Biomedicines

15 pages, 2293 KB

Open AccessArticle

Proteomic Study of Diffuse Large B-Cell Lymphoma Identifying Proteins Associated with R-CHOP Response

by Hulda Haraldsdóttir, Rasmus Froberg Brøndum, Marie Hairing Enemark, Bent Honoré, Maja Ludvigsen, Christopher Aboo, Allan Stensballe, Judit Mészáros Jørgensen, Hanne Due and Karen Dybkær

Biomedicines 2025, 13(11), 2709; https://doi.org/10.3390/biomedicines13112709 (registering DOI) - 4 Nov 2025

Abstract

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is a molecularly and pathogenically heterogenous disease with varying clinical outcomes, as reflected by the significant number of patients who develop relapse/refractory disease (rrDLBCL) following standard treatment with the combined R-CHOP regimen. The molecular background of rrDLBCL [...] Read more.

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is a molecularly and pathogenically heterogenous disease with varying clinical outcomes, as reflected by the significant number of patients who develop relapse/refractory disease (rrDLBCL) following standard treatment with the combined R-CHOP regimen. The molecular background of rrDLBCL is not yet fully understood, and prognostic and/or companion diagnostic biomarkers for identification and treatment stratification of these patients are in high demand. Methods: This exploratory study used comprehensive proteomic data to identify proteins associated with treatment response. Proteome profiles of DLBCL cells were analyzed through groupwise comparison between cell lines with a resistant or sensitive response to rituximab, cyclophosphamide, doxorubicin, and vincristine. Their responses were determined using subsequent drug response screens, mimicking the conditions of diagnostic samples prior to treatment. Results: A total of 98 differentially abundant proteins, including NSFL1C, GET4, PCNA, and SMC5, were found between resistant and sensitive cells. These same 98 proteins were examined in two cohorts of DLBCL patients, leading to the identification of 16 proteins whose expression was consistently associated with treatment response both in vitro and in patient tissue samples. Among these, GET4 and NSFL1C showed the highest enrichment in R-CHOP resistant patients compared to sensitive responders. In the cell line study, GET4 was enriched in cyclophosphamide-resistant cell lines and NSFL1C enriched in vincristine-resistant cell lines, associating GET4 and NSFL1C enrichment in patient samples to responsiveness to cyclophosphamide and vincristine, respectively. Enrichment of DNA damage repair proteins was observed within the differential proteins, highlighting the need to investigate DNA damage repair involvement in treatment responses. Conclusions: This study identifies 16 proteins with concordant treatment response specificity in DLBCL cell lines and lymphoma tissue patient samples, suggesting their potential as prognostic markers for DLBCL. Full article

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

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14 pages, 2004 KB

Open AccessArticle

Isotopic H/D Exchange in Hydrogen Bonds Between the Nitrogenous Bases of the CAG Repeat Tract Makes It Possible to Stabilize Its Expansion in the ATXN2 Gene

by Anna Dorohova, Luis Velázquez-Pérez, Mikhail Drobotenko, Oksana Lyasota, Jose Luis Hernandez-Caceres, Roberto Rodriguez-Labrada, Alexandr Svidlov, Olga Leontyeva, Yury Nechipurenko and Stepan Dzhimak

Biomedicines 2025, 13(11), 2708; https://doi.org/10.3390/biomedicines13112708 (registering DOI) - 4 Nov 2025

Abstract

Background: The isotopic composition of the body’s internal environment can affect its functional state. Such effects are realized, among other things, by inserting deuterium atoms into hydrogen bonds between pairs of nitrogenous bases of DNA molecules and modifying their mechanical properties. Methods [...] Read more.

Background: The isotopic composition of the body’s internal environment can affect its functional state. Such effects are realized, among other things, by inserting deuterium atoms into hydrogen bonds between pairs of nitrogenous bases of DNA molecules and modifying their mechanical properties. Methods: This study uses a coarse-grained mathematical model of DNA. Results: It has been established that in a certain range of the magnitude of the torque, with the presence of a deuterium atom within it, stabilization of the CAG repeat tract is observed. In addition, it was found that, regardless of which base pair the deuterium atom falls into in the CAG repeat tract, its stability increases and the probability of hairpin formation decreases, which may interfere with the reading of genetic information from the site encoding glutamine. Conclusions: Single H/D substitutions in the CAG repeat tract of the ATXN2 gene increase its stability by reducing the formation of open states, regardless of the position of deuterium. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Neurodegenerative Diseases (3rd Edition))

