relative abundances of the top 10 phyla (<b>A</b>) and top 20 species (<b>B</b>) in individual participants in the two groups. At the phylum level, the individual participant has either Bacteroidetes or Firmicutes as a dominant phylum (<b>A</b>); while at the species level, the dominant species are either <span class="html-italic">Faecalibacterium prausnitzii</span> or <span class="html-italic">Prevotella copri</span> or <span class="html-italic">Bacteroides vulgatus</span> or <span class="html-italic">Bacteroides uniformis</span> or <span class="html-italic">Alistipes putredinis</span> or <span class="html-italic">Bacteroides stercoris</span> or <span class="html-italic">Bacteroides dorei</span> (<b>B</b>).</p> Full article ">Figure 2
<p>Alpha diversity and richness variation of the two groups: (<b>A</b>) = Chao1 index; (<b>B</b>) = Shannon index. A.Baseline = PEA baseline; A.Final = PEA final; B.Baseline = placebo baseline; B.Final = placebo final.</p> Full article ">Figure 3
<p>Relative abundances: the relative abundance of the top 20 metabolic pathways in all participants in the two groups (PEA and placebo) at baseline and final sampling points.</p> Full article ">
11 pages, 1943 KiB  
Article
Developing a Polygenic Risk Score with Age and Sex to Identify High-Risk Myopia in Taiwan
by Hui-Ju Lin, Yu-Te Huang, Wen-Ling Liao, Yu-Chuen Huang, Ya-Wen Chang, Angel L. Weng and Fuu-Jen Tsai
Biomedicines 2024, 12(7), 1619; https://doi.org/10.3390/biomedicines12071619 - 20 Jul 2024
Viewed by 885
Abstract
Myopia is the leading cause of impaired vision, and its prevalence is increasing among Asian populations. This study aimed to develop a polygenic risk score (PRS) followed by replication to predict myopia in the Taiwanese population. In total, 23,688 participants with cycloplegic autorefraction-measured [...] Read more.
Myopia is the leading cause of impaired vision, and its prevalence is increasing among Asian populations. This study aimed to develop a polygenic risk score (PRS) followed by replication to predict myopia in the Taiwanese population. In total, 23,688 participants with cycloplegic autorefraction-measured mean spherical equivalent (SE), genetic, and demographic data were included. The myopia PRS was generated based on genome-wide association study (GWAS) outcomes in a Taiwanese population and previously published GWAS reports. The results demonstrated that the inclusion of age and sex in the PRS had an area under the curve (AUC) of 0.80, 0.78, and 0.73 (p < 0.001) for participants aged >18 years with high (SE < −6.0 diopters (D); n = 1089), moderate (−6.0 D < SE ≤ −3.0 D; n = 3929), and mild myopia (−3.0 D < SE ≤ −1.0 D; n = 2241), respectively. Participants in the top PRS quartile had a 1.30-fold greater risk of high myopia (95% confidence interval = 1.09–1.55, p = 0.003) compared with that in the remaining participants. Further, a higher PRS significantly increased the risk of high myopia (SE ≤ −2.0 D) in children ≤6 years of age (p = 0.027). In conclusion, including the PRS, age, and sex improved the prediction of high myopia risk in the Taiwanese population. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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<p>Manhattan plot of the GWAS in the discovery cohort, which included 2541 individuals with high myopia and 7615 individuals with no myopia. The solid line indicates the genome-wide significance threshold of <span class="html-italic">p</span> &lt; 5.0 × 10<sup>−8</sup>, while the dashed line indicates the suggestive significance threshold of <span class="html-italic">p</span> &lt; 1.0 × 10<sup>−6</sup>. Different colors represented each chromosome.</p> Full article ">Figure 2
<p>Flowchart of the study design.</p> Full article ">Figure 3
<p>Receiver operating characteristic (ROC) curve for detecting (<b>A</b>) high, (<b>B</b>) moderate, and (<b>C</b>) mild myopia versus no myopia controls (SE &gt; −1.0 D) with the PRS, age, and sex as predictors in participants aged &gt;18 years; the AUC and 95% confidence interval (CI) correspond to the PRS, age, and sex models.</p> Full article ">Figure 4
<p>ROC curve for detecting high myopia in participants aged (<b>A</b>) 7–18, (<b>B</b>) 7–13, and (<b>C</b>) ≤6 years with the PRS, age, and sex as predictors (blue line); green line represented reference line. The AUC and 95% CI correspond to the PRS, age, and sex model.</p> Full article ">
9 pages, 513 KiB  
Article
The Impact of Pentraxin 3 Serum Levels and Angiotensin-Converting Enzyme Polymorphism on Pulmonary Infiltrates and Mortality in COVID-19 Patients
by Zdravka Krivdić Dupan, Vlatka Periša, Mirjana Suver Stević, Martina Mihalj, Maja Tolušić Levak, Silva Guljaš, Tamer Salha, Domagoj Loinjak, Martina Kos, Matej Šapina, Ivana Canjko, Mirela Šambić Penc, Marin Štefančić and Nenad Nešković
Biomedicines 2024, 12(7), 1618; https://doi.org/10.3390/biomedicines12071618 - 20 Jul 2024
Viewed by 828
Abstract
Objectives: The aim of this study was to examine the impact of the pentraxin 3 (PTX3) serum level and angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on the severity of radiographic pulmonary infiltrates and the clinical outcomes of COVID-19. Methods: The severity of [...] Read more.
Objectives: The aim of this study was to examine the impact of the pentraxin 3 (PTX3) serum level and angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on the severity of radiographic pulmonary infiltrates and the clinical outcomes of COVID-19. Methods: The severity of COVID-19 pulmonary infiltrates was evaluated within a week of admission by analyzing chest X-rays (CXR) using the modified Brixia (MBrixa) scoring system. The insertion (I)/deletion (D) polymorphism of the ACE gene and the serum levels of PTX3 were determined for all patients included in the study. Results: This study included 80 patients. Using a cut-off serum level of PTX3 ≥ 2.765 ng/mL, the ROC analysis (AUC 0.871, 95% CI 0.787–0.954, p < 0.001) showed a sensitivity of 85.7% and specificity of 78.8% in predicting severe MBrixa scores. Compared to ACE I/I polymorphism, D/D polymorphism significantly increased the risk of severe CXR infiltrates, OR 7.7 (95% CI: 1.9–30.1), and p = 0.002. Significant independent predictors of severe CXR infiltrates include hypertension (OR 7.71), PTX3 (OR 1.20), and ACE D/D polymorphism (OR 18.72). Hypertension (OR 6.91), PTX3 (OR 1.47), and ACE I/I polymorphism (OR 0.09) are significant predictors of poor outcomes. Conclusion: PTX3 and ACE D/D polymorphism are significant predictors of the severity of COVID-19 pneumonia. PTX3 is a significant predictor of death. Full article
(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago? (2nd Edition))
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<p>ROC analysis of pentraxin-3 and age in predicting CXR infiltrate severity.</p> Full article ">
11 pages, 934 KiB  
Review
Expanding the Perspective on PARP1 and Its Inhibitors in Cancer Therapy: From DNA Damage Repair to Immunomodulation
by Flurina Böhi and Michael O. Hottiger
Biomedicines 2024, 12(7), 1617; https://doi.org/10.3390/biomedicines12071617 - 20 Jul 2024
Viewed by 2291
Abstract
The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated a multifaceted role of PARP1 beyond its canonical function in DNA damage repair. This [...] Read more.
The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated a multifaceted role of PARP1 beyond its canonical function in DNA damage repair. This review explores the expanding roles of PARP1, highlighting its crucial interplay with the immune system during tumorigenesis. We discuss PARP1’s immunomodulatory effects in macrophages and T cells, with a particular focus on cytokine expression. Understanding these immunomodulatory roles of PARP1 not only holds promise for enhancing the efficacy of PARP inhibitors in cancer therapy but also paves the way for novel treatment regimens targeting immune-mediated inflammatory diseases. Full article
(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)
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<p>PARPi effect in cancer cells and immune cells. Depicted in green are effects that are promoted by PARPi treatment, and effects that are inhibited by PARPi treatment are shown in red. (<b>A</b>) Synthetic lethality interaction of homologous recombination (HR)-deficient cancer cells and PARPi treatment leads to cancer cell death. (<b>B</b>) PARPi treatment also inhibits ADP-ribosylation of cGAS in cancer cells, thereby enhancing the cGAS/STING signaling pathway. (<b>C</b>) In macrophages, PARPi elevate levels of NAD<sup>+</sup> and ROS. This shift in metabolism enhances the anti-tumorigenic function of macrophages. (<b>D</b>–<b>G</b>) PARPi up- and downregulate the transcription of various cytokines in both macrophages and T cells. (<b>H</b>) In cancer cells, PARPi treatment upregulates PD-L1 expression, which may have implications for the interaction between cancer cells and the immune system.</p> Full article ">Figure 2
<p>Comparable PARP1 gene effects across tumor cell lines. To compare the effect of PARP1 and its enzymatic activity across different cell lines, we used publicly available datasets of genome-wide CRISPR loss-of-function and drug sensitivity screens. These datasets provide scores for gene dependency and drug sensitivity (<a href="https://depmap.org/portal/" target="_blank">https://depmap.org/portal/</a>, accessed on 9 July 2024). (<b>A</b>) Dependency on PARP1 in several of the examined cell lines. Colored groups represent cell lines derived from breast, ovarian, fallopian tube, and pancreas tumors, all of which are treated with PARPi in clinics. (<b>B</b>) Correlation plot of PARP1 gene dependency scores (<span class="html-italic">x</span>-axis) vs. Talazoparib sensitivity scores (<span class="html-italic">y</span>-axis). Except for lung cancer cell lines (colored in red), which show a significant correlation between PARP1 gene effect and PARPi treatment efficacy, most cancer cell lines, including those derived from breast, ovarian, fallopian tube and pancreas tumors (colored in green/light blue/ dark blue), exhibit a low and non-significant correlation between PARP1 gene effect and PARPi efficacy. The cancer types shown in gray are those for which data on the PARP1 gene dependency score (<a href="#biomedicines-12-01617-f002" class="html-fig">Figure 2</a>A) or data on the PARP1 gene dependency score and on the Talazoparib sensitivity score (<a href="#biomedicines-12-01617-f002" class="html-fig">Figure 2</a>B) were available for at least 10 cell lines. In none of these cancer types was a strong or significant correlation found between PARP1 gene effect and PARP1 inhibition. * = <span class="html-italic">p</span> ≤ 0.05.</p> Full article ">
9 pages, 347 KiB  
Article
Gemtuzumab Ozogamicin and Stem Cell Mobilization for Autologous Stem Cell Transplantation in Favorable Risk Acute Myeloid Leukemia
by Danaë Martinez Flores, Dilara Akhoundova, Katja Seipel, Myriam Legros, Marie-Noelle Kronig, Michael Daskalakis, Ulrike Bacher and Thomas Pabst
Biomedicines 2024, 12(7), 1616; https://doi.org/10.3390/biomedicines12071616 - 19 Jul 2024
Viewed by 915
Abstract
Gemtuzumab ozogamicin (GO), a CD33-targeting antibody drug conjugate, previously showed longer relapse-free survival when combined with induction chemotherapy in patients with favorable-risk acute myeloid leukemia (AML). In this patient population, characterized by lower relapse risk as compared to other ELN risk groups, autologous [...] Read more.
