Biomedicines

13 pages, 1649 KiB

Open AccessArticle

Comparison of Inflammatory Biomarkers in Females with and Without Patellofemoral Pain and Associations with Patella Position, Hip and Knee Kinematics, and Pain

by Lori A. Bolgla, Sharad Purohit, Daniel C. Hannah and David Monte Hunter

Biomedicines 2025, 13(3), 761; https://doi.org/10.3390/biomedicines13030761 - 20 Mar 2025

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Abstract

Background/Objectives: Patellofemoral pain (PFP) is believed to be a precursor to knee osteoarthritis (OA). The primary purpose of this study was to compare matrix metalloproteinase-9 (MMP-9) levels in young adult females with and without PFP. The secondary purpose was to determine the [...] Read more.

Background/Objectives: Patellofemoral pain (PFP) is believed to be a precursor to knee osteoarthritis (OA). The primary purpose of this study was to compare matrix metalloproteinase-9 (MMP-9) levels in young adult females with and without PFP. The secondary purpose was to determine the associations between MMP-9, patella position, hip and knee kinematics, and pain in females with PFP. Methods: Plasma was analyzed for MMP-9. Patellar position was measured using diagnostic ultrasound as the degree of offset (RAB angle) from the deepest aspect of the femoral trochlear groove to the inferior pole of the patella. A positive RAB angle suggested patella lateralization. Hip and knee kinematics during a single-leg squat were measured using 2-dimensional motion analysis and quantified as the dynamic valgus index (DVI), a combined measure of hip and knee motion. A higher DVI suggests increased valgus loading at the patellofemoral joint. Pain was measured using a 10 cm visual analog scale. Results: Females with PFP had significantly higher levels of MMP-9 than controls (72.7 vs. 58.0 ng/mL, p = 0.03). Females with PFP had a significant positive association between MMP-9 and patella lateralization (r = 0.38, p = 0.04), suggesting that greater patellar lateralization may contribute to increased joint inflammation. A significant inverse association was observed between MMP-9 and the DVI (r = −0.50, p = 0.007), indicating that individuals with higher inflammatory marker levels may adopt movement patterns that reduce valgus loading. Conclusions: The significant association between MMP-9 and patella lateralization suggested a potential link between patella alignment and joint inflammation, which may contribute to early joint degeneration. The inverse association between MMP-9 levels and the DVI suggested that subjects with higher MMP-9 levels adjusted their movement pattern as a compensatory mechanism to reduce knee valgus stress to reduce joint degeneration. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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12 pages, 765 KiB

Open AccessArticle

The Hospital Frailty Risk Score as a Predictor of Mortality, Complications, and Resource Utilization in Heart Failure: Implications for Managing Critically Ill Patients

by Nahush Bansal, Eun Seo Kwak, Abdel-Rhman Mohamed, Vaishnavi Aradhyula, Mohanad Qwaider, Alborz Sherafati, Ragheb Assaly and Ehab Eltahawy

Biomedicines 2025, 13(3), 760; https://doi.org/10.3390/biomedicines13030760 - 20 Mar 2025

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Abstract

Background: Frailty, with a high prevalence of 40–80% in heart failure, may have a significant bearing on outcomes in patients. This study utilizes the Hospital Frailty Risk Score (HFRS), a validated tool derived from the administrative International Classification of Diseases, 10th Revision, Clinical [...] Read more.

Background: Frailty, with a high prevalence of 40–80% in heart failure, may have a significant bearing on outcomes in patients. This study utilizes the Hospital Frailty Risk Score (HFRS), a validated tool derived from the administrative International Classification of Diseases, 10th Revision, Clinical Modifications (ICD-10-CM) codes, in investigating the mortality, morbidity, and healthcare resource utilization among heart failure hospitalizations using the Nationwide Inpatient Sample (NIS). Methods: A retrospective analysis of the 2021 NIS database was assessed to identify adult patients hospitalized with heart failure. These patients were stratified by the HFRS into three groups: low frailty (LF: <5), intermediate frailty (IF: 5–15), and high frailty (HF: >15). The outcomes analyzed included inpatient mortality, length of stay (LOS), hospitalization charges, and complications including cardiogenic shock, cardiac arrest, acute kidney injury, and acute respiratory failure. These outcomes were adjusted for age, race, gender, the Charlson comorbidity score, hospital location, region, and teaching status. Multivariate logistic and linear regression analyses were used to assess the association between frailty and clinical outcomes. STATA/MP 18.0 was used for statistical analysis. Results: Among 1,198,988 heart failure admissions, 47.5% patients were in the LF group, whereas the IF and HF groups had 51.1% and 1.4% patients, respectively. Compared to the LF group, the IF group showed a 4-fold higher (adjusted OR = 4.60, p < 0.01), and the HF group had an 11-fold higher (adjusted OR 10.90, p < 0.01) mortality. Frail patients were more likely to have a longer length of stay (4.24 days, 7.18 days, and 12.1 days in the LF, IF, and HF groups) and higher hospitalization charges (USD 49,081, USD 84,472, and USD 129,516 in the LF, IF, and HF groups). Complications were also noticed to be significantly (p < 0.01) higher with increasing frailty from the LF to HF groups. These included cardiogenic shock (1.65% vs. 4.78% vs. 6.82%), cardiac arrest (0.37% vs. 1.61% vs. 3.16%), acute kidney injury (19.2% vs. 54.9% vs. 74.6%), and acute respiratory failure (29.6% vs. 51.2% vs. 60.3%). Conclusions: This study demonstrates the application of HFRS in a national dataset as a predictor of outcome and resource utilization measures in heart failure admissions. Stratifying patients based on HFRS can help in holistic assessment, aid prognostication, and guide targeted interventions in heart failure. Full article

(This article belongs to the Special Issue The Treatment of Cardiovascular Diseases in the Critically Ill)

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20 pages, 769 KiB

Open AccessReview

Navigating Glioma Complexity: The Role of Abnormal Signaling Pathways in Shaping Future Therapies

by Qiang Chen, Jin Jin, Pian Li, Xiuping Wang and Qianyan Wang

Biomedicines 2025, 13(3), 759; https://doi.org/10.3390/biomedicines13030759 - 20 Mar 2025

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Abstract

Gliomas are a type of highly heterogeneous and invasive central nervous system tumor. Traditional treatment methods have limited efficacy, and the prognosis for patients remains poor. Recent studies have revealed the crucial roles of several abnormal signaling pathways in the pathogenesis of gliomas, [...] Read more.

Gliomas are a type of highly heterogeneous and invasive central nervous system tumor. Traditional treatment methods have limited efficacy, and the prognosis for patients remains poor. Recent studies have revealed the crucial roles of several abnormal signaling pathways in the pathogenesis of gliomas, including the Receptor Tyrosine Kinase/Rat Sarcoma Virus Oncogene/Phosphatidylinositol-3-Kinase (RTK/RAS/PI3K) pathway, the Wingless-Related Integration Site/β-Catenin (Wnt/β-Catenin) pathway, the Hippo/YAP (Hippo/Yes-associated protein) pathway, and the Slit/Robo (Slit Guidance Ligands/Roundabout) signaling pathway. These pathways play extremely vital roles in tumor proliferation, invasion, and treatment resistance. This article comprehensively and systematically reviews the molecular mechanisms of these signaling pathways, deeply summarizing the research progress of various treatment strategies, including targeted inhibitors, gene therapy, and nanomedicine against them. Moreover, the combination of targeted therapy and personalized treatment regimens is expected to overcome the current treatment bottleneck and provide a more favorable survival prognosis for glioblastoma patients. Full article

(This article belongs to the Special Issue Gliomas: Signaling Pathways, Molecular Mechanisms and Novel Therapies (2nd Edition))

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18 pages, 1667 KiB

Open AccessConference Report

Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence

by Jimi Olaghere, David A. Williams, Jeremy Farrar, Hildegard Büning, Cecelia Calhoun, Tony Ho, Maneesha S. Inamdar, David Liu, Julie Makani, Kwasi Nyarko, Sol Ruiz, John Tisdale, Joseph M. McCune, Esther Boadi and Reagan-Udall Foundation for the FDA

Biomedicines 2025, 13(3), 758; https://doi.org/10.3390/biomedicines13030758 - 20 Mar 2025

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Abstract

On 4 September 2024, the Reagan-Udall Foundation for the FDA (FDA Foundation) in collaboration with the Food and Drug Administration (FDA) and the Gates Foundation hosted a workshop titled “Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence”. The event brought together [...] Read more.