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23 pages, 3989 KB

Open AccessArticle

A Hot-Spring Water Improves Inflammatory Conditions in an Injury-Induced Atopic Dermatitis Mouse Model by Regulating Skin Barrier Function

by Yoko Naito, Abdullah Md. Sheikh, Jubo Bhuiya, Fatema Binte Abdullah, Jerin Fahmida, Shatera Tabassum, Hiro Tamegai, Kenichi Iwasa, Shozo Yano and Atsushi Nagai

Biomedicines 2025, 13(11), 2707; https://doi.org/10.3390/biomedicines13112707 - 4 Nov 2025

Abstract

Background: Atopic dermatitis (AD) is a common inflammatory skin condition in which skin barrier function plays a crucial role. Hot spring water is known for its beneficial effects on skin health. This study investigates the impact of a hot spring water on [...] Read more.

Background: Atopic dermatitis (AD) is a common inflammatory skin condition in which skin barrier function plays a crucial role. Hot spring water is known for its beneficial effects on skin health. This study investigates the impact of a hot spring water on AD pathology, focusing on skin barrier function. Methods: Using the tape-stripping method, we induced an AD mouse model, treated the mice with either hot-spring water or tap water, and assessed time-dependent changes in skin barrier function, histology, and AD-related proteins. Results: Transepithelial water loss (TEWL) was significantly increased after tape-stripping, which began to decrease from day 2 in both treatment groups. On day 3, water loss was significantly decreased in hot-spring-treated mice than tap water-treated mice. Histological analysis revealed thickening and vacuolization of the stratum spinosum from day 2, becoming more pronounced on day 3 in tap-water-treated mice. However, in hot-spring-treated mice, the stratum spinosum was significantly less thickened, and the stratum granulosum was better formed. Immunostaining showed that transient receptor potential vanilloid 4 (TRPV4) levels decreased at day 2 but returned to baseline by day 3, with no significant differences between groups. Filaggrin, a key skin barrier protein, was markedly low in tape-stripped areas at day 0, but increased progressively, with a higher level in the upper epidermis of hot-spring-treated mice compared to tap-water-treated counterparts. Additionally, hot spring water treatment significantly reduced CD8+ T cell numbers and IL-4 cytokine levels, mitigating inflammation. Conclusions: Threfore, hot spring water enhances skin barrier recovery and reduces inflammation in AD. Full article

(This article belongs to the Special Issue New Advances in Wound Healing and Skin Regeneration)

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20 pages, 5147 KB

Open AccessArticle

Polyunsaturated Fatty Acid (PUFA) Composition of Growth Medium Changes the Atherogenic Potential of Human Aortic Endothelial Cells (HAECs) Following Endotoxin Stimulation

by Nikolina Kolobarić, Zrinka Mihaljević, Mirjana Suver Stević, Ana Marinčić Žagar, Sandor G. Vari and Ines Drenjančević

Biomedicines 2025, 13(11), 2706; https://doi.org/10.3390/biomedicines13112706 - 4 Nov 2025

Abstract

Background/Objectives: Endothelial activation by lipopolysaccharides (LPS) contributes to inflammation and the development of cardiovascular disease, making n-3 polyunsaturated fatty acids (PUFAs) potential modulators capable of mitigating endothelial dysfunction. The current study examines the effects of long-chain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), [...] Read more.

Background/Objectives: Endothelial activation by lipopolysaccharides (LPS) contributes to inflammation and the development of cardiovascular disease, making n-3 polyunsaturated fatty acids (PUFAs) potential modulators capable of mitigating endothelial dysfunction. The current study examines the effects of long-chain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), along with their precursor, α-linolenic acid (ALA), on oxidative stress, adhesion molecule expression, and cytokine milieu in LPS-stimulated human aortic endothelial cells (HAECs). Methods: HAECs (fifth passage) were cultured in control medium under standard conditions: ~37 °C, 5% CO₂, ≥80% humidity. Cells were incubated in control basal cell medium or medium supplemented with ALA, EPA, DHA, and their combination (50 µM; n = 5 per group). After 48 h, cells were treated overnight (~16 h) with LPS from E. coli (0.75 and 1 µg/mL). HAECs and supernatants were collected for flow cytometry, Luminex, and ELISA assays. Significance was assessed using two-way analysis of variance ANOVA, followed by post hoc analyses (p < 0.05). Spearman’s correlation analysis was performed between markers, and p-values were adjusted using the Benjamini–Hochberg (BH) correction. Results: PUFA supplementation, particularly with DHA and ALA, significantly reduced intracellular reactive oxygen species (ROS) production and the expression of adhesion molecules (ICAM-1, E-selectin) in HAECs under both basal and LPS-stimulated inflammatory conditions. All PUFAs reduced pro-inflammatory cytokine levels (IFNγ, TNFα, IL-6), while ALA increased IL-1α and endoglin expression, indicating differential immunomodulatory effects. EPA exhibited antioxidant and anti-inflammatory effects primarily at higher LPS concentrations. Correlation analysis demonstrated strong interdependence between oxidative stress, inflammatory markers, and vascular activation, further confirming PUFA-mediated endothelial protection. Conclusions: PUFA supplementation produced molecule-specific effects on endothelial inflammation. DHA and ALA consistently showed anti-inflammatory and antioxidative effects, while EPA’s beneficial effect was more pronounced under inflammatory conditions, emphasising the importance of PUFA type and context in managing vascular inflammation. Full article