Gemtuzumab ozogamicin (GO), a CD33-targeting antibody drug conjugate, previously showed longer relapse-free survival when combined with induction chemotherapy in patients with favorable-risk acute myeloid leukemia (AML). In this patient population, characterized by lower relapse risk as compared to other ELN risk groups, autologous stem cell transplantation (ASCT) can be used as consolidation strategy. However, there are limited data on the impact of GO on the peripheral blood stem cell (PBSC) mobilization potential. We therefore retrospectively analyzed data from 54 AML patients with favorable-risk AML treated with (n = 17) or without (n = 37) GO during induction treatment. We observed no significant differences in the PBSC mobilization rate between patients treated with vs. without GO. The mobilization success in a first attempt directly following cycle 2 was 65% vs. 70% (p = 0.92); and the mobilization success in a subsequent second attempt after hematologic recovery and repeated stimulation procedure was 24% vs. 19% (p = 0.56). No significant impact on treatment outcome in terms of EFS (p = 0.31) or OS (p = 0.99) was observed. Thus, our results suggest that the addition of GO to induction regimens does not negatively impact PBSC mobilization in favorable-risk AML patients. To our best knowledge, this is the first study comparing the stem cell mobilization potential in favorable-risk AML patients treated with vs. without GO. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)
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<p>Kaplan—Meier curves illustrating (<b>A</b>) event-free survival of GO vs. control group; (<b>B</b>) overall survival of GO group and control group.</p> Full article ">
22 pages, 2938 KiB  
Article
Candidate Key Proteins in Tinnitus—A Bioinformatic Study of Synaptic Transmission in the Cochlear Nucleus
by Johann Gross, Marlies Knipper and Birgit Mazurek
Biomedicines 2024, 12(7), 1615; https://doi.org/10.3390/biomedicines12071615 - 19 Jul 2024
Viewed by 987
Abstract
The aim of this study was to identify key proteins of synaptic transmission in the cochlear nucleus (CN) that are involved in normal hearing, acoustic stimulation, and tinnitus. A gene list was compiled from the GeneCards database using the keywords “synaptic transmission” AND [...] Read more.
The aim of this study was to identify key proteins of synaptic transmission in the cochlear nucleus (CN) that are involved in normal hearing, acoustic stimulation, and tinnitus. A gene list was compiled from the GeneCards database using the keywords “synaptic transmission” AND “tinnitus” AND “cochlear nucleus” (Tin). For comparison, two gene lists with the keywords “auditory perception” (AP) AND “acoustic stimulation” (AcouStim) were built. The STRING protein–protein interaction (PPI) network and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and their high-score interaction proteins (HSIPs), together referred to as key proteins. The top1 key proteins of the Tin-process were BDNF, NTRK1, NTRK3, and NTF3; the top2 key proteins are FOS, JUN, CREB1, EGR1, MAPK1, and MAPK3. Highly significant GO terms in CN in tinnitus were “RNA polymerase II transcription factor complex”, “late endosome”, cellular response to cadmium ion”, “cellular response to reactive oxygen species”, and “nerve growth factor signaling pathway”, indicating changes in vesicle and cell homeostasis. In contrast to the spiral ganglion, where important changes in tinnitus are characterized by processes at the level of cells, important biological changes in the CN take place at the level of synapses and transcription. Full article
(This article belongs to the Special Issue Understanding Chronic Neurological Diseases: Pathophysiology, Biomarkers, and Therapeutic Approaches)
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<p>Workflow for studying the key proteins. AP—auditory perception; AS—acoustic stimulation; Tin—tinnitus; HDP—high-degree protein; HSIP—high-score interaction protein; CS—combined score.</p> Full article ">Figure 2
<p>Venn diagram. AP—auditory perception, AcouStim—acoustic stimulation, Tin—tinnitus.</p> Full article ">Figure 3
<p>PPI network of the AP, AcouStim, and Tin processes in the CN. (<b>A</b>) AP; (<b>B</b>) AcouStim; (<b>C</b>) Tin. Top HDP—red circle; Top2 HDP—blue circle. Triangles—HSIPs. Topological criteria (AP/AcouStim/Tin): number of nodes—18/24/30; number of edges—62/122/176; avg. number of neighbors—7.0/10.2/11.73; network (NW) radius (2/2/2); characteristic path length—1.77/1.74/1.71; NW heterogeneity—0.52/0.50/0.47; NW centralization 0.47/0.42/0.45.</p> Full article ">Figure 3 Cont.
<p>PPI network of the AP, AcouStim, and Tin processes in the CN. (<b>A</b>) AP; (<b>B</b>) AcouStim; (<b>C</b>) Tin. Top HDP—red circle; Top2 HDP—blue circle. Triangles—HSIPs. Topological criteria (AP/AcouStim/Tin): number of nodes—18/24/30; number of edges—62/122/176; avg. number of neighbors—7.0/10.2/11.73; network (NW) radius (2/2/2); characteristic path length—1.77/1.74/1.71; NW heterogeneity—0.52/0.50/0.47; NW centralization 0.47/0.42/0.45.</p> Full article ">Figure 4
<p>Frequency distribution of the degree (<b>A</b>) and CS values (<b>B</b>) of the AP, AcouStim, and Tin networks. The frequency distribution of the degree and CS values was calculated as the percentages of the number of nodes and edges (See legend of <a href="#biomedicines-12-01615-f003" class="html-fig">Figure 3</a>). The intervals of degree values are 2, and those of CS values are 50. The CS values of class 1 correspond to CS = 400–450, and those of class 12 correspond to CS = 950–999. Characteristic values of the degree frequency curves (AP/AcouStim/Tin): Median—7/12/12; 90th percentile—12/17/19. Characteristic values of the CS frequency distribution: Median—555/598/647; 90th percentile—865/966/991.</p> Full article ">Figure 5
<p>Interactions of BDNF and its HSIPs with proteins characterized by a CS value &gt; median. Meanings of colors: orange—members of the neurotrophic tyrosine receptor kinase (NTRK) family; pink—transcription factor; blue—proteins directly involved in synaptic transmission; green—growth factors; yellow—members of the MAP kinase family (alias extracellular signal-regulated kinases, ERKs), light gray—CTNNB1. Numbers indicate the corresponding CS values.</p> Full article ">Figure 6
<p>Synaptic locations and biological functions of key proteins and proteins with close interaction with BDNF according to the SynGO database. Bold letters are key proteins.</p> Full article ">
12 pages, 2063 KiB  
Article
Breakthrough COVID-19 Infections after Booster SARS-CoV-2 Vaccination in a Greek Cohort of People Living with HIV during the Delta and Omicron Waves
by Konstantinos Protopapas, Konstantinos Thomas, Charalampos D. Moschopoulos, Eirini Oktapoda, Eirini Marousi, Eirini Marselou, Nikiforos Stamoulis, Christos Filis, Pinelopi Kazakou, Chrysanthi Oikonomopoulou, Georgios Zampetas, Ourania Efstratiadou, Katerina Chavatza, Dimitra Kavatha, Anastasia Antoniadou and Antonios Papadopoulos
Biomedicines 2024, 12(7), 1614; https://doi.org/10.3390/biomedicines12071614 - 19 Jul 2024
Viewed by 975
Abstract
Introduction: Currently approved SARS-CoV-2 vaccines have been proven effective in protecting against severe COVID-19; however, they show variable efficacy against symptomatic infection and disease transmission. We studied the breakthrough COVID-19 infection (BTI) after booster vaccination against SARS-CoV-2 in people living with HIV (PWH). [...] Read more.
Introduction: Currently approved SARS-CoV-2 vaccines have been proven effective in protecting against severe COVID-19; however, they show variable efficacy against symptomatic infection and disease transmission. We studied the breakthrough COVID-19 infection (BTI) after booster vaccination against SARS-CoV-2 in people living with HIV (PWH). Methods: This was a retrospective, single-center, descriptive cohort study involving PWH, who were followed in the HIV Clinic of “Attikon” University Hospital in Athens, Greece. A BTI was defined as a case of laboratory-confirmed COVID-19 occurring at least 14 days after the third (booster) vaccine dose. Results: We studied 733 PWH [males: 89%, mean age: 45.2 ± 11.3 years, mean BMI: 26.1 ± 4.1, HIV stage at diagnosis (CDC classification): A/B/C = 80/9/11%, MSM: 72.6%] with well-controlled HIV infection. At least one comorbidity was recorded in 54% of cases. A history of ≥1 vaccination was reported by 90%, with 75% having been vaccinated with ≥3 vaccines. Four hundred and two (55%) PWH had a history of COVID-19 and 302 (41.2%) had a BTI, with only 15 (3.7%) needing hospitalization. Only one patient was admitted to the ICU, and no death was reported. Regarding BTI after booster dose, increased age (OR = 0.97, 95% CI: 0.96–0.99, per 1-year increase), and COVID-19 infection prior to booster dose (OR = 0.38, 95% CI: 0.21–0.68) were associated with a lower likelihood for BTI, whereas higher BMI (OR = 1.04, 95% CI: 1.01–1.08) and MSM as a mode of HIV transmission were associated with increased risk (OR = 2.59, 95% CI: 1.47–4.56). The incidence rate of total COVID-19 and BTI followed the epidemic curve of the general population, with the highest incidence recorded in June 2022. Conclusions: A significant proportion of PWH with well-controlled HIV infection experienced a BTI, with the majority of them having mild infection. These data, which include the period of Omicron variant predominance, confirm the importance of vaccination in the protection against severe COVID-19. Full article
(This article belongs to the Special Issue Emerging Insights into HIV)
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<p>Forest plot of multivariate Cox regression analysis of factors associated with BTI after booster vaccine dose. Note: Odds ratios (ORs) lower than 1 are depicted in red and ORs higher than 1 in blue. <span class="html-italic">p</span> values &lt;0.01 are marked with (**) and those &lt;0.001 with (***).</p> Full article ">Figure 2
<p>Kaplan–Meier curves, with the respective numbers of persons at risk showing the cumulative incidence of BTI after the 3rd vaccine dose according to the age (<b>A</b>) and history of prior COVID-19 infection (<b>B</b>).</p> Full article ">
17 pages, 2511 KiB  
Review
Nanofiber Graft Therapy to Prevent Shoulder Stiffness and Adhesions after Rotator Cuff Tendon Repair: A Comprehensive Review
by Jong Pil Yoon, Hyunjin Kim, Sung-Jin Park, Dong-Hyun Kim, Jun-Young Kim, Du Han Kim and Seok Won Chung
Biomedicines 2024, 12(7), 1613; https://doi.org/10.3390/biomedicines12071613 - 19 Jul 2024
Cited by 1 | Viewed by 1362
Abstract
Stiffness and adhesions following rotator cuff tears (RCTs) are common complications that negatively affect surgical outcomes and impede healing, thereby increasing the risk of morbidity and failure of surgical interventions. Tissue engineering, particularly through the use of nanofiber scaffolds, has emerged as a [...] Read more.