On 4 September 2024, the Reagan-Udall Foundation for the FDA (FDA Foundation) in collaboration with the Food and Drug Administration (FDA) and the Gates Foundation hosted a workshop titled “Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence”. The event brought together a diverse group of experts, including international regulatory bodies, regulated industries, healthcare professionals, patients, academic researchers and global health advocates, to discuss the rapid advancements in gene therapy and the pressing need for equitable access in low-and middle-income countries (LMICs), with sickle cell disease (SCD) serving as the model disorder for the discussions. Although there has been significant progress in gene therapy, such as breakthroughs in clustered regularly interspaced short palindromic repeats (CRISPR)-based technologies and FDA-approved therapies, access to these therapies remain limited in underresourced regions. The workshop addressed critical challenges, including the high cost of therapies, regulatory gaps and barriers and ethical concerns regarding informed consent and public engagement in LMICs. This paper highlights the critical discussion points from the workshop with a focus on exploring strategies for global regulatory convergence, the role of international collaborations and the potential pathways to making gene therapies affordable and accessible to all. Full article

(This article belongs to the Section Gene and Cell Therapy)

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27 pages, 3323 KiB

Open AccessArticle

Inhibition of the Renin–Angiotensin System Improves Hemodynamic Function of the Diabetic Rat Heart by Restoring Intracellular Calcium Regulation

by Krisztina Anna Paulik, Tamás Ivanics, Gábor A. Dunay, Ágnes Fülöp, Margit Kerék, Klára Takács, Zoltán Benyó and Zsuzsanna Miklós

Biomedicines 2025, 13(3), 757; https://doi.org/10.3390/biomedicines13030757 - 20 Mar 2025

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Abstract

Background/Objectives: Disrupted intracellular calcium (Ca²⁺_i) regulation and renin–angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: [...] Read more.

Background/Objectives: Disrupted intracellular calcium (Ca²⁺_i) regulation and renin–angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: Experiments were conducted on T1D and T2D Sprague-Dawley rats induced by streptozotocin and fructose-rich diet, respectively. In T1D, rats were treated with Enalapril (Ena) or Losartan (Los) for six weeks, whereas T2D animals received high-dose (HD) or low-dose (LD) Ena for 8 weeks. Heart function was assessed via echocardiography, Ca²⁺_i transients by Indo-1 fluorometry in Langendorff-perfused hearts, and key Ca²⁺_i cycling proteins by Western blot. Data: mean ± SD. Results: Diabetic hearts exhibited reduced contractile performance that was improved by RAS inhibition both in vivo (ejection fraction (%): T1D model: Control: 79 ± 7, T1D: 54 ± 11, T1D + Ena: 65 ± 10, T1D + Los: 69 ± 10, n = 18, 18, 15, 10; T2D model: Control: 73 ± 8, T2D: 52 ± 6, T2D + LDEna: 62 ± 8, T2D + HDEna: 76 ± 8, n = 9, 8, 6, 7) and ex vivo (+dPressure/dt_max (mmHg/s): T1D model: Control: 2532 ± 341, T1D: 2192 ± 208, T1D + Ena: 2523 ± 485, T1D + Los: 2643 ± 455; T2D model: Control: 2514 ± 197, T2D: 1930 ± 291, T2D + LDEna: 2311 ± 289, T2D + HDEna: 2614 ± 268). Analysis of Ca²⁺_i transients showed impaired Ca²⁺_i release and removal dynamics and increased diastolic Ca²⁺_i levels in both models that were restored by Ena and Los treatments. We observed a decrease in sarcoendoplasmic reticulum Ca²⁺-ATPase2a (SERCA2a) expression, accompanied by a compensatory increase in 16Ser-phosphorylated phospholamban (P-PLB) in T2D that was prevented by both LD and HD Ena (expression level (% of Control): SERCA2a: T2D: 36 ± 32, T2D + LDEna: 112 ± 32, T2D + HDEna: 106 ± 30; P-PLB: T2D: 557 ± 156, T2D + LDEna: 129 ± 38, T2D + HDEna: 108 ± 42; n = 4, 4, 4). Conclusions: The study highlights the critical role of RAS activation, most likely occurring at the tissue level, in disrupting Ca²⁺_i homeostasis in diabetic cardiomyopathy. RAS inhibition with Ena or Los mitigates these disturbances independent of blood pressure effects, underlining their importance in managing diabetic heart failure. Full article

(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology, 2nd Edition)

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18 pages, 5609 KiB

Open AccessArticle

Molecular Genetic Architecture of Morbid Obesity in Russian Children

by Ildar R. Minniakhmetov, Rita I. Khusainova, Olga V. Vasyukova, Daria A. Kopytina, Bulat I. Yalaev, Ramil R. Salakhov, Raisat M. Guseynova, Valentina A. Peterkova and Natalia G. Mokrysheva

Biomedicines 2025, 13(3), 756; https://doi.org/10.3390/biomedicines13030756 - 20 Mar 2025

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Abstract

Background: Over the past few decades, the prevalence of obesity has significantly increased worldwide, particularly among children. This trend represents a global health challenge. Considering the pivotal role of obesity in the development of metabolic disorders, the identification and characterization of pathogenic [...] Read more.

Background: Over the past few decades, the prevalence of obesity has significantly increased worldwide, particularly among children. This trend represents a global health challenge. Considering the pivotal role of obesity in the development of metabolic disorders, the identification and characterization of pathogenic gene variants in children with severe forms of obesity are key priorities in fundamental endocrinology. Methods: We performed whole-exome sequencing (WES) in 163 Russian children with morbid obesity and identified 96 pathogenic or likely pathogenic variants in 61 genes. These variants were clinically significant in 64 children (38.79% of the cohort). Results: Notably, 42 of the identified variants have not been previously described in the literature or reported in existing databases. Conclusions: The findings of this study will enable a more personalized approach to the diagnosis and treatment of patients with syndromic and polygenic forms of obesity. Moreover, these results advance our understanding of the genetic architecture of obesity in the Russian population. Full article

(This article belongs to the Special Issue Molecular Research in Obesity, 2nd Edition)

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17 pages, 3412 KiB

Open AccessHypothesis

Ethanol Induces Craniofacial Defects in Bmp Mutants Independent of nkx2.3 by Elevating Cranial Neural Crest Cell Apoptosis

by Hieu D. L. Vo and C. Ben Lovely

Biomedicines 2025, 13(3), 755; https://doi.org/10.3390/biomedicines13030755 - 20 Mar 2025

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Abstract

Background: Craniofacial malformations lie at the heart of fetal alcohol spectrum disorders (FASDs). While there is growing evidence for a genetic component in FASDs, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. The bone morphogenetic protein (Bmp) [...] Read more.

Background: Craniofacial malformations lie at the heart of fetal alcohol spectrum disorders (FASDs). While there is growing evidence for a genetic component in FASDs, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. The bone morphogenetic protein (Bmp) signaling pathway-dependent endoderm pouch formation is a key mechanism in facial development. We have previously shown that multiple Bmp mutants are sensitized to ethanol-induced facial defects. However, ethanol does not directly impact Bmp signaling. This suggests that downstream effectors, like nkx2.3, may mediate the impact of ethanol on Bmp mutants. Methods: We use an ethanol exposure paradigm with nkx2.3 knockdown approaches to test if nkx2.3 loss sensitizes Bmp mutants to ethanol-induced facial defects. We combine morphometric approaches with immunofluorescence and a hybridization chain reaction to examine the cellular mechanisms underlying Bmp–ethanol interactions. Results: We show that Bmp–ethanol interactions alter the morphology of the endodermal pouches, independent of nkx2.3 gene expression. Knockdown of nkx2.3 does not sensitize wild-type or Bmp mutants to ethanol-induced facial defects. However, we did observe a significant increase in CNCC apoptosis in ethanol-treated Bmp mutants, suggesting an ethanol sensitive, Bmp-dependent signaling pathway driving tissue interactions at the heart of FASDs. Conclusions: Collectively, our work builds on the mechanistic understanding of ethanol-sensitive genes and lays the groundwork for complex multi-tissue signaling events that have yet to be explored. Ultimately, our work provides a mechanistic paradigm of ethanol-induced facial defects and connects ethanol exposure with complex tissue signaling events that drive development. Full article

(This article belongs to the Special Issue Zebrafish Models for Development and Disease 4.0)

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12 pages, 1794 KiB

Open AccessArticle

Systemic Inflammatory Markers as Prognostic Factors in Oral Squamous Cell Carcinoma of the Tongue

by Maria Giulia Cristofaro, Francesco Ferragina, Federico Tolino and Ida Barca

Biomedicines 2025, 13(3), 754; https://doi.org/10.3390/biomedicines13030754 - 20 Mar 2025

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Abstract

Background: Oral tongue squamous cell carcinoma (OTSCC) is a common disease that can cause occult metastasis (OM). Methods: This study aims to investigate the role of the pre-treatment neutrophil-to-lymphocyte ratio (NLR) in predicting the presence of neck OM in early-stage OTSCC. [...] Read more.