(This article belongs to the Special Issue Pathophysiology of Fatty Acid Metabolism)

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Graphical abstract

26 pages, 1809 KB

Open AccessReview

Alternative Anticoagulation for Patients with Heparin-Induced Thrombocytopenia on ECMO: A Narrative Review

by Dragana Unic-Stojanovic, Petar Vukovic, Ivan Ilic, Milica Miljkovic Stojicic, Slobodan Tanaskovic, Nikolina Kangrga and Sasa Rajsic

Biomedicines 2025, 13(11), 2705; https://doi.org/10.3390/biomedicines13112705 - 4 Nov 2025

Abstract

Extracorporeal membrane oxygenation (ECMO) is a continuously evolving and increasingly utilized life-support therapy. ECMO requires systemic anticoagulation, which exposes patients to an increased risk of heparin-induced thrombocytopenia (HIT). Clinical experience with alternative anticoagulants in this setting remains limited. The 2022 Extracorporeal Life Support [...] Read more.

Extracorporeal membrane oxygenation (ECMO) is a continuously evolving and increasingly utilized life-support therapy. ECMO requires systemic anticoagulation, which exposes patients to an increased risk of heparin-induced thrombocytopenia (HIT). Clinical experience with alternative anticoagulants in this setting remains limited. The 2022 Extracorporeal Life Support Organization (ELSO)—Anticoagulation Guidelines provide no specific recommendations regarding anticoagulant selection for ECMO patients with HIT. This article aims to review current practices, available evidence, and most recent advances concerning the use of alternative anticoagulants in ECMO patients with HIT. In patients with a high suspicion or confirmed diagnosis of HIT, management includes discontinuing all forms of heparin exposure and initiating an alternative anticoagulant, such as a direct thrombin inhibitor and/or factor Xa inhibitor. Direct thrombin inhibitors act independently of antithrombin and have a short half-life, providing a more consistent and predictable anticoagulation effect. Most available data, primarily from retrospective studies, describe the use of argatroban in ECMO patients with HIT. Bivalirudin has also been used as an alternative anticoagulant in this population, with no significant increase in bleeding or thrombotic complications. However, the current evidence remains limited to small, retrospective, single-center or case–control studies. Fondaparinux has shown effectiveness in the HIT setting and appears to have a low risk of complications. Factor XIIa inhibitors represent a novel class of anticoagulants currently under investigation, evaluated only in animal models. Growing clinical experience with alternative anticoagulants, particularly direct thrombin inhibitors, suggests that their use will likely become a primary focus in ECMO anticoagulation management in the coming years. Full article

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

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14 pages, 695 KB

Open AccessArticle

Non-Motor Symptoms as Markers of Disease Severity in Parkinson’s Disease: Associations Between Constipation, Depression, REM Sleep Behavior Disorder, and Motor Impairment

by João Paulo Mota Telles, Júlia Haddad Labello, Lucas Camargo, Carla Pastora-Sesin, Anna Carolyna Gianlorenço and Felipe Fregni

Biomedicines 2025, 13(11), 2704; https://doi.org/10.3390/biomedicines13112704 - 3 Nov 2025

Abstract

Background: This study aims to investigate the association between the presence and severity of non-motor symptoms (constipation, REM sleep behavior disorder [RBD], hyposmia, and depression) and the severity of motor impairment in Parkinson’s disease (PD). Methods: We used data from Parkinson’s Progression Markers [...] Read more.