Stiffness and adhesions following rotator cuff tears (RCTs) are common complications that negatively affect surgical outcomes and impede healing, thereby increasing the risk of morbidity and failure of surgical interventions. Tissue engineering, particularly through the use of nanofiber scaffolds, has emerged as a promising regenerative medicine strategy to address these complications. This review critically assesses the efficacy and limitations of nanofiber-based methods in promoting rotator cuff (RC) regeneration and managing postrepair stiffness and adhesions. It also discusses the need for a multidisciplinary approach to advance this field and highlights important considerations for future clinical trials. Full article
(This article belongs to the Topic Advanced Functional Materials for Regenerative Medicine)
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<p>Schematic illustration of the shoulder anatomy highlighting normal structures (<b>left</b>) and regions affected by rotator cuff problems (<b>right</b>). The normal shoulder includes the supraspinatus tendon (rotator cuff), supraspinatus muscle, scapula (shoulder blade), long head of the biceps tendon, long head of the biceps muscle, and shoulder capsule. The problematic shoulder indicates tendon tears and the inflammatory response commonly associated with rotator cuff injuries. Created with BioRender.com.</p> Full article ">Figure 2
<p>Tissue engineering mechanism of nanofiber scaffolds.</p> Full article ">Figure 3
<p>Design considerations for nanofiber scaffolds.</p> Full article ">Figure 4
<p>Flowchart of the literature search and selection process.</p> Full article ">
24 pages, 9764 KiB  
Article
The Effects of Cathepsin B Inhibition in the Face of Diffuse Traumatic Brain Injury and Secondary Intracranial Pressure Elevation
by Martina Hernandez, Sean Regan, Rana Ansari, Amanda Logan-Wesley, Radina Lilova, Chelsea Levi, Karen Gorse and Audrey Lafrenaye
Biomedicines 2024, 12(7), 1612; https://doi.org/10.3390/biomedicines12071612 - 19 Jul 2024
Cited by 1 | Viewed by 898
Abstract
Traumatic brain injury (TBI) affects millions of people each year. Previous studies using the central fluid percussion injury (CFPI) model in adult male rats indicated that elevated intracranial pressure (ICP) was associated with long-term effects, including neuronal cell loss and increased sensory sensitivity [...] Read more.
Traumatic brain injury (TBI) affects millions of people each year. Previous studies using the central fluid percussion injury (CFPI) model in adult male rats indicated that elevated intracranial pressure (ICP) was associated with long-term effects, including neuronal cell loss and increased sensory sensitivity post-injury and secondary ICP elevation, which were not seen following injury alone. Investigations also indicated that cathepsin B (Cath B), a lysosomal cysteine protease, may play a role in the pathological progression of neuronal membrane disruption; however, the specific impact of Cath B inhibition following CFPI remained unknown. Thus, the focus of this study was to evaluate the effects of Cath B inhibition via the intracerebroventricular infusion of the Cath B inhibitor to the CA-074 methyl ester (CA-074Me) 2w following injury with or without secondary ICP elevation. This was accomplished using adult male rats continuously infused with CA-074Me or 10% DMSO as a vehicle control for 2w following either sham injury, CFPI only, or CFPI with subsequent ICP elevation to 20 mmHg. We assessed Cath B activity and evaluated the protein levels of Cath B and Cath B-binding partners AIF, Bcl-XL, and Bak. We also conducted histological analyses of the total cell counts to assess for cell loss, membrane disruption, and Cath B localization. Finally, we investigated somatosensory changes with the whisker nuisance task. Overall, this study demonstrated that Cath B is not a direct driver of membrane disruption; however, the administration of CA-074Me alters Cath B localization and reduces hypersensitivity, emphasizing Cath B as an important component in late secondary pathologies. Full article
(This article belongs to the Special Issue Brain Injury: New Insights into Mechanisms and Future Promising Treatments)
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<p>Schematic representation of the experimental procedures utilized in the current study. (<b>A</b>) The top panel represents the experimental design for animals processed for molecular studies and (<b>B</b>) the lower panel depicts the experimental design for animals processed for histological studies. All animals in both groups had whisker nuisance task (WNT, yellow arrow) behavioral assessments carried out prior to injury and at 2w (13 d) post-injury. On the day of injury, day 0, animals either sustained a central fluid percussion injury (CFPI) or a sham injury (red arrowhead). From 15 min to 1 h following sham or CFPI, animals either had intracranial pressure (ICP) monitoring or ICP elevation to 20 mmHg. An initial bolus of either the cathepsin B inhibitor CA-074Me or 10% DMSO vehicle followed by implantation of an osmotic pump for continuous intracerebroventricular (ICV) administration was completed 1 h to 2 h post-injury followed by recovery from anesthesia. At 2w post-sham or CFPI, animals used for histological analysis were anaesthetized for bilateral ICV infusion of the cell-impermeable 10 kDa Alexa-Fluor-488 fluorescently tagged dextran (green arrow), followed by transcardial perfusion 1 h later.</p> Full article ">Figure 2
<p>Cathepsin B (Cath B) activity was reduced following 2w of the Cath B inhibitor CA-074Me infusion into the left lateral ventricle. Cath B activity was significantly decreased in the left and right lateral neocortex following CA-074Me infusion (filled boxes) compared to 10% DMSO control (vehicle; unfilled boxes). Box and whisker graph depicting the average fluorescent intensity indicating Cath B activity in the right and left side of the lateral neocortex and the liver of sham-injured control animals (n = 12; grey unfilled boxes for n = 6 saline-treated animals and filled boxes for n = 6 CA-074Me-treated animals), animals sustaining a traumatic brain injury (TBI) only (n = 13; light blue unfilled boxes for n = 6 saline-treated animals and filled boxes for n = 7 CA-074Me-treated animals), or animals sustaining a TBI followed by secondary intracranial pressure (ICP) elevation (n = 12; dark blue unfilled boxes for n = 6 saline-treated animals and filled boxes for n = 6 CA-074Me-treated animals). Note that Cath B activity in the liver was significantly higher than that in the cortex regardless of injury group. Additionally, ICP infusion of CA-074Me did not impact Cath B activity in the liver; however, CA-074Me infusion did significantly lower Cath B activity in the left and right cortex compared to DMSO controls. * <span class="html-italic">p</span> &lt; 0.05 compared to injury type-matched vehicle control, # <span class="html-italic">p</span> &lt; 0.05 compared to injury type-matched liver. Mean ± S.E.M.</p> Full article ">Figure 3
<p>Cathepsin B (Cath B) protein levels were slightly increased in animals infused with the Cath B inhibitor CA-074Me. (<b>A</b>) Representative chemiluminescent blot image of the two mature Cath B bands at 24/27 kDa, which was normalized to (<b>B</b>) total protein. Box and whisker graphs depicting average (n = 6/group) quantities of (<b>C</b>) total Cath B protein, (<b>D</b>) the upper band of the Cath B doublet, and (<b>E</b>) the lower band of the Cath B doublet for sham-injured animals (grey boxes), animals sustaining a central fluid percussion injury (CFPI; light blue boxes), and animals sustaining both CFPI and secondary intracranial pressure (ICP) elevation (dark blue boxes) followed by a 2w intracerebroventricular infusion of either 10% DMSO (vehicle, left half of graphs) or the Cath B inhibitor, CA-074Me (right half of graphs). Amount of Cath B for each case was calculated as a percentage compared to a consistent naïve control that was run on all membranes. While there were no significant differences found for total Cath B protein or the upper band of the observed doublet, there was a significant increase in Cath B levels of the lower band of the doublet in animals infused with CA-074Me compared to their vehicle counterparts. * <span class="html-italic">p</span> &lt; 0.05 compared to vehicle. Mean ± S.E.M.</p> Full article ">Figure 4
<p>Protein levels of Bcl-XL were unchanged regardless of injury or infusion group. (<b>A</b>) Representative chemiluminescent blot image of Bcl-XL at 30 kDa, which was normalized to (<b>B</b>) total protein. (<b>C</b>) Box and whisker graph depicting average (n = 6/group) quantities of Bcl-XL protein for sham-injured animals (grey boxes), animals sustaining a central fluid percusion injury (CFPI; (light blue boxes), and animals sustaining both CFPI and secondary intracranial pressure (ICP) elevation (dark blue boxes) followed by a 2w ICF infusion of either 10% DMSO (vehicle, left half of graph) or the Cath B inhibitor, CA-074Me (right half of graph). Amount of Bcl-XL for each case was calculated as a percentage compared to a consistent naïve control that was run on all membranes. Mean ± S.E.M.</p> Full article ">Figure 5
<p>Protein quantification of BAK revealed no differences in the protein quantity regardless of group. (<b>A</b>) Representative chemiluminescent blot image of BAK at 25 kDa, which was normalized to (<b>B</b>) total protein. (<b>C</b>) Box and whisker graph depicting average (n = 6/group) quantities of BAK protein for sham-injured animals (grey boxes), animals sustaining a central fluid percussion injury (CFPI; light blue boxes), and animals sustaining both CFPI and secondary intracranial pressure (ICP) elevation (dark blue boxes) followed by a 2w ICF infusion of either 10% DMSO (vehicle, left half of graph) or the Cath B inhibitor, CA-074Me (right half of graph). Amount of BAK for each case was calculated as a percentage compared to a consistent naïve control that was run on all membranes. Mean ± S.E.M.</p> Full article ">Figure 6
<p>Protein quantification of AIF revealed no differences in the protein quantity regardless of group. (<b>A</b>) Representative chemiluminescent blot image of the two observed AIF bands at ~67/72 kDa, which was normalized to (<b>B</b>) total protein. Box and whisker graphs depicting average (n = 6/group) quantities of (<b>C</b>) the upper band of the AIF doublet and (<b>D</b>) the lower band of the AIF doublet for sham-injured animals (grey boxes), animals sustaining a central fluid percussion injury (CFPI; light blue boxes), and animals sustaining both CFPI and secondary intracranial pressure (ICP) elevation (dark blue boxes) followed by a 2w intracerebroventricular infusion of either 10% DMSO (vehicle, left half of graphs) or the Cath B inhibitor, CA-074Me (right half of graphs). Amount of AIF for each case was calculated as a percentage compared to a consistent naïve control that was run on all membranes. Mean ± S.E.M.</p> Full article ">Figure 7
<p>Representative fluorescent micrographs of membrane disruption in sham-injured animals (sham, (<b>A</b>,<b>D</b>)), animals sustaining a traumatic brain injury (TBI, (<b>B</b>,<b>E</b>)), and animals sustaining a TBI followed by secondary intracranial pressure (ICP) elevation (TBI+ 20 mmHg ICP elevation, (<b>C</b>,<b>F</b>)) paired with 2w of intracerebroventricular infusion of 10% DMSO (vehicle (<b>A</b>–<b>C</b>)) or the Cathepsin B inhibitor, CA-074Me (<b>D</b>–<b>F</b>). The left panel in blue depicts NeuroTrace Nissl-stained cells and the middle panel in green depicts cells containing a cell-impermeable Alexa-Fluor-488-tagged dextran (AF-dextran-488). The right panel is the overlay of the NeuroTrace and membrane-disrupted dextran images. The arrow heads indicate representative membrane-disrupted neurons. Scale bar 20 μm.</p> Full article ">Figure 8
<p>The total number of cells in the lateral neocortex layers V and VI is unaffected across injury and infusion groups. Bar graph depicting the average number of fluorescent NeuroTrace Nissl-stained neurons in sham-injured animals (grey boxes), animals sustaining a CFPI (light blue boxes), and animals sustaining both CFPI and secondary ICP elevation (dark blue boxes) followed by a 2w ICV infusion of either 10% DMSO (vehicle, left half of graphs) or the Cath B inhibitor, CA-074Me (right half of graphs). The mean number of cells was quantified per unit area (0.098 mm<sup>2</sup>) and averaged for each animal (n = 6/group). Mean ± S.E.M.</p> Full article ">Figure 9
<p>There were no significant changes in membrane disruption regardless of injury or Cathepsin B inhibitor infusion. Bar graph highlighting a consistently low average (n = 6/group) percentage of membrane-disrupted neurons in sham-injured animals (grey boxes), animals sustaining a central fluid percussion injury (CFPI; light blue boxes), and animals sustaining both CFPI and secondary intracranial pressure (ICP) elevation (dark blue boxes) followed by a 2w ICV infusion of either 10% DMSO (vehicle, left half of graph) or the Cathepsin B inhibitor CA-074Me (right half of graph). Mean ± S.E.M.</p> Full article ">Figure 10