Background: Oral tongue squamous cell carcinoma (OTSCC) is a common disease that can cause occult metastasis (OM). Methods: This study aims to investigate the role of the pre-treatment neutrophil-to-lymphocyte ratio (NLR) in predicting the presence of neck OM in early-stage OTSCC. We reprocessed the pre-treatment blood data to calculate the NLR and the PLR on patients treated for OTSCC. We used a logistic regression model and the ROC curve to estimate the probability of metastases in cervical lymph nodes using data from pre-surgery blood tests. Results: During the period under review, 113 patients were treated for OTSCC; however, only 74 met the inclusion criteria and were, therefore, enrolled in the study. Twenty-five patients (35.3%) had lymph node metastases, and 46 (64.7%) did not. Without the NLR influence, the probability of metastasis is less than 50% (β0 = −1.058). A higher NLR value means a higher chance of metastasis. This is shown by the positive value of the NLR level coefficient (β1 = 0.135) and the ROC curve (AUC = 0.83). Conclusions: Our study showed a statistical correlation between high pre-treatment NLR values and neck OM in patients with OTSCC. These results may help to identify which patients are at risk of developing OM and then choose the right treatment. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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14 pages, 3792 KiB

Open AccessArticle

The Causal Relationship Between Gut Microbiomes, Inflammatory Mediators, and Traumatic Brain Injury in Europeans: Evidence from Genetic Correlation and Functional Mapping Annotation Analyses

by Bingyi Song, Youjia Qiu, Zilan Wang, Yuchen Tao, Menghan Wang, Aojie Duan, Minjia Xie, Ziqian Yin, Zhouqing Chen, Chao Ma and Zhong Wang

Biomedicines 2025, 13(3), 753; https://doi.org/10.3390/biomedicines13030753 - 20 Mar 2025

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Abstract

Background: The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. Methods: We utilized Genome-Wide Association Study (GWAS) [...] Read more.

Background: The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. Methods: We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM and TBI. To assess the potential causal associations between GM and TBI, we employed the inverse-variance-weighted, MR-Egger, and weighted median methods. Mediation analysis was used to assess the possible mediating factors. Several sensitivity analyses methods were implemented to verify the stability of the results. Additionally, we utilized FUMA GWAS to map single-nucleotide polymorphisms to genes and conduct transcriptomic MR analysis. Results: We identified potential causal relationships between nine bacterial taxa and TBI. Notably, class Methanobacteria, family Methanobacteriaceae, and order Methanobacteriales (p = 0.0003) maintained a robust positive correlation with TBI. This causal association passed false discovery rate (FDR) correction (FDR < 0.05). Genetically determined 1 inflammatory protein, 30 immune cells and 3 inflammatory factors were significantly causally related to TBI. None of them mediated the relationship between GMs and TBI. The outcome of the sensitivity analysis corroborated the findings. Regarding the mapped genes of significant GMs, genes such as CLK4, MTRF1, NAA16, SH3BP5, and ZNF354A in class Methanobacteria showed a significant causal correlation with TBI. Conclusions: Our study reveals the potential causal effects of nine GMs, especially Methanogens on TBI, and there was no link between TBI and GM through inflammatory protein, immune cells, and inflammatory factors, which may offer fresh insights into TBI biomarkers and therapeutic targets through specific GMs. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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13 pages, 558 KiB

Open AccessSystematic Review

Investigation into the Use of Surufatinib and Donafenib as Novel Multi-Kinase Inhibitors Therapeutic Agents in Managing Advanced Differentiated Thyroid Cancer: A Systematic Review

by Danut Dejeu, Paula Dejeu, Anita Muresan, Paula Bradea and Viorel Dejeu

Biomedicines 2025, 13(3), 752; https://doi.org/10.3390/biomedicines13030752 - 20 Mar 2025

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Abstract

Background and Objectives: Differentiated thyroid cancer is the predominant form of endocrine cancer, with most cases being treatable. However, some patients develop resistance to traditional treatments. This review examines the use of the new multi-kinase inhibitors surufatinib and sonafenib, which target pathways related [...] Read more.

Background and Objectives: Differentiated thyroid cancer is the predominant form of endocrine cancer, with most cases being treatable. However, some patients develop resistance to traditional treatments. This review examines the use of the new multi-kinase inhibitors surufatinib and sonafenib, which target pathways related to angiogenesis and tumor growth in these patients. Methods: An extensive search of the literature was performed to find research involving these drugs in treating differentiated thyroid cancer. Four relevant studies were found, including two each for surufatinib and donafenib. Information regarding the research design, participant details, treatment methods, results on effectiveness, and side effects was collected and analyzed. Results: Surufatinib showed encouraging results, with response rates between 23.2% and 60% and progression-free survival times as long as 11.1 months. Donafenib also demonstrated improved progression-free survival times (12.9 months) compared to a placebo (6.4 months) and had response rates as high as 23.3%. Both drugs were well tolerated, with the most frequent side effects being hypertension and hand−foot syndrome. Conclusions: Both urufatinib and donafenib offer substantial benefits for patients with advanced differentiated thyroid cancer and have acceptable safety profiles. These results support their potential inclusion in treatment strategies for resistant cases, and further investigation of their clinical application is recommended. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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13 pages, 31619 KiB

Open AccessArticle

PRKAG2 Syndrome: Clinical Features, Imaging Findings and Cardiac Events

by Maria Sudomir, Przemysław Chmielewski, Grażyna Truszkowska, Mariusz Kłopotowski, Mateusz Śpiewak, Marta Legatowicz-Koprowska, Monika Gawor-Prokopczyk, Justyna Szczygieł, Joanna Zakrzewska-Koperska, Mariusz Kruk, Jolanta Krzysztoń-Russjan, Jacek Grzybowski, Rafał Płoski and Zofia T. Bilińska

Biomedicines 2025, 13(3), 751; https://doi.org/10.3390/biomedicines13030751 - 19 Mar 2025

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Abstract

Background/Objectives: PRKAG2 syndrome (PS) is a rare genocopy of hypertrophic cardiomyopathy (HCM). Our goal was to expand knowledge about PS by analyzing patient clinical, imaging, and follow-up data. Methods: The study included carriers of likely pathogenic or pathogenic PRKAG2 variants identified [...] Read more.