Background: This study aims to investigate the association between the presence and severity of non-motor symptoms (constipation, REM sleep behavior disorder [RBD], hyposmia, and depression) and the severity of motor impairment in Parkinson’s disease (PD). Methods: We used data from Parkinson’s Progression Markers Initiative (PPMI), comprising patients with established PD, prodromal PD, and healthy controls. Motor disability was evaluated with the MDS-UPDRS part III. Non-motor symptoms were assessed with standardized scales for constipation (MDS-UPDRS part I sub-item), depression (15-item GDS), RBD questionnaire (RBDQ), and hyposmia (UPSIT). The relationships between non-motor symptoms and motor severity were explored using linear regression models (adjusted for age/sex). Results: Constipation was significantly more prevalent in PD and prodromal PD and independently associated with greater motor severity in both groups (p < 0.001). Constipation also correlated with increased freezing and falls. Depressive symptoms were similar across groups, but in prodromal PD, higher GDS scores were associated with worse UPDRS III scores (p = 0.02), as well as higher freezing and fall scores. Hyposmia was strongly reduced in PD and prodromal PD compared with controls but was not independently associated with motor severity. Higher RBDQ scores were associated with worse motor impairment in PD, but not in prodromal PD after adjustment. Conclusions: Constipation and REM sleep behavioral disorder were independent correlates of worse motor severity in prodromal and established PD, whereas depressive symptoms predicted more severe parkinsonism only within the prodromal phase. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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16 pages, 769 KB

Open AccessReview

Combined Pulmonary Fibrosis and Emphysema (CPFE): A “New” Smoking-Related Interstitial Lung Disease (ILD)

by Carina Adina Afloarei, Tudor Birladeanu, Adriana Loredana Pintilie, David Toma, Dragos Traian Marius Marcu, Andreea Zabara Antal, Mihai Zabara and Radu Crisan Dabija

Biomedicines 2025, 13(11), 2703; https://doi.org/10.3390/biomedicines13112703 - 3 Nov 2025

Abstract

Background: Combined Pulmonary Fibrosis and Emphysema (CPFE) is a distinct syndrome characterized by upper-lobe emphysema and lower-lobe fibrosis, predominantly in older male smokers. Despite often preserved spirometric volumes, patients exhibit severely reduced diffusing capacity and high susceptibility to complications, including pulmonary hypertension (PH), [...] Read more.

Background: Combined Pulmonary Fibrosis and Emphysema (CPFE) is a distinct syndrome characterized by upper-lobe emphysema and lower-lobe fibrosis, predominantly in older male smokers. Despite often preserved spirometric volumes, patients exhibit severely reduced diffusing capacity and high susceptibility to complications, including pulmonary hypertension (PH), acute exacerbations, and lung cancer, contributing to poor prognosis. Purpose: This review aims to synthesize current evidence on CPFE, focusing on clinical phenotype, functional impairment, differential diagnosis, complications, and emerging management strategies, highlighting distinctions from idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Methods: A narrative review of observational cohorts, retrospective series, and clinical studies examining CPFE patients was performed. Data on demographics, smoking history, symptomatology, pulmonary function, radiology, comorbidities, complications, and treatment approaches were extracted and integrated. Results: CPFE affects mainly males aged 65–70, with >90% reporting > 40 pack–years smoking history. Dyspnea is the cardinal symptom (>95%), often disproportionate to preserved FVC and TLC, accompanied by chronic cough in 30–70%. Exercise-induced desaturation is frequent, correlating with PH, observed in 47–90% of patients. Pulmonary function tests reveal preserved volumes, normal or near-normal FEV1/FVC, and severely reduced DLCO (35–45%), distinguishing CPFE from COPD and IPF. HRCT confirms the combined emphysematous and fibrotic pattern, critical for differential diagnosis. Acute exacerbations occur in 20–28% of cases, lung cancer in 22–46% (mostly squamous cell), and long-term oxygen therapy is required in >70%. Five-year survival is 35–55%, lower than emphysema alone and comparable or worse than IPF. Management focuses on smoking cessation, antifibrotics, oxygen therapy, and complication-specific treatments, and selected patients may undergo lung transplantation. Conclusions: CPFE is a clinically and functionally unique entity with a high burden of pulmonary and systemic complications. Accurate recognition using HRCT and DLCO, along with early intervention and tailored management, is essential to improve patient outcomes and guide prognostic stratification. Full article

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

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21 pages, 606 KB

Open AccessReview

Clostridioides difficile Infection in Special Populations: Focus on Inflammatory Bowel Disease—A Narrative Review from Pathogenesis to Management

by Cristina Seguiti, Enrico Tettoni, Edoardo Pezzuto, Viviana Gerardi, Alessandro Quadarella, Paola Cesaro and Paolo Colombini

Biomedicines 2025, 13(11), 2702; https://doi.org/10.3390/biomedicines13112702 - 3 Nov 2025

Abstract

Clostridioides difficile infection (CDI) is a major complication in inflammatory bowel disease (IBD), due to coexistence of altered microbiota, chronic inflammation, and immune dysregulation. This narrative review summarizes recent evidence on the epidemiology, pathogenesis, risk factors, diagnosis, and management of CDI in IBD. [...] Read more.