<p>Representative fluorescent micrographs of cathepsin B (Cath B) localization in membrane-disrupted and non-disrupted neurons within the lateral neocortex layers V and VI in sham-injured animals, animals sustaining a traumatic brain injury (TBI), and animals sustaining a TBI followed by secondary intracranial pressure (ICP) elevation (TBI + 20 mmHg ICP elevation) paired with 2w of intracerebroventricular infusion of 10% DMSO (vehicle) or the Cath B inhibitor CA-074Me. The left-most panel contains DAPI-labeled nuclei (blue). Neurons were identified as non-disrupted (yellow arrows) or membrane-disrupted (white arrowheads) based upon uptake of cell-impermeable Alexa-Fluor-488-tagged 10 kDa dextran (AF-dextran-488; second panel in green), which diffused throughout the parenchyma. Immunolabeling for Cath B (third panel in red) allowed investigation of Cath B localization inside lysosomal puncta or outside lysosomes. The right-most panel is an overlay of the single channel images. Scale bar 20 μm.</p> Full article ">Figure 11
<p>Cathepsin B (Cath B) inhibition with CA-074Me impacted the distribution of Cath B within lysosomal puncta. Bar graph depicting the percent of neurons within the non-disrupted (left half of graph; sham DMSO n = 214 neurons [dark green bars], sham CA-074Me n = 248 [light green bars], traumatic brain injury (TBI) DMSO n = 238 neurons [dark blue bars], TBI CA-074Me n = 275 neurons [light blue bars], TBI + intracranial pressure (ICP) DMSO n = 226 neurons [dark pink bars], and TBI + ICP CA-074Me n = 351 neurons [light pink bars]) and membrane-disrupted (right half of graph; sham DMSO n = 159 neurons [dark green bars], sham CA-074Me n = 176 neurons [light green bars], TBI DMSO n = 204 neurons [dark blue bars], TBI CA-074Me n = 205 neurons [light blue bars], TBI + ICP DMSO n = 153 neurons [dark pink bars], TBI + ICP CA-074Me n = 199 neurons [light pink bars]) populations that exhibited punctate localization of Cath B. Note that Cath B localization within puncta was impacted by inhibitor infusion, injury group, and membrane disruption status of the neurons analyzed. * <span class="html-italic">p</span> &lt; 0.05 compared to non-disrupted counterpart, # <span class="html-italic">p</span> &lt; 0.05 compared to sham and CA-074Me, <span>$</span> <span class="html-italic">p</span> &lt; 0.05 compared to vehicle-treated counterpart, ^ <span class="html-italic">p</span> &lt; 0.05 compared to TBI-only infusion group counterpart. Mean ± S.E.M.</p> Full article ">Figure 12
<p>Somatosensory sensitivity was impacted by injury, particularly with secondary ICP elevation, and further impacted by cathepsin B inhibition with CA-074Me. Bar graph depicting the average whisker nuisance task (WNT) score pre-injury (tan bars) and at 2w post-injury or sham (blue bars). Sham animals infused with 10% DMSO (n = 11) had slightly higher WNT scores post-injury compared to sham animals infused with CA-074Me (n = 13). Animals sustaining traumatic brain injury (TBI) infused with 10% DMSO (n = 12) demonstrated similar post-injury WNT scores as TBI animals infused with CA-074Me (n = 13). Injured animals with secondary intracranial pressure (ICP) elevations (TBI + 20 mmHg ICP) infused with CA-074Me (n = 12) had lower WNT scores compared to injured and ICP-elevated animals infused with 10% DMSO (n = 11), resulting in an overall reduction in post-injury WNT score in animals infused with CA-074Me. * <span class="html-italic">p</span> &lt; 0.05 compared pre-injury WNT score for that group, # <span class="html-italic">p</span> &lt; 0.05 compared to sham 10% DMSO. Mean ± S.E.M.</p> Full article ">
13 pages, 2960 KiB  
Article
Overexpression of BubR1 Mitotic Checkpoint Protein Predicts Short Survival and Influences the Progression of Cholangiocarcinoma
by Nongnapas Pokaew, Piya Prajumwongs, Kulthida Vaeteewoottacharn, Sopit Wongkham, Chawalit Pairojkul and Kanlayanee Sawanyawisuth
Biomedicines 2024, 12(7), 1611; https://doi.org/10.3390/biomedicines12071611 - 19 Jul 2024
Viewed by 928
Abstract
Budding Uninhibited by Benzimidazole-Related 1 (BubR1) or BUB1 Mitotic Checkpoint Serine/Threonine Kinase B (BUB1B) is an essential component of the spindle assembly checkpoint (SAC), which controls chromosome separation during mitosis. Overexpression of BubR1 has been associated with the progression of various cancers. This [...] Read more.
Budding Uninhibited by Benzimidazole-Related 1 (BubR1) or BUB1 Mitotic Checkpoint Serine/Threonine Kinase B (BUB1B) is an essential component of the spindle assembly checkpoint (SAC), which controls chromosome separation during mitosis. Overexpression of BubR1 has been associated with the progression of various cancers. This study demonstrated that high expression of BubR1 correlated with cholangiocarcinogenesis in a hamster cholangiocarcinoma (CCA) model and was associated with shorter survival in patients with CCA. Co-expression of BubR1 and MPS1, which is a SAC-related protein, indicated a shorter survival rate in patients with CCA. Knockdown of BubR1 expression by specific siRNA (siBubR1) significantly decreased cell proliferation and colony formation while inducing apoptosis in CCA cell lines. In addition, suppression of BubR1 inhibited migration and invasion abilities via epithelial–mesenchymal transition (EMT). A combination of siBubR1 and chemotherapeutic drugs showed synergistic effects in CCA cell lines. Taken together, this finding suggested that BubR1 had oncogenic functions, which influenced CCA progression. Suppression of BubR1 might be an alternative option for CCA treatment. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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<p>BubR1 is related to cholangiocarcinogenesis in a hamster model. (<b>A</b>) BubR1 was stained using immunohistochemistry (IHC) in the liver tissues of hamsters in four groups at one, three, and six months after treatment: control, N-nitrosodimethylamine (NDMA)-treated, Ov-infected, and a combination of NDMA + Ov. (<b>B</b>) A comparison of BubR1 expression between NBD and pathological bile ducts (HP/DP and CCA). The samples were divided into low-BubR1 and high-BubR1 groups, using a cutoff value of a median H-score of 133. NBD, normal bile duct; HP/DP, hyperplasia/dysplasia; CCA, cholangiocarcinoma; Ov, <span class="html-italic">Opisthorchis viverrini</span>.</p> Full article ">Figure 2
<p>BubR1 was overexpressed in human CCA tissue. (<b>A</b>) BubR1 transcript levels in 36 human CCA tissues and nine normal bile ducts (NBDs) are shown in a box plot; TPM or transcripts per million. * <span class="html-italic">p</span> &lt; 0.05. For a comparison of overall survival and BubR1 expression using Kaplan–Meier analysis, information was taken from the GEPIA database. (<b>B</b>) The distribution of BubR1 transcript levels in 183 human patients with CCA was categorized into normal (n = 92) and tumor groups (n = 91), using the median value of BubR1 expression (normal 4.2, tumor 5.0). Data were retrieved from the GEO database, *** <span class="html-italic">p</span> &lt; 0.001. (<b>C</b>) Immunohistochemistry staining of BubR1 in human CCA tissues (n = 189). Low expression of BubR1 in the normal bile duct (NBD); low and high expression of BubR1 in the tumor area. (<b>D</b>) Distribution of BubR1 expression in 24 NBDs and 189 CCA tissues. The median H-score of NBDs was 100, and for CCA was 140, *** <span class="html-italic">p</span> &lt; 0.001. (<b>E</b>) Kaplan–Meier analysis of the correlation between BubR1 expression and overall survival. A high expression of BubR1 (n = 98) had significantly shorter overall survival than that of BubR1 low expression (n = 91).</p> Full article ">Figure 3
<p>Association between BubR1 and MPS1 in CCA. (<b>A</b>) The correlation between the mRNA expression of BubR1 and MPS1 in CCA (n = 91). Data were retrieved from the GEO database (GSE76297). The solid line indicates mean mRNA expression, whereas the dotted line shows the standard deviation of mRNA expression. (<b>B</b>) A Kaplan–Meier plot of 152 patients with CCA who expressed high levels of both BubR1 and MPS1 (purple line) versus patients who expressed high BubR1 but low MPS1 (yellow line), high MPS1 but low BubR1 (green line), and low levels of both BubR1 and MPS1 (blue line).</p> Full article ">Figure 4
<p>Suppression of BubR1 expression reduced cell proliferation, colony formation, and induced a sub-G1 population in a CCA cell line. (<b>A</b>) Representative Western blotting analysis of BubR1 expression after knockdown of BubR1 by siRNA at 24 to 96 h. (<b>B</b>) The cell proliferation rate was determined at 24 to 96 h using MTT and (<b>C</b>) clonogenic assays show the percentage of colonies after BubR1 knockdown in CCA cell lines. (<b>D</b>,<b>E</b>) Flow cytometry histograms demonstrate a sub-G1 population and a percentage of sub-G1 cell content in siBubR1-treated cells at 48 h. (<b>F</b>) Representative Western blotting analysis of Mcl-1, caspase 9, cleaved caspase 9, PARP, and cleaved PARP expression after knockdown of BubR1 at 48 h. (<b>G</b>) The bar graph represents the fold-change expression quantified using GAPDH, and the scramble (sc) control was set to one. The results (mean ± SD) are averages from three independent experiments; * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 5
<p>Knockdown of BubR1 inhibited cell migration and invasion of CCA cell lines. A Boyden chamber assay shows the percentage of (<b>A</b>) migrated and (<b>B</b>) invaded cells compared with those of scramble cells (100%). BubR1 regulated CCA cell migration and invasion abilities via the EMT process. (<b>C</b>) Representative Western blotting analysis of ZO-1, vimentin, and slug expression after knockdown of BubR1 at 24 h. (<b>D</b>) The bar graph represents the fold-change expression quantified using GAPDH, and the scramble (sc) control was set to one. The results (mean ± SD) are averages from three independent experiments; ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">
18 pages, 1364 KiB  
Review
The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma
by Qian Jiang, Jingyi Xiao, Yao-Ching Hsieh, Neha Love Kumar, Lei Han, Yuntao Zou and Huang Li
Biomedicines 2024, 12(7), 1610; https://doi.org/10.3390/biomedicines12071610 - 19 Jul 2024
Viewed by 1424
Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, representing a significant public health problem with a poor prognosis. The development of efficient therapeutic strategies for HNSCC prevention and treatment is urgently needed. The PI3K/AKT/mTOR (PAM) signaling [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, representing a significant public health problem with a poor prognosis. The development of efficient therapeutic strategies for HNSCC prevention and treatment is urgently needed. The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Dysfunction in components of this pathway, such as hyperactivity of PI3K, loss of PTEN function, and gain-of-function mutations in AKT, are well-known drivers of treatment resistance and disease progression in cancer. In this review, we discuss the major mutations and dysregulations in the PAM signaling pathway in HNSCC. We highlight the results of clinical trials involving inhibitors targeting the PAM signaling pathway as a strategy for treating HNSCC. Additionally, we examine the primary mechanisms of resistance to drugs targeting the PAM pathway and potential therapeutic strategies. Full article
(This article belongs to the Special Issue mTOR Signaling in Disease and Therapy)
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<p>The PAM signaling pathway composition and function.</p> Full article ">Figure 2
<p>The PAM signaling mutations in HNSCC.</p> Full article ">Figure 3
<p>Strategy may prevent tumor resistance to PAM pathway inhibitors.</p> Full article ">
11 pages, 1060 KiB  
Article
Analysis of Ferritin, Hepcidin, Zinc, C-Reactive Protein and IL-6 Levels in COVID-19 in Patients Living at Different Altitudes in Peru
by Wilmer Silva-Caso, Sungmin Kym, Alfredo Merino-Luna, Miguel Angel Aguilar-Luis, Yordi Tarazona-Castro, Hugo Carrillo-Ng, Eliezer Bonifacio-Velez de Villa, Ronald Aquino-Ortega and Juana del Valle-Mendoza
Biomedicines 2024, 12(7), 1609; https://doi.org/10.3390/biomedicines12071609 - 19 Jul 2024
Viewed by 940
Abstract
Background: Despite great scientific efforts, understanding the role of COVID-19 clinical biomarkers remains a challenge. Methods: A cross-sectional descriptive study in two Peruvian cities at different altitudes for comparison: Lima and Huaraz. In each place, three groups were formed, made up of 25 [...] Read more.