Background/Objectives: PRKAG2 syndrome (PS) is a rare genocopy of hypertrophic cardiomyopathy (HCM). Our goal was to expand knowledge about PS by analyzing patient clinical, imaging, and follow-up data. Methods: The study included carriers of likely pathogenic or pathogenic PRKAG2 variants identified in the years 2011–2022. Cardiac involvement was assessed by electrocardiography, echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy (EMB). We recorded concomitant diseases and cardiac events, including the implantation of electronic cardiac devices, arrhythmia, heart failure (HF), and death. Results: Seven patients from four families (median age 43 years) with PRKAG2 variants: Phe293Leu, Val336Leu, Arg302Gln, and His530Arg were included. At the first evaluation, 3 carriers were in New York Heart Association (NYHA) functional class II–III, while the remaining were in NYHA class I. Left ventricular hypertrophy (LVH) was present in 5 patients; 2 had ventricular pre-excitation, one was in atrial flutter and pacemaker-dependent; 2 had bradycardia. Two female carriers had concomitant chronic renal disease. In the EMB of one of the patients, staining for glycogen deposits was positive. Furthermore, we provide a link between the Val336Leu PRKAG2 variant and autophagy identified on EMB. After a median follow-up of 13.1 years, 6 carriers had LVH, 3 required admission for HF, and 1 had sustained ventricular tachycardia with subsequent cardioverter defibrillator implantation, and despite this, died suddenly; there were two de novo pacemaker implantations due to symptomatic bradycardia. Conclusions: PR is a distinctive disorder with an early onset of arrhythmic events, often leading to HF. Full article

(This article belongs to the Special Issue Advanced Research in Hypertrophic Cardiomyopathy)

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12 pages, 1524 KiB

Open AccessArticle

Lower Plasma IL-32 Levels Linked to Better Survival in Sepsis

by Patricia Mester, Alexander Utrata, Niklas Schmidtner, Charlotte Birner, Stephan Schmid, Martina Müller, Vlad Pavel and Christa Buechler

Biomedicines 2025, 13(3), 750; https://doi.org/10.3390/biomedicines13030750 - 19 Mar 2025

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Abstract

Background/Objectives: Interleukin-32 (IL-32) is a pro-inflammatory cytokine primarily produced by immune cells and involved in bacterial and viral infections. This study investigates whether plasma IL-32 is associated with sepsis severity and clinical outcomes. Methods: Plasma IL-32 levels were measured in 186 patients with [...] Read more.

Background/Objectives: Interleukin-32 (IL-32) is a pro-inflammatory cytokine primarily produced by immune cells and involved in bacterial and viral infections. This study investigates whether plasma IL-32 is associated with sepsis severity and clinical outcomes. Methods: Plasma IL-32 levels were measured in 186 patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock, as well as in 40 controls. The relationship between IL-32 levels and SARS-CoV-2 or bacterial infections, alongside underlying etiological conditions, was assessed. Results: Patients with liver cirrhosis exhibited elevated plasma IL-32 levels. After excluding these patients, IL-32 levels were lower in SIRS/sepsis patients compared to the controls. No significant differences in IL-32 levels were observed among SIRS, sepsis, and septic shock patients. Additionally, underlying conditions such as pancreatitis and cholangitis did not influence IL-32 levels. Patients with bloodstream bacterial infections, SARS-CoV-2 infections, or no documented infection had comparable IL-32 levels. Notably, higher IL-32 levels were associated with increased mortality. Conclusions: These findings suggest that a reduction in plasma IL-32 levels may be protective in SIRS/sepsis patients, as elevated levels are linked to poor survival outcomes. Full article

(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)

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14 pages, 4251 KiB

Open AccessArticle

Multi-Omics Integration Reveals Mitochondrial Gene Regulation as a Determinant of Tuberculosis Susceptibility: A Mendelian Randomization Approach

by Tingting Fang, Yu Chen, Feifei Yuan, Yuyan Ma, Qingqing Wang, Yumeng Yao, Sishi Cai, Wenting Jin, Qing Miao and Bijie Hu

Biomedicines 2025, 13(3), 749; https://doi.org/10.3390/biomedicines13030749 - 19 Mar 2025

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Abstract

Background/Objectives: Mitochondrial dysfunction has been implicated in the pathogenesis of tuberculosis (TB). Despite emerging evidence of the importance of mitochondrial gene regulation in the immune response, the specific role of mitochondrial-related genes in TB susceptibility remains to be fully elucidated. Methods: We employed [...] Read more.

Background/Objectives: Mitochondrial dysfunction has been implicated in the pathogenesis of tuberculosis (TB). Despite emerging evidence of the importance of mitochondrial gene regulation in the immune response, the specific role of mitochondrial-related genes in TB susceptibility remains to be fully elucidated. Methods: We employed a multi-omics approach integrating genetic, methylation, and protein-level data. Mendelian randomization (MR) and colocalization analyses were conducted to explore causal associations between mitochondrial gene features—expression quantitative trait loci (eQTL), methylation quantitative trait loci (mQTL), and protein quantitative trait loci (pQTL)—and TB susceptibility. Data were obtained from the FinnGen cohort and validated using independent datasets. Results: Our analyses identified several key mitochondrial genes (e.g., ACSF3, AK3, LYRM4, and PDHB) significantly associated with TB susceptibility. Random forest analysis and gene set enrichment analysis (GSEA) supported the predictive power of these genes. Furthermore, we observed significant correlations between mitochondrial gene expression and immune cell infiltration in TB patients, suggesting a role of these genes in modulating immune responses during infection. Receiver operating characteristic (ROC) analysis confirmed strong predictive accuracy for the identified feature genes, with area under the curve (AUC) values exceeding 0.7. Conclusions: This study demonstrates that mitochondrial-related gene regulation influences TB susceptibility across genetic, methylation, and protein levels. The integration of multi-omics data provides valuable insight into the molecular mechanisms underlying TB, highlighting the potential of mitochondrial genes as biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment of Mycobacterium Tuberculosis Infection)

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17 pages, 2449 KiB

Open AccessArticle

Endocrine-Disrupting Activities of Flavones on Steroid Receptors: Structural Requirements and Synthesis of Novel Flavone with Improved Estrogenic Activity

by Steven K. Nordeen, Vijay Kumar, Betty J. Bona, Joshua D. Batson, Donald S. Backos and Michael F. Wempe

Biomedicines 2025, 13(3), 748; https://doi.org/10.3390/biomedicines13030748 - 19 Mar 2025

Viewed by 327

Abstract

Background/Objectives: Flavonoids are common ubiquitous components of plants and are consumed by humans and livestock in their diets. Many different activities have been proposed for a variety of flavonoids that play a role in the benefits of a plant-rich diet. On the downside, [...] Read more.

Background/Objectives: Flavonoids are common ubiquitous components of plants and are consumed by humans and livestock in their diets. Many different activities have been proposed for a variety of flavonoids that play a role in the benefits of a plant-rich diet. On the downside, excessive exposure to some flavonoids comes with a risk of endocrine disruption. Our objective was to define the structural elements of flavones and selected other flavonoids required for endocrine-disrupting activities on each of four steroid receptors, estrogen, androgen, progesterone, and glucocorticoid receptors. Methods: This work presents a systematic screen for the hormone agonist or antagonist activity of a selected panel of flavonoids on estrogen, androgen, progesterone, and glucocorticoid receptors. The screen is focused on the positional requirements of hydroxyl substituents on the flavone backbone. Results: Each receptor exhibited a distinct pattern for structural requirements of the flavones to impact receptor signaling. The most active flavones exhibited antagonist activity on androgen and progesterone receptors with an IC₅₀ of 0.5 and 2 µM, respectively. Flavones only exhibited weak antagonism on glucocorticoid receptors. When active, flavones acted as estrogen receptor agonists. The findings were utilized to design and synthesize a novel flavone, 3-fluoro, 6,4′-dihydroxyflavone 14, that displays increased potency as an estrogen agonist (EC₅₀~30 nM). Modeling of the binding of this novel flavone predicts increased preference for ERα versus ERβ relative to the estrogenic phytoestrogen, genistein. Conclusions: The structural requirements for flavones to act as estrogen agonists and antagonists of other steroid receptors are defined. The synthesis of a novel flavone offers potential for topical applications where systemic estrogen activity is undesired. However, the results highlight the potential for endocrine disruption when certain flavones are consumed in quantity as supplements. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Steroid Hormone Action—2nd Edition)

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17 pages, 1999 KiB

Open AccessArticle

Understanding Causal Relationships Between Imaging-Derived Phenotypes and Parkinson’s Disease: A Mendelian Randomization and Observational Study

by Yichi Zhang, Min Zhong, Zhao Yang, Xiaojin Wang, Zhongxun Dong, Liche Zhou, Qianyi Yin, Bingshun Wang, Jun Liu, Yuanyuan Li and Mengyue Niu

Biomedicines 2025, 13(3), 747; https://doi.org/10.3390/biomedicines13030747 - 18 Mar 2025

Viewed by 372

Abstract

Background/Objectives: Observational studies have suggested a correlation between brain imaging alterations and Parkinson’s disease (PD). However, data on causal relationships are still lacking. This study aimed to examine the causal relationship between brain imaging-derived phenotypes (IDPs) and PD. Methods: A bidirectional two-sample Mendelian [...] Read more.