Clostridioides difficile infection (CDI) is a major complication in inflammatory bowel disease (IBD), due to coexistence of altered microbiota, chronic inflammation, and immune dysregulation. This narrative review summarizes recent evidence on the epidemiology, pathogenesis, risk factors, diagnosis, and management of CDI in IBD. Overall, IBD patients have a four- to five-fold higher risk of CDI than the general population and face more severe courses, higher rates of hospitalization, colectomy, recurrence, and mortality. Pathogenesis involves profound dysbiosis with loss of butyrate-producing Firmicutes and Bacteroidetes, bile acid imbalance that promotes spore germination, and enhanced toxin effects on an already inflamed mucosa. Major risk factors include active colonic disease, broad-spectrum antibiotic exposure, prolonged hospitalization, and corticosteroid or combined immunosuppressive therapy. Diagnosis requires careful integration of stool assays with clinical evaluation, supported by endoscopy or imaging when needed, to distinguish infection from IBD flares. Recommended first-line treatments are fidaxomicin or oral vancomycin, reserving fecal microbiota transplantation for recurrent or high-risk cases. Optimal IBD control is essential to reduce both primary and recurrent infection. CDI and IBD share a mutual pathogenic interplay in which microbial, immune, and therapeutic factors from each condition drive and magnify the other. Early recognition, guideline-based antibiotic therapy, judicious use of immunosuppression, and microbiota-based preventive strategies are crucial to improve patient outcomes and limit recurrence, thus reducing healthcare costs. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis and Treatment of Infectious Diseases)

11 pages, 824 KB

Open AccessBrief Report

Evaluation of Oral Mucosa Capillaries in Fibromyalgia Patients

by Salvatore Nigliaccio, Davide Alessio Fontana, Francesca Pusateri, Emanuele Di Vita, Pietro Messina, Enzo Cumbo and Giuseppe Alessandro Scardina

Biomedicines 2025, 13(11), 2701; https://doi.org/10.3390/biomedicines13112701 - 3 Nov 2025

Abstract

Background: Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread musculoskeletal pain, fatigue, unrefreshed sleep, and cognitive disturbances. Despite extensive research, its pathophysiology remains incompletely understood, and there are no validated biomarkers for diagnosis. Videocapillaroscopy is a non-invasive imaging technique that enables [...] Read more.

Background: Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread musculoskeletal pain, fatigue, unrefreshed sleep, and cognitive disturbances. Despite extensive research, its pathophysiology remains incompletely understood, and there are no validated biomarkers for diagnosis. Videocapillaroscopy is a non-invasive imaging technique that enables detailed visualization of microvascular structures and may provide insights into microcirculatory alterations associated with FM. Methods: Thirty patients with FM and 30 healthy controls underwent oral videocapillaroscopy at four sites: right and left buccal mucosa and upper and lower labial mucosa. Quantitative parameters, including capillary caliber, density, and length, were extracted using a validated neural-network-based software, while qualitative parameters, including visibility, orientation, and the presence of microhemorrhages, were assessed by the operator. Results: Capillary length was significantly reduced in fibromyalgia patients (297.49 ± 26.82 µm) compared to healthy controls (324.43 ± 37.59 µm; p = 0.002), and capillary orientation differed significantly between groups (p < 0.05). Capillary caliber, density, and visibility did not show statistically significant differences. Conclusions: These findings indicate subtle microvascular alterations in the oral mucosa of patients with fibromyalgia. Although the observed changes are not sufficient for diagnostic purposes or early detection, they provide preliminary evidence that videocapillaroscopy can detect microvascular features associated with FM in the oral mucosa. Further studies with larger cohorts and longitudinal designs are warranted to clarify the clinical relevance of these observations and to explore their potential association with symptom severity or disease progression. Full article

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

10 pages, 333 KB

Open AccessArticle

Do Cancer Patients Present a Different Phenotype of Atrial Fibrillation or a Different Arrhythmia Management?

by Maja Hawryszko, Grzegorz Sławiński, Weronika Pusz-Bulas, Mikołaj Młyński, Kalina Wiśniewska, Patryk Macuk, Aleksandra Liżewska-Springer, Ludmiła Daniłowicz-Szymanowicz and Ewa Lewicka

Biomedicines 2025, 13(11), 2700; https://doi.org/10.3390/biomedicines13112700 - 3 Nov 2025

Abstract

Background/Objectives: Along with cardiovascular disease, cancer is the leading cause of death worldwide. The aim of the study was to compare the clinical and echocardiographic characteristics of atrial fibrillation (AF) among patients with active cancer (study group) and those without cancer (control [...] Read more.