Background: Despite great scientific efforts, understanding the role of COVID-19 clinical biomarkers remains a challenge. Methods: A cross-sectional descriptive study in two Peruvian cities at different altitudes for comparison: Lima and Huaraz. In each place, three groups were formed, made up of 25 patients with COVID-19 in the ICU, 25 hospitalized patients with COVID-19 who did not require the ICU, and 25 healthy subjects as a control group. Five biomarkers were measured: IL-6, hepcidin, ferritin, C-reactive protein, and zinc using ELISA assays. Results: Ferritin, C-reactive protein, and IL-6 levels were significantly higher in the ICU and non-ICU groups at both study sites. In the case of hepcidin, the levels were significantly higher in the ICU group at both study sites compared to the non-ICU group. Among the groups within each study site, the highest altitude area presented statistically significant differences between its groups in all the markers evaluated. In the lower altitude area, differences were only observed between the groups for the zinc biomarker. Conclusion: COVID-19 patients residing at high altitudes tend to have higher levels of zinc and IL-6 in all groups studied compared to their lower altitude counterparts. Full article
(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago?)
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<p>Statistic comparison of biomarkers by groups according to the altitude of the study site. (<b>a</b>) Ferritin: Mean levels, standard deviation, maximum and minimum levels, and interquartile ranges. (<b>b</b>) Hepcidin: Mean levels, standard deviation, maximum and minimum levels, and interquartile ranges. (<b>c</b>) Zinc: Mean levels, standard deviation, maximum and minimum levels, and interquartile ranges. (<b>d</b>) C-reactive protein (CPR): Mean levels, standard deviation, maximum and minimum levels, and interquartile ranges. (<b>e</b>) IL-6: Mean levels, standard deviation, maximum and minimum levels, and interquartile ranges.</p> Full article ">Figure 2
<p>ROC curve analysis of different predictors of hospital admission in the intensive care unit (ICU) and no-ICU. ROC (receiver operating characteristic).</p> Full article ">
21 pages, 1414 KiB  
Review
Treating Cardiovascular Disease in the Inflammatory Setting of Rheumatoid Arthritis: An Ongoing Challenge
by Saloni Godbole, Jenny Lue Solomon, Maryann Johnson, Ankita Srivastava, Steven E. Carsons, Elise Belilos, Joshua De Leon and Allison B. Reiss
Biomedicines 2024, 12(7), 1608; https://doi.org/10.3390/biomedicines12071608 - 19 Jul 2024
Viewed by 1726
Abstract
Despite progress in treating rheumatoid arthritis, this autoimmune disorder confers an increased risk of developing cardiovascular disease (CVD). Widely used screening protocols and current clinical guidelines are inadequate for the early detection of CVD in persons with rheumatoid arthritis. Traditional CVD risk factors [...] Read more.
Despite progress in treating rheumatoid arthritis, this autoimmune disorder confers an increased risk of developing cardiovascular disease (CVD). Widely used screening protocols and current clinical guidelines are inadequate for the early detection of CVD in persons with rheumatoid arthritis. Traditional CVD risk factors alone cannot be applied because they underestimate CVD risk in rheumatoid arthritis, missing the window of opportunity for prompt intervention to decrease morbidity and mortality. The lipid profile is insufficient to assess CVD risk. This review delves into the connection between systemic inflammation in rheumatoid arthritis and the premature onset of CVD. The shared inflammatory and immunologic pathways between the two diseases that result in subclinical atherosclerosis and disrupted cholesterol homeostasis are examined. The treatment armamentarium for rheumatoid arthritis is summarized, with a particular focus on each medication’s cardiovascular effect, as well as the mechanism of action, risk–benefit profile, safety, and cost. A clinical approach to CVD screening and treatment for rheumatoid arthritis patients is proposed based on the available evidence. The mortality gap between rheumatoid arthritis and non-rheumatoid arthritis populations due to premature CVD represents an urgent research need in the fields of cardiology and rheumatology. Future research areas, including risk assessment tools and novel immunotherapeutic targets, are highlighted. Full article
(This article belongs to the Special Issue Emerging Trends in Lipoprotein and Cardiovascular Diseases)
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<p>Schematic representation of common mechanisms in the pathogenesis of cardiovascular disease and rheumatoid arthritis. Increased levels of pro-inflammatory cytokines are found in the joint space and the systemic circulation. The combination of pro-inflammatory mediators and reduced levels of atheroprotective nitric oxide and IL-10 trigger endothelial dysfunction. Dysfunctional endothelium, poorly functioning pro-inflammatory HDL, highly atherogenic citrullinated LDL, and an altered blood lipid profile contribute to atherosclerosis and thrombosis, which favor accelerated development of cardiovascular disease in patients with rheumatoid arthritis. ↑ = increases; ↓ = decreases; → = progresses to.</p> Full article ">Figure 2
<p>Illustration of the effects of three cytokines, TNF-α, IL-1β, and IFN-γ on the musculoskeletal system (left side) and cardiovascular system (right side).</p> Full article ">
13 pages, 2078 KiB  
Article
Flow Cytometry as a New Accessible Method to Evaluate Diagnostic Osmotic Changes in Patients with Red Blood Cell Membrane Defects
by Asunción Beltrán, María Sánchez-Villalobos, Eduardo Salido, Carmen Algueró, Eulalia Campos, Ana Belén Pérez-Oliva, Miguel Blanquer and José M. Moraleda
Biomedicines 2024, 12(7), 1607; https://doi.org/10.3390/biomedicines12071607 - 19 Jul 2024
Viewed by 1029
Abstract
Hereditary spherocytosis (HS) is a membranopathy that impacts the vertical junctions between the cytoskeleton and the plasma membrane of erythrocytes. The gold standard method for diagnosing it is osmotic gradient ektacytometry (OGE). However, access to this technique is scarce. We have devised a [...] Read more.
Hereditary spherocytosis (HS) is a membranopathy that impacts the vertical junctions between the cytoskeleton and the plasma membrane of erythrocytes. The gold standard method for diagnosing it is osmotic gradient ektacytometry (OGE). However, access to this technique is scarce. We have devised a straightforward approach utilizing flow cytometry to quantify variations in an osmotic gradient, relying on FSC-H/SSC-H patterns. We studied 14 patients (9 pediatric, 5 adults) and 54 healthy controls (16 pediatric, 38 adults). After assessing the behavior of the samples in several osmolar gradients we selected for the study the 176, 308, and 458 mOsm/kg levels as hypo-osmolar, iso-osmolar, and hyper-osmolar references. We then selected the iso-osmolar point for assessment to determine its efficacy in discriminating between patient and control groups using a receiver operating characteristic curve. In the pediatric group, the area under the curve (AUC) was 1.0, indicating 100% sensitivity and 93.3% specificity. Conversely, in the adult group, the AUC was 0.98, with 80% sensitivity and 90.9% specificity. We introduce a method that is easily replicable and demonstrates high sensitivity and specificity. This technique could prove valuable in the diagnosis of spherocytosis. Full article
(This article belongs to the Special Issue Advanced Research in Spherocytosis)
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<p>Distribution of age and gender among patients diagnosed with hereditary spherocytosis (HS).</p> Full article ">Figure 2
<p>The technique operates on a simple principle: a laser beam is directed onto red blood cells within a flow cell. As the cells are subjected to hydrodynamic forces within the flow system, they transition from a resting position to an elliptical shape due to shear force. By analyzing patterns FSC/SSC, we can observe changes in these patterns under constant shear force. The ratio of these two parameters yields the elongation index calculated by flow cytometry (EI-FC = (FSC-H − SSC-H)/(FSC-H + SSC-H)). Graphically, the Y-axis represents the EI-FC, while the X-axis denotes various osmolarities.</p> Full article ">Figure 3
<p>The elongation index by flow cytometry (EI-FC) was assessed in control cohorts comprising healthy adults and children. Peripheral blood samples obtained from a cohort of healthy adults (HA) (<span class="html-italic">n</span> = 38) and healthy children (HC) (<span class="html-italic">n</span> = 16) underwent flow cytometry analysis to assess the FSC/SSC parameters. The Y-axis depicted the EI-FC, whereas the X-axis represented different osmolarities. (<b>A</b>) HA curve of the adults. (<b>B</b>) HC curve of the children.</p> Full article ">Figure 4
<p>Comparison of gradient points with the iso-osmolar point in adult and pediatric control populations (<b>A</b>,<b>B</b>). Each bar represents the cumulative mean of the curve points. Unpaired Kruskal–Wallis tests were applied as needed. ** <span class="html-italic">p</span> &lt; 0.01 and **** <span class="html-italic">p</span> &lt; 0.00001.</p> Full article ">Figure 5
<p>(<b>A</b>) Adult population and (<b>B</b>) pediatric population comparison of means was conducted between the control group (CTL) and the patient group (HS) staging at the osmolality levels of 176, 308, and 458 mOsm/kg. Unpaired Mann–Whitney tests were conducted where applicable (* <span class="html-italic">p</span> &lt; 0.05 and **** <span class="html-italic">p</span> &lt; 0.0001).</p> Full article ">Figure 6
<p>Displays the ROC curve for the data points at 176, 308, and 458 mOsm/Kg. The values obtained from the EI-FC of both patients and controls were compared with the positive and negative results of the EMA binding test in the respective groups.</p> Full article ">Figure 7
<p>Illustrates the osmotic gradients derived from the average values of the adult and pediatric control groups in comparison to the curves observed in patients with HS. (<b>A</b>) Pediatric curve. (<b>B</b>) Adult group curve.</p> Full article ">Figure 8
<p>Correlation between EI-FC (EI-FC HS patients) and hematological parameters.</p> Full article ">
36 pages, 752 KiB  
Review
Diabetes Mellitus in Non-Functioning Adrenal Incidentalomas: Analysis of the Mild Autonomous Cortisol Secretion (MACS) Impact on Glucose Profile
by Alexandra-Ioana Trandafir, Adina Ghemigian, Mihai-Lucian Ciobica, Claudiu Nistor, Maria-Magdalena Gurzun, Tiberiu Vasile Ioan Nistor, Eugenia Petrova and Mara Carsote
Biomedicines 2024, 12(7), 1606; https://doi.org/10.3390/biomedicines12071606 - 18 Jul 2024
Viewed by 1341
Abstract
Non-functioning adrenal incidentalomas (NFAIs) have been placed in relationship with a higher risk of glucose profile anomalies, while the full-blown typical picture of Cushing’s syndrome (CS) and associated secondary (glucocorticoid-induced) diabetes mellitus is not explicitly confirmed in this instance. Our objective was to [...] Read more.