Background/Objectives: Observational studies have suggested a correlation between brain imaging alterations and Parkinson’s disease (PD). However, data on causal relationships are still lacking. This study aimed to examine the causal relationship between brain imaging-derived phenotypes (IDPs) and PD. Methods: A bidirectional two-sample Mendelian randomization analysis was conducted to explore the causal association between IDPs and PD. Summary-level data for IDPs (n = 39,691), PD (n = 482,730), and PD symptoms (n = 4093) were obtained from genome-wide association studies of European ancestry. Clinical validation was performed in an Asian cohort, which involved healthy controls (n = 81), patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD) (n = 47), and patients with PD (n = 85). Results: We found 13 IDPs with significant causal effects on PD and seven reciprocal effects of PD on IDPs. For instance, increased median T2star in the right caudate (odds ratio = 1.23, 95% confidence interval 1.08–1.40, p = 0.0057) and bilateral putamen (left: odds ratio = 1.25, 95% confidence interval 1.09–1.43, p = 0.0056; right: odds ratio = 1.25, 95% confidence interval 1.10–1.43, p = 0.0056) were associated with PD. Enlargement of the left thalamus (odds ratio = 1.50, 95% confidence interval 1.14–1.96, p = 0.016) demonstrated causal links with PD. No reverse causal effects were detected. Observational analyses results in the Asian cohort (healthy controls, iRBD, PD) aligned with the Mendelian randomization results. Conclusions: Our results suggest bidirectional causal links between IDPs and PD, offering insights into disease mechanisms and potential imaging biomarkers for PD. Full article

(This article belongs to the Special Issue Molecular Research of Neurodegenerative and Psychiatric Diseases, 2nd Edition)

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22 pages, 1163 KiB

Open AccessReview

Silent Effects of High Salt: Risks Beyond Hypertension and Body’s Adaptation to High Salt

by Raisa Nazir Ahmed Kazi

Biomedicines 2025, 13(3), 746; https://doi.org/10.3390/biomedicines13030746 - 18 Mar 2025

Viewed by 438

Abstract

Hypertension is a major contributor to heart disease, renal failure, and stroke. High salt is one of the significant risk factors associated with the onset and persistence of hypertension. Experimental and observational studies have confirmed cardiovascular and non-cardiovascular detrimental effects associated with chronic [...] Read more.

Hypertension is a major contributor to heart disease, renal failure, and stroke. High salt is one of the significant risk factors associated with the onset and persistence of hypertension. Experimental and observational studies have confirmed cardiovascular and non-cardiovascular detrimental effects associated with chronic intake of high salt. Because of convenience and present urban lifestyles, consumption of fast food has led to daily salt intake above the recommended level by the World Health Organization. This study provides an understanding of the body regulatory mechanisms that maintain sodium homeostasis under conditions of high salt intake, without health consequences, and how these mechanisms adapt to chronic high salt load, leading to adverse cardiovascular, renal, and non-cardiovascular outcomes. Recent research has identified several mechanisms through which high sodium intake contributes to hypertension. Of them, heightened renin–angiotensin–aldosterone and sympathetic activity associated with impaired pressure diuresis and natriuresis and decreased renal excretory response are reported. Additionally, there is the possibility of endothelial and nitric oxide dysfunction leading to vascular remodeling. These changes raise cardiac output and peripheral vascular resistance. Knowing how these collective mechanisms adapt to chronic intakes of high salt helps develop effective therapeutic policies to fight salt-induced hypertension. Full article

(This article belongs to the Special Issue Feature Reviews on Cardiovascular and Metabolic Diseases)

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14 pages, 2817 KiB

Open AccessArticle

Clinical Outcome of Conversion Surgery for Stage IV Esophageal Cancer Following Chemoradiation

by Hu-Lin Christina Wang, Ke-Cheng Chen, Pei-Ming Huang, Chih-Hung Hsu, Chia-Hsien Cheng, Feng-Ming Hsu, Ta-Chen Huang, Jhe-Cyuan Guo and Jang-Ming Lee

Biomedicines 2025, 13(3), 745; https://doi.org/10.3390/biomedicines13030745 - 18 Mar 2025

Viewed by 337

Abstract

Purpose: We aimed to identify the impact of conversion surgery to survival in patients with stage IV esophageal cancer who have a stabilized disease and good treatment response before surgery. Patients and Methods: This retrospective study included patients with esophageal cancer M1 disease [...] Read more.

Purpose: We aimed to identify the impact of conversion surgery to survival in patients with stage IV esophageal cancer who have a stabilized disease and good treatment response before surgery. Patients and Methods: This retrospective study included patients with esophageal cancer M1 disease treated at a tertiary medical center from April 2002 to June 2021. For patients with a good clinical response to chemoradiation and well-controlled metastatic lesions, esophagectomy and lymphadenectomy were performed. A propensity score-matching (PSM) study with a 1:2 ratio and based on patient age, tumor stage, and metastasis status was conducted for verifying the results. Results: We enrolled 162 patients, including 124 treated with concurrent chemoradiation therapy (CCRT) alone and 38 treated with CCRT followed by esophagectomy. A total of 114 patients were analyzed using PSM, including 76 patients treated with CCRT alone and 38 patients treated with CCRT and surgery. The 3- and 5-year OS was 24.6% vs. 2.8% and 12.3% vs. 1.4% (p = 0.006), and PSM was 24.6% vs. 4.6% and 12.3% vs. 2.3% (p = 0.033) for those with or without esophagectomy, respectively. Multivariate analysis revealed surgery with esophagectomy as an independent prognostic factor for OS with odd ratios (95% confidence interval [CI]) of 1.91 (1.23–2.95) (p = 0.004). Conclusions: Surgical resection following CCRT holds a potential survival benefit for the patients with a favorable response to CCRT for patients with stage IV esophageal cancer. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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30 pages, 1537 KiB

Open AccessReview

Cardiometabolic Phenotype in HFpEF: Insights from Murine Models

by Ekaterina Ogurtsova, Tatiana Arefieva, Anastasiia Filatova, Natalya Radyukhina and Artem Ovchinnikov

Biomedicines 2025, 13(3), 744; https://doi.org/10.3390/biomedicines13030744 - 18 Mar 2025

Viewed by 501

Abstract

Heart failure with preserved ejection fraction (HFpEF) remains a significant challenge in modern healthcare. It accounts for the majority of heart failure cases and their number worldwide is steadily increasing. With its high prevalence and substantial clinical impact, therapeutic strategies for HFpEF are [...] Read more.

Heart failure with preserved ejection fraction (HFpEF) remains a significant challenge in modern healthcare. It accounts for the majority of heart failure cases and their number worldwide is steadily increasing. With its high prevalence and substantial clinical impact, therapeutic strategies for HFpEF are still inadequate. This review focuses on the cardiometabolic phenotype of HFpEF which is characterised by such conditions as obesity, type 2 diabetes mellitus, and hypertension. Various murine models that mimic this phenotype are discussed. Each model’s pathophysiological aspects, namely inflammation, oxidative stress, endothelial dysfunction, changes in cardiomyocyte protein function, and myocardial metabolism alterations are examined in detail. Understanding these models can provide insight into the mechanisms underlying HFpEF and aid in the development of effective therapeutic interventions. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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23 pages, 4272 KiB

Open AccessArticle

ATT-Myc Transgenic Mouse Model and Gene Expression Identify Genotoxic and Non-Genotoxic Chemicals That Accelerating Liver Tumor Growth in Short-Term Toxicity

by Mahmoud Elalfy, Jürgen Borlak, Ahmed Jaafar Aljazzar and Mona G. Elhadidy

Biomedicines 2025, 13(3), 743; https://doi.org/10.3390/biomedicines13030743 - 18 Mar 2025

Viewed by 370

Abstract

Introduction: Diethyl nitrosamine (DEN), a known carcinogen, has been used for validating the RasH2 and P53 transgenic models in chemical testing and has been shown to enhance primary liver tumor growth in the ATT-Myc transgenic mouse model of liver cancer. Material and Methods: [...] Read more.