Background/Objectives: Along with cardiovascular disease, cancer is the leading cause of death worldwide. The aim of the study was to compare the clinical and echocardiographic characteristics of atrial fibrillation (AF) among patients with active cancer (study group) and those without cancer (control group). Methods: This retrospective study included patients diagnosed with both AF and active cancer referred for consultation to the Cardiac Arrhythmias Outpatient Clinic at our institution in 2022. They were matched in a 1:1 ratio, by age and sex to patients with AF without cancer. The matching criteria for the study and control groups were limited to age and gender. Variables such as comorbidities, atrial fibrillation duration, tumor stage, and treatment were not included in the matching criteria. Results: We examined 216 patients, 57.4% of whom were men. There were 110 patients in the study group with a mean age of 70 (10) years. Several parameters in the study group attracted our particular attention: N-terminal pro-B-type natriuretic peptide (NT-proBNP) was lower (703 pg/mL vs. 1549 pg/mL, p = 0.01), echocardiography revealed smaller left atrial size (43 (6) mm vs. 47 (7) mm, p = 0.015), left ventricular (LV) diastolic dimension (49 mm vs. 52 mm, p = 0.009) and better LV systolic function expressed as LV ejection fraction (54% (9%) vs. 51% (12%), p = 0.025), and global longitudinal strain (−16% (4%) vs. −13% (3%), p = 0.016). Antiarrhythmic pharmacotherapy was used less frequently in the study group, which may also have been due to physicians’ reluctance to treat AF aggressively in a more morbid population. Conclusions: Patients with cancer and atrial fibrillation may have a different clinical profile, suggesting a different pathophysiology. Understanding these differences may help reduce the incidence of AF and improve patient outcomes and prognosis during cancer treatment. Full article

(This article belongs to the Special Issue Cardiac Arrhythmias and Arrhythmogenic Disorders: Technological Frontiers, Drug Development and Future Directions)

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22 pages, 978 KB

Open AccessReview

Urea Transporters in Cancer: Emerging Roles and Their Clinical Implications

by Huimin Sun, Qiaoting Yang, Meng Ding, Shirui Li and Yi Xue

Biomedicines 2025, 13(11), 2699; https://doi.org/10.3390/biomedicines13112699 - 3 Nov 2025

Abstract

Background/Objective: The SLC14A gene family in mammals encodes the urea transporters UT-A and UT-B (UTs), whose primary function is urea transport. In recent years, increasing research has shown that UTs are involved in tumor formation and progression. The purpose of this article is [...] Read more.

Background/Objective: The SLC14A gene family in mammals encodes the urea transporters UT-A and UT-B (UTs), whose primary function is urea transport. In recent years, increasing research has shown that UTs are involved in tumor formation and progression. The purpose of this article is to review the current knowledge in the potential of urea transporters as tumor biomarkers and therapeutic targets. Methods: An extensive review of the literature was performed utilizing both PubMed and Web of Science databases focusing on articles published within the last ten years. Results: UTs are significantly downregulated in various tumor tissues. They are associated with the staging and prognosis of cancers such as bladder cancer (BC). They participate in the metabolic reprogramming of tumor cells via glycosylation, enhancing the energy supply and material synthesis of tumor cells. They participate in remodeling the tumor microenvironment, influencing the interactions between fibroblasts and tumor cells. Additionally, they interact with other signaling pathways to participate in tumorigenesis and development. Conclusions: The mechanisms by which UTs function in tumorigenesis and progression remain to be fully elucidated, but their potential as tumor biomarkers and therapeutic targets has gradually attracted attention. Full article

(This article belongs to the Section Cell Biology and Pathology)

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14 pages, 340 KB

Open AccessReview

Under a Spell: Neurologic Evaluation of Presyncope as a Feature of Dysautonomia

by Svetlana Blitshteyn, Kamal R. Chémali and Dennis H. Lau

Biomedicines 2025, 13(11), 2698; https://doi.org/10.3390/biomedicines13112698 - 3 Nov 2025

Abstract

While syncope is characterized by a sudden and temporary loss of consciousness caused by decreased blood flow to the brain and is easily recognized by its clinical features, presyncope involves a sensation of impending fainting, often accompanied by autonomic symptoms. Presyncope is less [...] Read more.