Non-functioning adrenal incidentalomas (NFAIs) have been placed in relationship with a higher risk of glucose profile anomalies, while the full-blown typical picture of Cushing’s syndrome (CS) and associated secondary (glucocorticoid-induced) diabetes mellitus is not explicitly confirmed in this instance. Our objective was to highlight the most recent data concerning the glucose profile, particularly, type 2 diabetes mellitus (T2DM) in NFAIs with/without mild autonomous cortisol secretion (MACS). This was a comprehensive review of the literature; the search was conducted according to various combinations of key terms. We included English-published, original studies across a 5-year window of publication time (from January 2020 until 1 April 2024) on PubMed. We excluded case reports, reviews, studies on T1DM or secondary diabetes, and experimental data. We identified 37 studies of various designs (14 retrospective studies as well 13 cross-sectional, 4 cohorts, 3 prospective, and 2 case–control studies) that analysed 17,391 individuals, with a female-to-male ratio of 1.47 (aged between 14 and 96 years). T2DM prevalence in MACS (affecting 10 to 30% of NFAIs) ranged from 12% to 44%. The highest T2DM prevalence in NFAI was 45.2% in one study. MACS versus (non-MACS) NFAIs (n = 16) showed an increased risk of T2DM and even of prediabetes or higher fasting plasma glucose or HbA1c (no unanimous results). T2DM prevalence was analysed in NFAI (N = 1243, female-to-male ratio of 1.11, mean age of 60.42) versus (non-tumour) controls (N = 1548, female-to-male ratio of 0.91, average age of 60.22) amid four studies, and two of them were confirmatory with respect to a higher rate in NFAIs. Four studies included a sub-group of CS compared to NFAI/MACS, and two of them did not confirm an increased rate of glucose profile anomalies in CS versus NFAIs/ACS. The longest period of follow-up with concern to the glycaemic profile was 10.5 years, and one cohort showed a significant increase in the T2DM rate at 17.9% compared to the baseline value of 0.03%. Additionally, inconsistent data from six studies enrolling 1039 individuals that underwent adrenalectomy (N = 674) and conservative management (N = 365) pinpointed the impact of the surgery in NFAIs. The regulation of the glucose metabolism after adrenalectomy versus baseline versus conservative management (n = 3) was improved. To our knowledge, this comprehensive review included one of the largest recent analyses in the field of glucose profile amid the confirmation of MACS/NFAI. In light of the rising incidence of NFAI/AIs due to easier access to imagery scans and endocrine evaluation across the spectrum of modern medicine, it is critical to assess if these patients have an increased frequency of cardio-metabolic disorders that worsen their overall comorbidity and mortality profile, including via the confirmation of T2DM. Full article
(This article belongs to the Special Issue Neuroendocrine Neoplasia and Endocrine Tumors: Pathogenic Features, Prognostic Markers and New Therapeutic Approaches)
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<p>Flow chart diagram of search and main sections of results according to our methods.</p> Full article ">
15 pages, 1915 KiB  
Review
Exploring Synergistic Effects of Bioprinted Extracellular Vesicles for Skin Regeneration
by Manal Hussein Taghdi, Barathan Muttiah, Alvin Man Lung Chan, Mh Busra Fauzi, Jia Xian Law and Yogeswaran Lokanathan
Biomedicines 2024, 12(7), 1605; https://doi.org/10.3390/biomedicines12071605 - 18 Jul 2024
Viewed by 1147
Abstract
Regenerative medicine represents a paradigm shift in healthcare, aiming to restore tissue and organ function through innovative therapeutic strategies. Among these, bioprinting and extracellular vesicles (EVs) have emerged as promising techniques for tissue rejuvenation. EVs are small lipid membrane particles secreted by cells, [...] Read more.
Regenerative medicine represents a paradigm shift in healthcare, aiming to restore tissue and organ function through innovative therapeutic strategies. Among these, bioprinting and extracellular vesicles (EVs) have emerged as promising techniques for tissue rejuvenation. EVs are small lipid membrane particles secreted by cells, known for their role as potent mediators of intercellular communication through the exchange of proteins, genetic material, and other biological components. The integration of 3D bioprinting technology with EVs offers a novel approach to tissue engineering, enabling the precise deposition of EV-loaded bioinks to construct complex three-dimensional (3D) tissue architectures. Unlike traditional cell-based approaches, bioprinted EVs eliminate the need for live cells, thereby mitigating regulatory and financial obstacles associated with cell therapy. By leveraging the synergistic effects of EVs and bioprinting, researchers aim to enhance the therapeutic outcomes of skin regeneration while addressing current limitations in conventional treatments. This review explores the evolving landscape of bioprinted EVs as a transformative approach for skin regeneration. Furthermore, it discusses the challenges and future directions in harnessing this innovative therapy for clinical applications, emphasizing the need for interdisciplinary collaboration and continued scientific inquiry to unlock its full therapeutic potential. Full article
(This article belongs to the Special Issue Skin Tissue Regeneration and Wound Healing)
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<p>Schematic illustration of intracellular manifestation of the extracellular vesicles (EVs), followed by its categorical size (nm) and its supposed content.</p> Full article ">Figure 2
<p>Schematic illustration of the human skin and its supporting tissues.</p> Full article ">Figure 3
<p>Schematic illustration of the wound healing process.</p> Full article ">Figure 4
<p>Schematic illustration of 3D bioprinted EVs using different GF-enriched or tissue-specific EVs, their wound management, and the potential of imaging and AI-assisted technology.</p> Full article ">
17 pages, 771 KiB  
Review
Impact of Diabetes Mellitus on Outcomes in Patients with Left Ventricular Assist Devices
by William Crugnola, Andrew Cinquina, Daniel Mattimore, Savannah Bitzas, Jonathon Schwartz, Saleem Zaidi and Sergio D. Bergese
Biomedicines 2024, 12(7), 1604; https://doi.org/10.3390/biomedicines12071604 - 18 Jul 2024
Viewed by 1030
Abstract
Heart failure (HF) represents a significant health burden in the United States, resulting in substantial mortality and healthcare costs. Through the array of treatment options available, including lifestyle modifications, medications, and implantable devices, HF management has evolved. Left ventricular assist devices (LVADs) have [...] Read more.
Heart failure (HF) represents a significant health burden in the United States, resulting in substantial mortality and healthcare costs. Through the array of treatment options available, including lifestyle modifications, medications, and implantable devices, HF management has evolved. Left ventricular assist devices (LVADs) have emerged as a crucial intervention, particularly in patients with advanced HF. However, the prevalence of comorbidities such as diabetes mellitus (DM) complicates treatment outcomes. By elucidating the impact of DM on LVAD outcomes, this review aims to inform clinical practice and enhance patient care strategies for individuals undergoing LVAD therapy. Patients with DM have higher rates of hypertension, dyslipidemia, peripheral vascular disease, and renal dysfunction, posing challenges to LVAD management. The macro/microvascular changes that occur in DM can lead to cardiomyopathy and HF. Glycemic control post LVAD implantation is a critical factor affecting patient outcomes. The recent literature has shown significant decreases in hemoglobin A1c following LVAD implantation, representing a possible bidirectional relationship between DM and LVADs; however, the clinical significance of this decrease is unclear. Furthermore, while some studies show increased short- and long-term mortality in patients with DM after LVAD implantation, there still is no literature consensus regarding either mortality or major adverse outcomes in DM patients. Full article
(This article belongs to the Section Cell Biology and Pathology)
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<p>Summary of the relationship between diabetes mellitus (DM), diabetic complications, heart failure (HF), inflammation, glycemic control, and major outcomes/mortality after left ventricular assist device (LVAD) implantation. DM can cause hyperglycemia, leading to cardiac lipotoxicity, the disruption of calcium hemostasis, and atherosclerotic plaques. These changes can cause cardiomyopathy and/or ischemia, leading to HF. Also, HF has been associated with chronic inflammatory changes including endothelial dysfunction, cytokine production, and renin-angiotensin-aldosterone system (RAAS) activation, which can further worsen insulin resistance in a positive feedback loop (indicated by the dashed line). Severe HF may necessitate LVAD implantation. The literature has shown an improvement in glycemic control (as decreased A1c) after LVAD implantation, with increased muscle mass, improved cardiac output and organ perfusion, and/or improved exercise tolerance as potential explanations; however, the long-term clinical impact on diabetic co-morbidities remains unknown (indicated by the question mark). Additionally, there still is no literature consensus (indicated by the black lines with question marks) regarding the impact of DM on all-cause mortality and major adverse outcomes (pump thrombosis, stroke, infection, etc.) after LVAD implantation (question marks in this figure).</p> Full article ">
23 pages, 7098 KiB  
Article
Anti-Microbial Drug Metronidazole Promotes Fracture Healing: Enhancement in the Bone Regenerative Efficacy of the Drug by a Biodegradable Sustained-Release In Situ Gel Formulation
by Shivali Duggal, Shivani Sharma, Nikhil Rai, Divya Chauhan, Vishal Upadhyay, Swati Srivastava, Konica Porwal, Chirag Kulkarni, Arun K. Trivedi, Jiaur R. Gayen, Prabhat R. Mishra, Naibedya Chattopadhyay and Subhashis Pal
Biomedicines 2024, 12(7), 1603; https://doi.org/10.3390/biomedicines12071603 - 18 Jul 2024
Viewed by 1392
Abstract
Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone [...] Read more.
Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures. Full article
(This article belongs to the Special Issue Development of Bone Anabolic Agents and Scaffolds for Improved Fracture Healing)
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<p>Metronidazole (MTZ) has osteogenic activity. (<b>A</b>) rBMSCs and mBMSCs were treated with 1 nM of MTZ in the differentiation medium for 7 days, and ALP activity was measured. BMP-2 (100 ng/mL) was used as a positive control. (<b>B</b>) rBMSCs and mBMSCs were exposed to the vehicle (0.1% DMSO) or MTZ (1 nM) for 24 h, and the proliferation rate was measured by BrdU incorporation by ELISA. (<b>C</b>) Exposing rBMSCs and mBMSCs to MTZ for 21 days in the differentiation medium significantly increased mineralized nodules compared to the vehicle, as assessed by Alizarin Red S staining. Left panel shows representative Alizarin S dye-stained nodules and right panel shows the quantified data after dye extraction by cetylpyridinium chloride (CPC). (<b>D</b>) rBMSCs and mBMSCs treated with 1 nM of MTZ for 24 h resulted in an increase in the mRNA levels of BMP-2 and Runx-2. All values are expressed as mean ± SEM. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001 compared to the vehicle (0.1% DMSO).</p> Full article ">Figure 2
<p>MTZ stimulates the Wnt signaling pathway in osteoblasts. (<b>A</b>) Exposing C3H10T1/2 cells to MTZ for 21 days in the differentiation medium significantly increased mineralized nodules compared to the vehicle, as assessed by Alizarin Red S staining. Left panel shows representative Alizarin S dye-stained nodules and right panel shows the quantified data after dye extraction by CPC. (<b>B</b>) Exposing C3H10T1/2 cells to MTZ (10 nM) increased Runx2 expression. Left panel shows the representative blots and right panel showing the quantification of Runx2 expression from 3 independent experiments. (<b>C</b>) TOP-Flash reporter assay to evaluate the Wnt transactivation by MTZ. (<b>D</b>) Exposing RCO to MTZ (10 nM) showed an early increase in p-GSK levels. Top panel shows the representative blots and bottom panel shows the quantification of p-GSK and GSK expression from 3 independent experiments. (<b>E</b>) Exposing RCO to MTZ (10 nM) increased β-catenin nuclear translocation. Wnt3a was used as a positive control. Top panel shows the representative images and bottom panel shows the quantification of the data. All values are expressed as the mean ± SEM (n = 3). * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001 compared to the vehicle (water) or as indicated.</p> Full article ">Figure 3
<p>MTZ treatment increased new bone formation at the fracture site. (<b>A</b>) Top panel showing representative confocal images (10×) of calcein labeling at the callus site after 12 days of oral dosing of MTZ. Bottom panel showing quantification of the mean intensity of calcein label and bone volume (BV/TV) quantification. (<b>B</b>) Top panel showing representative confocal images (10×) of calcein labeling at the callus site after 12 days of oral dosing with 235 mg/kg MTZ in OVX rats. Bottom panel showing the quantification of the mean intensity of calcein label and bone volume (BV/TV) quantification. All values are expressed as mean ± SEM (n = 6 rats/group). * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001 compared to the vehicle (water).</p> Full article ">Figure 4
<p>MTZ treatment (235 mg/kg) improved trabecular microarchitecture in OVX osteopenic rats. (<b>A</b>) MTZ treatment for 3 months increased bone mineral density (BMD), bone volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) and decreased structure model index (SMI) in femur metaphysis compared to the vehicle (water)-treated animals. (<b>B</b>) MTZ treatment for 3 months improved the tibia metaphysis’s trabecular microarchitecture compared to the vehicle (water)-treated rats. (<b>C</b>) MTZ treatment for 3 months failed to improve L5 trabecular microarchitecture compared to the vehicle-treated rats. (<b>D</b>) Femur head compression showed increase in maximum load-bearing capacity and energy to failure after 3 months of MTZ treatment compared to the vehicle-treated osteopenic rats. All values are expressed as mean ± SEM (n = 8 rats/group). * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001 compared to the vehicle (water) or as indicated.</p> Full article ">Figure 5
<p>MTZ treatment (235 mg/kg) improved trabecular microarchitecture in OVX osteopenic rats via an osteoanabolic mechanism. (<b>A</b>) Upper panel shows a representative image of double calcein labeling. Lower panel indicating quantified mineralized bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR). (<b>B</b>) Serum bone turnover marker analysis demonstrates a significant increase in serum PINP after the MTZ treatment without altering serum CTX-1 compared to the vehicle-treated rats. (<b>C</b>) Bone mRNA data analysis reveals a significant increase in Runx2 and BMP2 expression in MTZ-treated bones, without altering TRAP expression compared to the vehicle-treated rats. All values are expressed as mean ± SEM (n = 3–6 rats/group). ns, <span class="html-italic">p</span> &gt; 0.05, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001 compared to the vehicle (water) or as indicated.</p> Full article ">Figure 6
<p>Characterization of the biodegradable PLGA-based in situ gel formulation of 40 mg MTZ. (<b>A</b>) Particle size distribution of in situ gel nanoparticle of MTZ. The average globular size and PDI of MTZ@In situ gel were found to be 164 d.nm and 0.297, respectively. (<b>B</b>) Scanning electron microscope (SEM) image of the PLGA-based in situ gel formulation of MTZ. (<b>a</b>). Liquid state. (<b>b</b>). Dried state. (<b>C</b>) FTIR spectra of MTZ, PLGA, NMP, and MTZ@In situ gel formulation. (<b>D</b>) In vitro cumulative drug release vs. time plot for free drug (MTZ) and MTZ@In situ gel formulation in PBS. Data are represented as the mean ± SD.</p> Full article ">Figure 7
<p>Comparative PK profiles after a single administration of MTZ and the MTZ@In situ gel at 40 mg/rat (n = 4). Data are represented as the mean ± SD.</p> Full article ">Figure 8
<p>MTZ@In situ gel formulation improved MTZ dose efficacy. (<b>A</b>) Representative image shows calcein-labeled image of the fracture site after 12 days of MTZ treatment (MTZ@In situ gel of MTZ and unformulated MTZ) at a dose of 40 mg/rat. (<b>B</b>) Quantification data of calcein-labeled newly formed bone at the fracture site after the treatment with the MTZ@In situ gel and unformulated MTZ. (<b>C</b>) Callus volume at the fracture site was quantified by µCT after 12 days of the indicated treatments. All values are expressed as the mean ± SEM (n = 6 rats/group). ns, <span class="html-italic">p</span> &gt; 0.05 and *** <span class="html-italic">p</span> &lt; 0.001 compared to the vehicle (water or MTZ vehicle) or as indicated.</p> Full article ">
18 pages, 1668 KiB  
Review
Cardiomyopathy and Sudden Cardiac Death: Bridging Clinical Practice with Cutting-Edge Research
by Raffaella Mistrulli, Armando Ferrera, Luigi Salerno, Federico Vannini, Leonardo Guida, Sara Corradetti, Lucio Addeo, Stefano Valcher, Giuseppe Di Gioia, Francesco Raffaele Spera, Giuliano Tocci and Emanuele Barbato
Biomedicines 2024, 12(7), 1602; https://doi.org/10.3390/biomedicines12071602 - 18 Jul 2024
Cited by 1 | Viewed by 1604
Abstract
Sudden cardiac death (SCD) prevention in cardiomyopathies such as hypertrophic (HCM), dilated (DCM), non-dilated left ventricular (NDLCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) remains a crucial but complex clinical challenge, especially among younger populations. Accurate risk stratification is hampered by the variability in [...] Read more.
Sudden cardiac death (SCD) prevention in cardiomyopathies such as hypertrophic (HCM), dilated (DCM), non-dilated left ventricular (NDLCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) remains a crucial but complex clinical challenge, especially among younger populations. Accurate risk stratification is hampered by the variability in phenotypic expression and genetic heterogeneity inherent in these conditions. This article explores the multifaceted strategies for preventing SCD across a spectrum of cardiomyopathies and emphasizes the integration of clinical evaluations, genetic insights, and advanced imaging techniques such as cardiac magnetic resonance (CMR) in assessing SCD risks. Advanced imaging, particularly CMR, not only enhances our understanding of myocardial architecture but also serves as a cornerstone for identifying at-risk patients. The integration of new research findings with current practices is essential for advancing patient care and improving survival rates among those at the highest risk of SCD. This review calls for ongoing research to refine risk stratification models and enhance the predictive accuracy of both clinical and imaging techniques in the management of cardiomyopathies. Full article
(This article belongs to the Special Issue Pathogenesis, Diagnosis and Treatment of Cardiomyopathy and Cardiac Arrhythmias)
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<p>Comparison between European and American guidelines for SCD prevention in HCM patients. CMR: cardiac magnetic resonance; EF: ejection fraction; FH: family history of sudden cardiac death; LVH: left ventricular hypertrophy; LGE: late gadolinium enhancement; and NSVT: non-sustained ventricular tachycardia.</p> Full article ">Figure 2
<p>Established and emerging risk factors for sudden cardiac death in dilated cardiomyopathy. LMNA, lamin A/C; DSP, desmoplakin; PLN, phospholamban; FLNC, filamin C; RBM20, RNA-binding motif protein 20; DES, desmin; TTN, titin; LGE, late gadolinium enhancement; ECG, electrocardiogram; NSVT: non-sustained ventricular tachycardia; VE, premature ventricular complexes; PES, programmed electrical stimulation; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; and SCD, sudden cardiac death.</p> Full article ">Figure 3
<p>Established and emerging risk factors for sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy. DSP, desmoplakin; TMEM43, transmembrane protein 43; LMNA, lamin A/C; PLN, phospholamban; CMR, cardiac magnetic resonance; LV, left ventricular; RV, right ventricular; ECG, electrocardiogram; NSVT; non-sustained ventricular tachycardia; VE, premature ventricular complexes; VT, ventricular tachycardia; and PES, programmed electrical stimulation.</p> Full article ">Figure 4
<p>Overlapping genetic background in cardiomyopathies. * The list is not exhaustive. ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; DES, desmin; DSG, desmoglein; DSP, desmoplakin; FLNC, filamin C; JUP, plakoglobin; LMNA, lamin A/C; NDLVC, non-dilated left ventricular cardiomyopathy; PKP, plakophilin; PLN, phospholamban; TMEM43, transmembrane protein 43; RBM20, RNA-binding motif protein 20; and SCN5A, sodium channel protein type 5.</p> Full article ">
16 pages, 6019 KiB  
Article
Diet and the Gut Microbiome as Determinants Modulating Metabolic Outcomes in Young Obese Adults
by Elena N. Livantsova, Georgy E. Leonov, Antonina V. Starodubova, Yurgita R. Varaeva, Aleksey A. Vatlin, Stanislav I. Koshechkin, Tatyana N. Korotkova and Dmitry B. Nikityuk
Biomedicines 2024, 12(7), 1601; https://doi.org/10.3390/biomedicines12071601 - 18 Jul 2024
Cited by 1 | Viewed by 1714
Abstract
Obesity, along with metabolic disorders such as dyslipidemia and insulin resistance, increases the risk of cardiovascular disease, diabetes, various cancers, and other non-communicable diseases, thereby contributing to higher mortality rates. The intestinal microbiome plays a crucial role in maintaining homeostasis and influencing human [...] Read more.
Obesity, along with metabolic disorders such as dyslipidemia and insulin resistance, increases the risk of cardiovascular disease, diabetes, various cancers, and other non-communicable diseases, thereby contributing to higher mortality rates. The intestinal microbiome plays a crucial role in maintaining homeostasis and influencing human metabolism. This study enrolled 82 young obese individuals, who were stratified into groups with or without metabolic disturbances. No significant differences in the alpha or beta diversity of the microbiota were observed among the groups. Insulin resistance was characterized by an increase in the number of Adlercreutzia and Dialister as well as a decrease in Collinsella, Coprococcus and Clostridiales. The dyslipidemia and dyslipidemia+insulin resistance groups had no significant differences in the gut microbiota. Dietary patterns also influenced microbial composition, with high protein intake increasing Leuconostoc and Akkermansia, and high fiber intake boosting Lactobacillus and Streptococcus. The genus Erwinia was associated with increases in visceral fat and serum glucose as well as a decrease in high-density lipoprotein cholesterol. Our findings highlight a significant association between gut microbiota composition and metabolic disturbances in young obese individuals, and they suggest that dietary modifications may promote a healthy microbiome and reduce the risk of developing metabolic disorders. Full article
(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development)
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<p>Flowchart visualizing participant recruitment. A total of 82 participants were enrolled in the study. Individuals were stratified into groups with or without dyslipidemia (DLD), insulin resistance (IR), and the combination (DLD-IR).</p> Full article ">Figure 2
<p>Summary of relative daily macronutrient contribution (% energy) in the study groups (<b>a</b>). Measured differences in daily intake (g/day) of nutrients among different groups. Data are presented as median and interquartile range (<b>b</b>). * <span class="html-italic">p</span> ≤ 0.05.</p> Full article ">Figure 3
<p>Gut microbiota composition. The average relative abundance of the 5 most abundant phyla showed a high prevalence of <span class="html-italic">Firmicutes</span> and a reduced number of the remaining phyla (<b>a</b>). The composition of the average relative abundance of the 20 most represented genera (<b>b</b>).</p> Full article ">Figure 4
<p>Comparative analysis of gut microbiota in the DLD (+/−), IR (+/−) and DLD-IR (+/−) groups. Alpha diversity was assessed using several metrics: Chao1 index (<b>a</b>), Shannon index (<b>b</b>) (ns: not significant). Beta diversity of bacteria identified with the principal coordinates analysis (PCoA) using Unifrac distances measures (<b>c</b>). To assess statistical differences between groups, a permutation test was used and log2FC was calculated. log2FC &lt; 0 means that this taxon is more presented in IR (+) patients, log2FC &gt; 0 means that the taxon is more presented in IR (−) patients. Significant intergroup changes were identified at the genus and species level. log2FC was calculated for each significantly different taxon (<span class="html-italic">p</span>-value &lt; 0.05) (<b>d</b>).</p> Full article ">Figure 5
<p>Heatmap analysis of association between gut bacterial taxa and body composition (<b>a</b>), serum glucose and lipids (<b>b</b>). Interactions between bacteria at the genus level associated with changes in BMI/fat mass, lipids, and glucose metabolism (<b>c</b>). * <span class="html-italic">p</span> ≤ 0.05.</p> Full article ">Figure 6
<p>Pearson correlation between the relative abundance of gut bacteria (at the genus and species level) and dietary macronutrient intake (<b>a</b>). Crossover between microorganisms that have been associated with the Western-style diet, insulin resistance, dyslipidemia and obesity in this study (<b>b</b>). * <span class="html-italic">p</span> ≤ 0.05.</p> Full article ">
11 pages, 1715 KiB  
Article
Nocturnal Glucose Profile According to Timing of Dinner Rapid Insulin and Basal and Rapid Insulin Type: An Insulclock® Connected Insulin Cap-Based Real-World Study
by Fernando Gómez-Peralta, Xoan Valledor, Cristina Abreu, Elsa Fernández-Rubio, Laura Cotovad, Pedro Pujante, Sharona Azriel, Jesús Pérez-González, Alba Vallejo, Luis Ruiz-Valdepeñas and Rosa Corcoy
Biomedicines 2024, 12(7), 1600; https://doi.org/10.3390/biomedicines12071600 - 18 Jul 2024
Viewed by 783
Abstract
Background: A study to assess the glucose levels of people with type 1 diabetes (T1D) overnight, based on the insulin type and timing. Methods: A real-world, retrospective study of T1D, using multiple daily insulin injections. Continuous glucose monitoring and insulin injection data were [...] Read more.