Introduction: Diethyl nitrosamine (DEN), a known carcinogen, has been used for validating the RasH2 and P53 transgenic models in chemical testing and has been shown to enhance primary liver tumor growth in the ATT-Myc transgenic mouse model of liver cancer. Material and Methods: to better understand the mechanism of hepatocellular carcinoma acceleration following DEN, BHT and vehicles treatments in ATT-Myc, transgenic and non-transgenic, mice. We employed an exon array, RT-PCR, Western blotting, and IHC to investigate the complex interplay between the c-Myc transgene and other growth factors in treated mice versus control transgenic and non-transgenic mice. Results: Notably, DEN treatment induced a 12-fold increase in c-Myc expression compared to non-transgenic mice. Furthermore, tumor growth in the DEN group was strongly associated with increased proliferation of transformed or carcinogenic hepatocytes, as evidenced by proliferative cell nuclear antigen and bromodeoxyuridine expression. Internally, the loss of c-Met signaling, enriched transcription factors, and the diminished expression of antioxidants, such as superoxide dismutase (SOD1) and NRF2, further enhanced c-Myc-induced liver tumor growth as early as four months post-DEN treatment. Discussion: Extensive tumor growth was observed at 8.5 months, coinciding with the downregulation of tumor suppressors such as p53. In contrast, at these time points, ATT-Myc transgenic mice exhibited only dysplastic hepatocytes without tumor formation. Additionally, the antioxidant butylated hydroxytoluene maintained c-Met expression and did not promote liver tumor formation. Conclusions: the persistent upregulation of c-Myc in the ATT-Myc liver cancer model, at both the gene and protein levels following DEN treatment inhibited the ETS1 transcription factor, further exacerbating the decline of c-Met signaling, SOD1, and NRF2. These changes led to increased reactive oxygen species production and promoted rapid liver tumor growth. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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12 pages, 1237 KiB

Open AccessArticle

Metabolic Disruptions and Non-Communicable Disease Risks Associated with Long-Term Particulate Matter Exposure in Northern Thailand: An NMR-Based Metabolomics Study

by Churdsak Jaikang, Giatgong Konguthaithip, Yutti Amornlertwatana, Narongchai Autsavapromporn, Sirichet Rattanachitthawat, Nitip Liampongsabuddhi and Tawachai Monum

Biomedicines 2025, 13(3), 742; https://doi.org/10.3390/biomedicines13030742 - 18 Mar 2025

Viewed by 312

Abstract

Background/Objectives: Particulate matter (PM) is a primary health hazard associated with metabolic pathway disruption. Population characteristics, topography, sources, and PM components contribute to health impacts. Methods: In this study, NMR-based metabolomics was used to evaluate the health impacts of prolonged exposure [...] Read more.

Background/Objectives: Particulate matter (PM) is a primary health hazard associated with metabolic pathway disruption. Population characteristics, topography, sources, and PM components contribute to health impacts. Methods: In this study, NMR-based metabolomics was used to evaluate the health impacts of prolonged exposure to PM. Blood samples (n = 197) were collected from healthy volunteers in low- (control; CG) and high-exposure areas (exposure; EG) in Northern Thailand. Non-targeted metabolite analysis was performed using proton nuclear magnetic resonance spectroscopy (¹H-NMR). Results: Compared to CG, EG showed significantly increased levels of dopamine, N6-methyladenosine, 3-hydroxyproline, 5-carboxylcytosine, and cytidine (p < 0.05), while biopterin, adenosine, L-Histidine, epinephrine, and norepinephrine were significantly higher in CG (p < 0.05). These metabolic disturbances suggest that chronic exposure to particulate matter (PM) impairs energy and amino acid metabolism while enhancing oxidative stress, potentially contributing to the onset of non-communicable diseases (NCDs) such as cancer and neurodegenerative conditions. Conclusions: This study highlighted the connection between sub-chronic PM2.5 exposure, metabolic disturbances, and an increased risk of non-communicable diseases (NCDs), stressing the critical need for effective PM2.5 reduction strategies in Northern Thailand. Full article

(This article belongs to the Section Endocrinology and Metabolism Research)

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14 pages, 1712 KiB

Open AccessArticle

Impact of Protein Kinase C Activation and Monoclonal Antibodies on Immune Checkpoint Regulation and B Cell Function in Patients with Chronic Lymphocytic Leukemia

by Aviwe Ntsethe, Phiwayinkosi Vusi Dludla and Bongani Brian Nkambule

Biomedicines 2025, 13(3), 741; https://doi.org/10.3390/biomedicines13030741 - 18 Mar 2025

Viewed by 292

Abstract

Background: Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of dysfunctional B cells, resulting in significant immune dysregulation. Patients with CLL exhibit varied responses to B cell receptor (BCR) targeted therapies, emphasizing the need for tailored immunotherapy approaches. This study investigated [...] Read more.

Background: Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of dysfunctional B cells, resulting in significant immune dysregulation. Patients with CLL exhibit varied responses to B cell receptor (BCR) targeted therapies, emphasizing the need for tailored immunotherapy approaches. This study investigated B cell function in untreated patients with CLL, and we further explored the effects of ex vivo protein kinase C activation on immune checkpoint expression and B cell profiles. Methods: Peripheral blood samples were collected from 21 untreated patients with CLL at King Edward Hospital in South Africa, between 2019 and 2022. B cells were stimulated with phorbol myristate acetate (PMA) and ionomycin. Using flow cytometry, the study explored the levels of B cell subsets and immune checkpoint proteins programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) expression on various B cell subsets. Results: PMA and ionomycin B cell stimulation upregulated PD-1, CTLA-4 and PD-L2 expression on B cell subsets (p < 0.01). As expected, monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 significantly downregulated the CTLA-4 expression of B cell subsets (p < 0.05), while PD-L2 exhibited varied responses in different B cell subsets. Moreover, PD-1 and PD-L1 expression on total B cells significantly declined following their blockage (p < 0.01). In addition, these monoclonal antibodies increased the levels of CD19⁺CD27⁺ B cells (p < 0.0128) and activated CD19⁺CD27⁺ B cells (p < 0.01). Conclusions: Protein kinase C activation on B cells stimulates immune checkpoint expression. The use of monoclonal antibodies on B cells plays a critical role in the B cell function through the reduction in CD38 expressing activated B cells and upregulation of CD19⁺CD27⁺ B cells. Moreover, the monoclonal antibody targeting PD-1, PD-L1 and CTLA-4 are effective in reducing the expression of CTLA-4 on B cell subsets, while PD-1 and PD-L1 blockage may be effective in reducing the expression of these immune checkpoints on total B cells. Full article

(This article belongs to the Special Issue Innovative Approaches to Molecular Pathogenesis and Therapy of Lymphoid Malignancies)

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11 pages, 1122 KiB

Open AccessArticle

Biomarker-Based Nomogram to Predict Neoadjuvant Chemotherapy Response in Muscle-Invasive Bladder Cancer

by Meritxell Pérez, Juan José Lozano, Mercedes Ingelmo-Torres, Montserrat Domenech, Caterina Fernández Ramón, J. Alfred Witjes, Antoine G. van der Heijden, Maria José Requena, Antonio Coy, Ricard Calderon, Begoña Mellado, Antonio Alcaraz, Antoni Vilaseca and Maria J. Ribal

Biomedicines 2025, 13(3), 740; https://doi.org/10.3390/biomedicines13030740 - 18 Mar 2025

Viewed by 296

Abstract

Background/Objectives: The aim of this study was to identify response prediction and prognostic biomarkers in muscle-invasive bladder cancer (MIBC) patients undergoing neoadjuvant chemotherapy (NAC). Methods: A retrospective multicentre study including 191 patients with MIBC who received NAC previous to radical cystectomy (RC) [...] Read more.