While syncope is characterized by a sudden and temporary loss of consciousness caused by decreased blood flow to the brain and is easily recognized by its clinical features, presyncope involves a sensation of impending fainting, often accompanied by autonomic symptoms. Presyncope is less characterized and studied than syncope, presenting a particular diagnostic challenge in neurology clinics. Neurologists commonly encounter patients with presyncope in outpatient settings or during consultation at the emergency department after cardiopulmonary causes have been excluded. Differential diagnosis of recurrent presyncope is broad but from a neurologic standpoint falls into multiple neurologic categories, including complex partial seizures, basilar or vestibular migraine, dysautonomia, cataplexy, alteration in cerebrospinal fluid flow, Meniere’s disease, posterior circulation transient ischemic attacks and others. Here, we review presyncope as a feature of dysautonomia and common autonomic disorders, such as neurocardiogenic syncope, postural orthostatic tachycardia syndrome, orthostatic hypotension and orthostatic intolerance. We discuss clinical and neurologic exam findings, diagnostic tests, differential diagnosis and treatment of presyncope as a manifestation of common autonomic disorders. Full article

(This article belongs to the Special Issue Autonomic Disorders: From Mechanisms to Therapeutic Approaches)

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6 pages, 174 KB

Open AccessEditorial

The “Now” and “Next” in Precision Cardiovascular Medicine

by Panteleimon Pantelidis and Polychronis E. Dilaveris

Biomedicines 2025, 13(11), 2697; https://doi.org/10.3390/biomedicines13112697 - 3 Nov 2025

Abstract

The convergence of Artificial Intelligence (AI), genomic medicine, and precision therapeutics is fundamentally transforming cardiovascular care from reactive treatment paradigms toward proactive, individualized approaches [...] Full article

(This article belongs to the Special Issue Cardiovascular Diseases in the Era of Precision Medicine)

19 pages, 5052 KB

Open AccessArticle

Hydrogen Sulfide Attenuates Cisplatin-Induced Acute Kidney Injury via Dual Inhibition of Apoptosis and Pyroptosis

by Zhenyuan Han, Yutao Jia, Dechao Yan, Ying Xue, Tianyu Deng, Ping Wang, Leijuan Xiao and Xiaoyan Wang

Biomedicines 2025, 13(11), 2696; https://doi.org/10.3390/biomedicines13112696 - 3 Nov 2025

Abstract

Purpose: Cisplatin chemotherapy is complicated by acute kidney injury (cis-AKI), driven by regulated cell death pathways, including apoptosis and pyroptosis. However, the temporal relationship between apoptosis and pyroptosis in cis-AKI remains unclear. This study investigated the roles of these pathways and evaluated the [...] Read more.

Purpose: Cisplatin chemotherapy is complicated by acute kidney injury (cis-AKI), driven by regulated cell death pathways, including apoptosis and pyroptosis. However, the temporal relationship between apoptosis and pyroptosis in cis-AKI remains unclear. This study investigated the roles of these pathways and evaluated the renoprotective effect of the hydrogen sulfide (H₂S) donor GYY4137. Method: Cis-AKI was modeled in mice and HK2 cells, divided into control, cisplatin, and cisplatin + GYY groups. Kidney function parameters, histopathology, and cell death were evaluated. Markers of apoptosis and pyroptosis, along with the H₂S-producing enzyme, were analyzed. Results: Renal impairment progressed from BUN elevation to increased Scr, coupled with aggravated renal tissue damage. Apoptotic signaling peaked at 24 h, evidenced by a raised Bax/Bcl-2 ratio and caspase-3 cleavage. Pyroptosis pathways, via both NLRP3/caspase-1/GSDMD and caspase-3/GSDME axes, were activated later at 72 h, with concurrent rises in IL-1β and IL-18. GYY4137 treatment significantly ameliorated renal dysfunction, reducing serum creatinine and BUN levels by 22.64% and 22.5%, respectively. It suppressed both the early apoptotic and delayed pyroptosis cascades without reversing CBS downregulation. Conclusions: GYY4137 mitigated both apoptosis and pyroptosis, offering a promising multi-targeted therapy for cis-AKI. Full article

(This article belongs to the Special Issue Molecular Mechanism in Inflammation and Immunity)

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17 pages, 703 KB

Open AccessReview

Neuroplasticity Across the Autism–Schizophrenia Continuum

by Evangelia Kesidou, Nikolaos Mitsoudis, Olympia Damianidou, Charilaos Taloumtzis, Marianna Tsakiridou, Eleni Polyzoidou, Eleni Grigoriadou, Christos Bakirtzis, Evangelia Spandou and Constantina Simeonidou

Biomedicines 2025, 13(11), 2695; https://doi.org/10.3390/biomedicines13112695 - 2 Nov 2025

Abstract

Plasticity is a fundamental property of the brain that enables the nervous system to respond appropriately to internal and external stimuli. It primarily involves changes at the synaptic level, mediated by a wide array of molecules, ultimately leading to cognitive and behavioral changes. [...] Read more.