Background: A study to assess the glucose levels of people with type 1 diabetes (T1D) overnight, based on the insulin type and timing. Methods: A real-world, retrospective study of T1D, using multiple daily insulin injections. Continuous glucose monitoring and insulin injection data were collected for ten hours after dinner using the Insulclock® connected cap. Meal events were identified using the ROC detection methodology. The timing of the rapid insulin, second injections, and the type of insulin analogs used, were evaluated. Results: The nocturnal profiles (n = 775, 49 subjects) were analyzed. A higher glucose AUC of over 180 mg/dL was observed in subjects with delayed injections (number; %; mg/dL × h): −45–15 min (n = 136; 17.5%, 175.9 ± 271.0); −15–0 min (n = 231; 29.8%, 164.0 ± 2 37.1); 0 + 45 min (n = 408; 52.6%, 203.6 ± 260.9), (p = 0.049). The use of ultrarapid insulin (FiAsp®) (URI) vs. rapid insulin (RI) analogs was associated with less hypoglycemia events (7.1 vs. 13.6%; p = 0.005) and TBR70 (1.7 ± 6.9 vs. 4.6 ± 13.9%; p = 0.003). Users of glargine U300 vs. degludec had a higher TIR (70.7 vs. 58.5%) (adjusted R-squared: 0.22, p < 0.001). The use of a correction injection (n = 144, 18.6%) was associated with a higher number of hypoglycemia events (18.1 vs. 9.5%; p = 0.003), TBR70 (5.5 ± 14.2 vs. 3.0 ± 11.1%; p = 0.003), a glucose AUC of over 180 mg/dL (226.1 ± 257.8 vs. 178.0 ± 255.3 mg/dL × h; p = 0.001), and a lower TIR (56.0 ± 27.4 vs. 62.7 ± 29.6 mg/dL × h; p = 0.004). Conclusion: The dinner rapid insulin timing, insulin type, and the use of correction injections affect the nocturnal glucose profile in T1D. Full article
(This article belongs to the Special Issue New Advances in Insulin—100 Years since Its Discovery)
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Full article ">Figure 1
<p>Nighttime glucose dynamics depending on the rapid insulin injection time.</p> Full article ">Figure 2
<p>Nighttime glucose AUC of over 180 mg/dL [10 mmol/L] depending on the rapid insulin injection time.</p> Full article ">Figure 3
<p>Time below the range of glucose 70 mg/dL (3.9 mmol/L) (TBR70) according to the use of ultrarapid insulin (URI) vs. rapid insulin (RI) analogs.</p> Full article ">Figure 4
<p>Nighttime glucose dynamics depending on the second-generation basal insulin type used (degludec vs. glargine U300).</p> Full article ">
17 pages, 1349 KiB  
Article
Evaluation of Patellar Tendon Structural Changes following Biological Treatments: Secondary Analysis of Double-Blinded Clinical Trial of Bone Marrow Mesenchymal Stromal Cells and Leukocyte-Poor Platelet-Rich Plasma
by Silvia Ortega-Cebrián, Robert Soler-Rich, Lluis Orozco and Gil Rodas
Biomedicines 2024, 12(7), 1599; https://doi.org/10.3390/biomedicines12071599 - 18 Jul 2024
Viewed by 990
Abstract
Objective quantification of tendon structural changes through imaging is only achieved by evaluating tendon structure using ultrasound tissue characterization (UTC) technology. This study compares the effects of bone marrow mesenchymal stromal cells (BM-MSC) and leukocyte-poor platelet-rich plasma (Lp-PRP) on tendon structure and clinical [...] Read more.
Objective quantification of tendon structural changes through imaging is only achieved by evaluating tendon structure using ultrasound tissue characterization (UTC) technology. This study compares the effects of bone marrow mesenchymal stromal cells (BM-MSC) and leukocyte-poor platelet-rich plasma (Lp-PRP) on tendon structure and clinical outcomes in male patients with patellar tendinopathy measured with UTC at 3, 6, and 12 months after treatment. This is a double-blinded clinical trial with a randomized active control study with 20 male patients diagnosed with patellar tendinopathy who underwent BM-MSC and Lp-PRP. Bilateral ultrasound tissue characterization scans of the patellar tendon were carried out after 3, 6, and 12 months, as well as tests for strength and pain. UTC patellar tendon was analyzed at the insertion, proximal, and mid-tendon. BM-MSC showed a greater capacity to promote further positive changes than Lp-PRP. Lp-PRP presented higher disorganized echo-type II in the mid-tendon (p = 0.04; ES = 1.06) and III (p = 0.02; ES = −1.47) after 3 months in the Lp-PRP group. Similar results were seen after 6 and 12 months. Pain and strength data show improvement in the treated tendon. BM-MSC treatment demonstrates a superior capacity to promote tendon regeneration and organization, restore strength, and reduce pain compared to Lp-PRP, after 3, 6, and 12 months in male patients with patellar tendinopathy. Full article
(This article belongs to the Special Issue Recent Advances in Arthritis and Tendinopathy)
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<p>Ultrasound tissue characterization of the proximal tendon. Resection of the crossed sectional area at 20% tendon length. Color green, blue, red and black correspond to echo-type I, II, III, and IV respectively.</p> Full article ">Figure 2
<p>Tendon structural changes of echo-type I–IV at 3, 6, and 12 months after BM-MSC, Lp-PRP, and phase B-BM-MSC of the symptomatic and asymptomatic tendon at the insertional, proximal, and mid-tendon area (mean, 95% IC).</p> Full article ">
12 pages, 2412 KiB  
Article
Diagnoses and Treatment Recommendations—Interrater Reliability of Uroflowmetry in People with Multiple Sclerosis
by Anke K. Jaekel, Julia Rieger, Anna-Lena Butscher, Sandra Möhr, Oliver Schindler, Fabian Queissert, Aybike Hofmann, Paul Schmidt, Ruth Kirschner-Hermanns and Stephanie C. Knüpfer
Biomedicines 2024, 12(7), 1598; https://doi.org/10.3390/biomedicines12071598 - 18 Jul 2024
Viewed by 834
Abstract
Background: Uroflowmetry (UF) is an established procedure in urology and is recommended before further investigations of neurogenic lower urinary tract dysfunction (NLUTD). Some authors even consider using UF instead of urodynamics (UD). Studies on the interrater reliability of UF regarding treatment recommendations are [...] Read more.
Background: Uroflowmetry (UF) is an established procedure in urology and is recommended before further investigations of neurogenic lower urinary tract dysfunction (NLUTD). Some authors even consider using UF instead of urodynamics (UD). Studies on the interrater reliability of UF regarding treatment recommendations are rare, and there are no relevant data on people with multiple sclerosis (PwMS). The aim of this study was to investigate the interrater reliability (IRR) of UF concerning diagnosis and therapy in PwMS prospectively. Methods: UF of 92 PwMS were assessed by 4 raters. The diagnostic criteria were normal findings (NFs), detrusor overactivity (DO), detrusor underactivity (DU), detrusor–sphincter dyssynergia (DSD) and bladder outlet obstruction (BOO). The possible treatment criteria were as follows: no treatment (NO), catheter placement (CAT), alpha-blockers, detrusor-attenuating medication, botulinum toxin (BTX), neuromodulation (NM), and physiotherapy/biofeedback (P/BF). IRR was assessed by kappa (κ). Results: κ of diagnoses were NFs = 0.22; DO = 0.17; DU = 0.07; DSD = 0.14; and BOO = 0.18. For therapies, the highest κ was BTX = 0.71, NO = 0.38 and CAT = 0.44. Conclusions: There is a high influence of the individual rater. UD should be subject to the same analysis and a comparison should be made between UD and UF. This may have implications for the value of UF in the neuro-urological management of PwMS, although at present UD remains the gold standard for the diagnostics of NLUTD in PwMS. Full article
(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Advances in Multiple Sclerosis)
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<p>Visualisation of the potential answers on the evaluation form. “+/−“—a combination of both single choices is optional, but not mandatory.</p> Full article ">Figure 2
<p>Interrater reliability of single suspected diagnoses from anamnesis and bladder diary between the raters paired and overall.</p> Full article ">Figure 3
<p>Interrater reliability of all suspected diagnoses from anamnesis and bladder diary between the raters paired and overall.</p> Full article ">Figure 4
<p>Interrater reliability of the single suspected diagnoses between the paired raters and overall (analysis B-1).</p> Full article ">Figure 5
<p>Interrater reliability of the single therapy suggestions between the raters paired and overall.</p> Full article ">
15 pages, 754 KiB  
Review
Anti-B-Cell-Activating Factor (BAFF) Therapy: A Novel Addition to Autoimmune Disease Management and Potential for Immunomodulatory Therapy in Warm Autoimmune Hemolytic Anemia
by Mahija Cheekati and Irina Murakhovskaya
Biomedicines 2024, 12(7), 1597; https://doi.org/10.3390/biomedicines12071597 - 18 Jul 2024
Viewed by 1883
Abstract
Although rituximab is not specifically approved for the treatment of warm autoimmune hemolytic anemia (WAIHA), the First International Consensus Group recommends considering its use as part of the initial therapy for patients with severe disease and as a second-line therapy for primary WAIHA. [...] Read more.
Although rituximab is not specifically approved for the treatment of warm autoimmune hemolytic anemia (WAIHA), the First International Consensus Group recommends considering its use as part of the initial therapy for patients with severe disease and as a second-line therapy for primary WAIHA. Some patients do not respond to rituximab, and relapses are common. These relapses are associated with elevated B-cell-activating factor (BAFF) levels and the presence of quiescent long-lived plasma cells (LLPCs) in the spleen. A new group of immunomodulatory drugs, B-cell-activating factor inhibitors (BAFF-i), demonstrated efficacy in multiple autoimmune diseases and have the potential to improve WAIHA treatment outcomes by targeting B-cells and LLPCs. This article reviews the role of BAFF in autoimmune disorders and the currently available literature on the use of BAFF-directed therapies in various immunologic disorders, including WAIHA. Collectively, the clinical data thus far shows robust potential for targeting BAFF in WAIHA therapy. Full article
(This article belongs to the Special Issue Autoimmune Diseases and Immune Modulation: Current Research and Future Outlook)
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<p>Anti-BAFF agents’ mechanisms of action.</p> Full article ">
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