Background/Objectives: The aim of this study was to identify response prediction and prognostic biomarkers in muscle-invasive bladder cancer (MIBC) patients undergoing neoadjuvant chemotherapy (NAC). Methods: A retrospective multicentre study including 191 patients with MIBC who received NAC previous to radical cystectomy (RC) between 1996 and 2013. Gene expression patterns were analysed in 34 samples from transurethral resection of the bladder (TURB) using Illumina microarrays. The expression levels of 45 selected differentially expressed genes between responders and non-responders to NAC were validated by quantitative PCR in an independent cohort of 157 patients. Regression analysis was used to identify predictors of downstaging and relapse. A nomogram for predicting downstaging and relapse—including clinicopathological and gene expression variables—was developed. Results: The expression levels of 1352 transcripts differed between responders and non-responders to NAC. A nomogram based on the most predictive clinical variables (age, Tis (in situ), gender, history of NMIBC, and lymphadenopathy) and genes selected following the Akaike information criterion (AIC) (CBTB16, CHMP6, DDX54, CASP8, LOR, and PLEC) was then created. In addition, a three-gene expression prognostic model to predict tumour relapse was generated. This model was able to discriminate between two groups of patients with a significantly different probability of tumour relapse (HR: 2.11; CI: 1.16–3.83, p = 0.01). Conclusions: Our nomogram based on gene expression and clinical data is a useful tool to predict downstaging and tumour relapse after NAC in MIBC patients. Further validation is warranted. Full article

(This article belongs to the Special Issue Urogenital Cancers: New Molecular and Translational Aspects on Carcinogenesis and Treatments)

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13 pages, 724 KiB

Open AccessArticle

Ramp Sequence May Explain Synonymous Variant Association with Alzheimer’s Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)

by Justin B. Miller, J. Anthony Brandon, Lauren M. Harmon, Hady W. Sabra, Chloe C. Lucido, Josue D. Gonzalez Murcia, Kayla A. Nations, Samuel H. Payne, Mark T. W. Ebbert, John S. K. Kauwe and Perry G. Ridge

Biomedicines 2025, 13(3), 739; https://doi.org/10.3390/biomedicines13030739 - 18 Mar 2025

Viewed by 273

Abstract

Background: The synonymous variant NC_000007.14:g.100373690T>C (rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimer’s disease (AD) in genome-wide association studies, but its biological impact is largely unknown. Objective: We [...] Read more.

Background: The synonymous variant NC_000007.14:g.100373690T>C (rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimer’s disease (AD) in genome-wide association studies, but its biological impact is largely unknown. Objective: We hypothesized that rs2405442:T>C decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5′ end of PILRA. Methods: We assessed rs2405442:T>C predicted effects on PILRA through quantitative polymerase chain reactions (qPCRs) and enzyme-linked immunosorbent assays (ELISAs) using Chinese hamster ovary (CHO) cells. RESULTS: Both mRNA (p = 1.9184 × 10⁻¹³) and protein (p = 0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on the destruction of a ramp sequence. Conclusions: We show that rs2405442:T>C alone directly impacts PILRA mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product. Full article

(This article belongs to the Special Issue Alzheimer's Disease Genetics)

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18 pages, 1022 KiB

Open AccessArticle

Enhancing Mild Cognitive Impairment Auxiliary Identification Through Multimodal Cognitive Assessment with Eye Tracking and Convolutional Neural Network Analysis

by Na Li, Ziming Wang, Wen Ren, Hong Zheng, Shuai Liu, Yi Zhou, Kang Ju and Zhongting Chen

Biomedicines 2025, 13(3), 738; https://doi.org/10.3390/biomedicines13030738 - 18 Mar 2025

Viewed by 340

Abstract

Background: Mild Cognitive Impairment (MCI) is a critical transitional phase between normal aging and dementia, and early detection is essential to mitigate cognitive decline. Traditional cognitive assessment tools, such as the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), exhibit [...] Read more.

Background: Mild Cognitive Impairment (MCI) is a critical transitional phase between normal aging and dementia, and early detection is essential to mitigate cognitive decline. Traditional cognitive assessment tools, such as the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), exhibit limitations in feasibility, which potentially and partially affects results for early-stage MCI detection. This study developed and tested a supportive cognitive assessment system for MCI auxiliary identification, leveraging eye-tracking features and convolutional neural network (CNN) analysis. Methods: The system employed eye-tracking technology in conjunction with machine learning to build a multimodal auxiliary identification model. Four eye movement tasks and two cognitive tests were administered to 128 participants (40 MCI patients, 57 elderly controls, 31 young adults as reference). We extracted 31 eye movement and 8 behavioral features to assess their contributions to classification accuracy using CNN analysis. Eye movement features only, behavioral features only, and combined features models were developed and tested respectively, to find out the most effective approach for MCI auxiliary identification. Results: Overall, the combined features model achieved a higher discrimination accuracy than models with single feature sets alone. Specifically, the model’s ability to differentiate MCI from healthy individuals, including young adults, reached an average accuracy of 74.62%. For distinguishing MCI from elderly controls, the model’s accuracy averaged 66.50%. Conclusions: Results show that a multimodal model significantly outperforms single-feature models in identifying MCI, highlighting the potential of eye-tracking for early detection. These findings suggest that integrating multimodal data can enhance the effectiveness of MCI auxiliary identification, providing a novel potential pathway for community-based early detection efforts. Full article

(This article belongs to the Special Issue Biomedical and Biochemical Basis of Neurodegenerative Diseases)

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19 pages, 6319 KiB

Open AccessReview

Histopathological Analysis of Vacuum-Assisted Breast Biopsy in Relation to Microcalcification Findings on Mammography: A Pictorial Review

by Jana Bebek, Nikolina Novak, Marina Dasović, Eugen Divjak, Čedna Tomasović-Lončarić, Boris Brkljačić and Gordana Ivanac

Biomedicines 2025, 13(3), 737; https://doi.org/10.3390/biomedicines13030737 - 18 Mar 2025

Viewed by 385

Abstract

Mammography is an essential tool in breast screening, often revealing lesions that appear as microcalcifications with or without an associated mass. Decisions about biopsy requirements are guided by the BI-RADS system, aiming to confirm the histopathology of suspicious lesions while avoiding unnecessary procedures. [...] Read more.

Mammography is an essential tool in breast screening, often revealing lesions that appear as microcalcifications with or without an associated mass. Decisions about biopsy requirements are guided by the BI-RADS system, aiming to confirm the histopathology of suspicious lesions while avoiding unnecessary procedures. A vacuum-assisted breast biopsy (VABB) is a minimally invasive procedure for diagnosing breast abnormalities. Precise lesion targeting is ensured under stereotactic guidance, reducing the need for repeated procedures. Compared to traditional core needle biopsy (CNB) and fine-needle aspiration cytology (FNAC), it differs in using vacuum assistance to gather more tissue volume, increasing diagnostic accuracy and reducing the likelihood of histological underestimation. This is particularly crucial in cases where microcalcifications are the primary finding, as they are often the earliest signs of ductal carcinoma in situ (DCIS). Managing such findings requires precise diagnostic tools to differentiate benign from malignant lesions without subjecting patients to unnecessary surgical interventions. Building on several years of experience in our department, we have assembled a selection of ten interesting cases encountered in our clinical practice. Each case is documented with paired mammographic images and their corresponding image of histopathological findings, offering a comprehensive view of the diagnostic journey. These cases were selected for their educational value, highlighting the integration of imaging modalities, histopathological evaluation, and clinical decision-making. All cases underwent an extensive diagnostic workup at our facility. This compilation aims to provide valuable insights for both clinicians and researchers, offering a deeper understanding of advanced diagnostic techniques and their role in improving patient outcomes. Full article

(This article belongs to the Special Issue Breast Cancer: New Diagnostic and Therapeutic Approaches)

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18 pages, 3460 KiB

Open AccessArticle

Brain Structural Alterations Underlying Mood-Related Deficits in Schizophrenia

by Margherita Biondi, Marco Marino, Dante Mantini and Chiara Spironelli

Biomedicines 2025, 13(3), 736; https://doi.org/10.3390/biomedicines13030736 - 18 Mar 2025

Viewed by 396

Abstract

Background/Objectives: Schizophrenia (SZ) is a complex psychiatric disorder characterized by neurodegenerative processes, but the structural brain alterations associated with its progression remain poorly understood. This study investigated structural brain changes in SZ, particularly in the fronto-temporal and limbic regions, and explored their relationship [...] Read more.

Background/Objectives: Schizophrenia (SZ) is a complex psychiatric disorder characterized by neurodegenerative processes, but the structural brain alterations associated with its progression remain poorly understood. This study investigated structural brain changes in SZ, particularly in the fronto-temporal and limbic regions, and explored their relationship with symptom severity, with a focus on mood- and emotion-related symptoms. Methods: We analyzed structural MRI data from 74 SZ patients and 91 healthy controls (HCs) using voxel-based morphometry (VBM) to compare whole-brain grey matter volumes (GMVs). The analysis focused on the fronto-temporal and limbic regions, and correlations between GMV and symptom severity were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Generalized Psychopathology (GP) scale. Results: SZ patients exhibited significant reductions in GMV in the fronto-temporal and limbic regions, including the dorsolateral prefrontal cortex (dlPFC) and the temporal pole, compared to HCs. Notably, a significant positive association was found between GMV in the right inferior temporal gyrus (ITG) and the severity of generalized psychopathology, as well as with anxiety, depression, mannerisms, and unusual thought content. Further post hoc analysis identified a specific cluster of mood-related symptoms contributing to the GP scale, which correlated with GMV changes in the right ITG. Conclusions: Our findings provide new evidence of structural brain alterations in SZ, particularly in the fronto-temporal and limbic regions, suggesting a progressive neurodegenerative pattern. The role of the right ITG in mood- and emotion-related symptoms requires further exploration, as it could offer insights into SZ pathophysiology and aid in distinguishing SZ from other mood-related disorders. Full article

(This article belongs to the Special Issue Neurodegeneration in Cognitive Impairment and Mood Disorders for Experimental, Clinical, and Translational Neuropsychiatry—Second Edition)

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14 pages, 3920 KiB

Open AccessArticle

Aberrant Expression and Oncogenic Activity of SPP1 in Hodgkin Lymphoma

by Stefan Nagel and Corinna Meyer

Biomedicines 2025, 13(3), 735; https://doi.org/10.3390/biomedicines13030735 - 17 Mar 2025

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Abstract

Background: Hodgkin lymphoma (HL) is a B-cell-derived malignancy and one of the most frequent types of lymphoma. The tumour cells typically exhibit multiple genomic alterations together with aberrantly activated signalling pathways, driven by paracrine and/or autocrine modes. SPP1 (alias osteopontin) is a [...] Read more.

Background: Hodgkin lymphoma (HL) is a B-cell-derived malignancy and one of the most frequent types of lymphoma. The tumour cells typically exhibit multiple genomic alterations together with aberrantly activated signalling pathways, driven by paracrine and/or autocrine modes. SPP1 (alias osteopontin) is a cytokine acting as a signalling activator and has been connected with relapse in HL patients. To understand its pathogenic role, here, we investigated the mechanisms and function of deregulated SPP1 in HL. Methods: We screened public patient datasets and cell lines for aberrant SPP1 expression. HL cell lines were stimulated with SPP1 and subjected to siRNA-mediated knockdown. Gene and protein activities were analyzed by RQ-PCR, ELISA, Western blot, and immuno-cytology. Results: SPP1 expression was detected in 8.3% of classic HL patients and in HL cell line SUP-HD1, chosen to serve as an experimental model. The gene encoding SPP1 is located at chromosomal position 4q22 and is genomically amplified in SUP-HD1. Transcription factor binding site analysis revealed TALE and HOX factors as potential regulators. Consistent with this finding, we showed that aberrantly expressed PBX1 and HOXB9 mediate the transcriptional activation of SPP1. RNA-seq data and knockdown experiments indicated that SPP1 signals via integrin ITGB1 in SUP-HD1. Accordingly, SPP1 activated NFkB in addition to MAPK/ERK which in turn mediated the nuclear import of ETS2, activating oncogenic JUNB expression. Conclusions: SPP1 is aberrantly activated in HL cell line SUP-HD1 via genomic copy number gain and by homeodomain transcription factors PBX1 and HOXB9. SPP1-activated NFkB and MAPK merit further investigation as potential therapeutic targets in affected HL patients. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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30 pages, 1333 KiB

Open AccessReview

Ca²⁺ Signaling in Cardiac Fibroblasts: An Emerging Signaling Pathway Driving Fibrotic Remodeling in Cardiac Disorders

by Francesco Moccia, Antonio Totaro, Germano Guerra and Gianluca Testa

Biomedicines 2025, 13(3), 734; https://doi.org/10.3390/biomedicines13030734 - 17 Mar 2025

Viewed by 484

Abstract

Cardiac fibrosis is a scarring event that occurs in the myocardium in response to multiple cardiovascular disorders, such as acute myocardial infarction (AMI), ischemic cardiomyopathy, dilated cardiomyopathy, hypertensive heart disease, inflammatory heart disease, diabetic cardiomyopathy, and aortic stenosis. Fibrotic remodeling is mainly sustained [...] Read more.

Cardiac fibrosis is a scarring event that occurs in the myocardium in response to multiple cardiovascular disorders, such as acute myocardial infarction (AMI), ischemic cardiomyopathy, dilated cardiomyopathy, hypertensive heart disease, inflammatory heart disease, diabetic cardiomyopathy, and aortic stenosis. Fibrotic remodeling is mainly sustained by the differentiation of fibroblasts into myofibroblasts, which synthesize and secrete most of the extracellular matrix (ECM) proteins. An increase in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in cardiac fibroblasts is emerging as a critical mediator of the fibrogenic signaling cascade. Herein, we review the mechanisms that may shape intracellular Ca²⁺ signals involved in fibroblast transdifferentiation into myofibroblasts. We focus our attention on the functional interplay between inositol-1,4,5-trisphosphate (InsP₃) receptors (InsP₃Rs) and store-operated Ca²⁺ entry (SOCE). In accordance with this, InsP₃Rs and SOCE drive the Ca²⁺ response elicited by G_q-protein coupled receptors (G_qPCRs) that promote fibrotic remodeling. Then, we describe the additional mechanisms that sustain extracellular Ca²⁺ entry, including receptor-operated Ca²⁺ entry (ROCE), P2X receptors, Transient Receptor Potential (TRP) channels, and Piezo1 channels. In parallel, we discuss the pharmacological manipulation of the Ca²⁺ handling machinery as a promising approach to mitigate or reverse fibrotic remodeling in cardiac disorders. Full article

(This article belongs to the Special Issue The Role of Ion Channels and Transporters in Human Health and Diseases (2nd Edition))

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27 pages, 666 KiB

Open AccessReview

Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments

by Giuseppe Magro, Vincenzo Laterza and Federico Tosto

Biomedicines 2025, 13(3), 733; https://doi.org/10.3390/biomedicines13030733 - 17 Mar 2025

Viewed by 689

Abstract

Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues [...] Read more.

Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment. Full article

(This article belongs to the Special Issue Progress in Neurodevelopmental Disorders Research)

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23 pages, 882 KiB

Open AccessReview

Beyond Bone Remodeling: Denosumab’s Multisystemic Benefits in Musculoskeletal Health, Metabolism, and Age-Related Diseases—A Narrative Review

by Yi-Ting Hung, Wen-Tien Wu, Ru-Ping Lee, Ting-Kuo Yao and Kuang-Ting Yeh

Biomedicines 2025, 13(3), 732; https://doi.org/10.3390/biomedicines13030732 - 17 Mar 2025

Viewed by 619

Abstract

Background: Denosumab, a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, demonstrates therapeutic effects beyond traditional osteoporosis management through the RANK/RANKL/osteoprotegerin pathway. Methods: This narrative review analyzed 37 studies (2018–2024) examining denosumab’s broader physiological effects and clinical applications. Results: Long-term safety data [...] Read more.

Background: Denosumab, a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, demonstrates therapeutic effects beyond traditional osteoporosis management through the RANK/RANKL/osteoprotegerin pathway. Methods: This narrative review analyzed 37 studies (2018–2024) examining denosumab’s broader physiological effects and clinical applications. Results: Long-term safety data spanning 10 years showed sustained fracture prevention efficacy with a favorable benefit/risk profile. Compared to bisphosphonates, denosumab demonstrated superior outcomes in bone mineral density improvement and fracture risk reduction, particularly in elderly and frail populations. It enhanced muscular function by improving appendicular lean mass and grip strength while reducing fall risk. The drug showed potential cardiovascular benefits through its effects on cardiac and smooth muscle function. Notably, denosumab use was associated with reduced Type II diabetes mellitus risk through improved glucose metabolism. Additionally, it demonstrated promise in osteoarthritis treatment by suppressing osteoclast activity and chondrocyte apoptosis. While there are multisystem benefits, vigilance is required regarding adverse events, including hypocalcemia, infection risk, cutaneous reactions, and osteonecrosis of the jaw. Conclusions: Denosumab exhibits potential benefits in bone and systemic metabolism. Further research is needed to fully understand its therapeutic potential beyond osteoporosis and optimize clinical applications across different populations. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases: From Molecular Basis to Therapy (Volume II))

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Biomedicines, Volume 13, Issue 3 (March 2025) – 232 articles

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