Plasticity is a fundamental property of the brain that enables the nervous system to respond appropriately to internal and external stimuli. It primarily involves changes at the synaptic level, mediated by a wide array of molecules, ultimately leading to cognitive and behavioral changes. This review critically contrasts the developmental timing and mechanisms of plasticity in Autism spectrum disorder (early hyperplasticity and excitation–inhibition imbalance) versus Schizophrenia (adolescent overpruning and NMDAR hypofunction) and evaluates evidence for interventions that harness plasticity to improve cognitive and behavioral outcomes. Preclinical and small clinical studies suggest that interventions targeting plasticity-related pathways may improve specific cognitive and behavioral domains. However, effects appear to be symptom-domain-specific and protocol-dependent and larger randomized controlled trials are needed to confirm efficacy. Cognitive remediation for Schizophrenia has been associated with improved executive function and increased hippocampal volume, while virtual reality-based training for Autism spectrum disorder has shown gains in attention and planning skills. By highlighting both molecular mechanisms and therapeutic strategies, this review aims to provide an integrated perspective on how plasticity-targeted interventions could be optimized across neurodevelopmental and neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Multidisciplinary Approaches to Neurodegenerative Disorders)

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27 pages, 2009 KB

Open AccessReview

Intracellular Calcium Dysregulation: The Hidden Culprit in the Diabetes–Gout Nexus

by Hongbin Shi, Yisi Shan, Kewei Qian, Ruofei Zhao and Hong Li

Biomedicines 2025, 13(11), 2694; https://doi.org/10.3390/biomedicines13112694 - 2 Nov 2025

Abstract

Type 2 diabetes and gout are both common metabolic disorders that frequently occur together. Research indicates that disturbances in intracellular calcium balance may be a key molecular factor linking the development of these two diseases. Calcium signaling disturbances promote the synergistic progression of [...] Read more.

Type 2 diabetes and gout are both common metabolic disorders that frequently occur together. Research indicates that disturbances in intracellular calcium balance may be a key molecular factor linking the development of these two diseases. Calcium signaling disturbances promote the synergistic progression of both diseases through multiple pathways: In pancreatic β-cells, endoplasmic reticulum (ER) calcium imbalance triggers ER stress, mitochondrial dysfunction, and apoptosis, autophagy, and pyroptosis, leading to impaired insulin secretion. Concurrently, calcium overload exacerbates insulin resistance by disrupting insulin signal transduction in peripheral tissues, while hyperinsulinemia further inhibits uric acid excretion through activation of the renal URAT1 transporter, creating a vicious cycle. Additionally, calcium homeostasis dysregulation activates the NLRP3 inflammasome and promotes the release of pro-inflammatory cytokines, aggravating chronic low-grade inflammation, which further deteriorates β-cell function and peripheral metabolic disorders, collectively driving the pathological link between type 2 diabetes and gout. Although calcium channel modulators show potential in improving β-cell function and reducing inflammation, their clinical application faces challenges such as tissue-specific effects and a lack of high-quality clinical trials. We propose that intracellular calcium dysregulation serves as a central pathological amplifier in the diabetes–gout nexus. Future research on targeted calcium signaling interventions, guided by this integrative concept, may help overcome the therapeutic challenges in managing type 2 diabetes complicated by gout. Full article

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

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9 pages, 883 KB

Open AccessArticle

RB1 Sequence Variants in Retinoblastoma: Analysis of RB1 Variants in a Database for Correlation with pRB Protein Domains and Clinical Presentation

by Nicohol Tovar Martelo and Irene Szijan

Biomedicines 2025, 13(11), 2693; https://doi.org/10.3390/biomedicines13112693 - 2 Nov 2025

Abstract

Background: Retinoblastoma (RB) is the most common pediatric ocular tumor that occurs due to the biallelic inactivation of the RB1 tumor suppressor gene. RB may be unilateral or bilateral and is hereditary in 50% of cases. An inactivation of the RB1 gene [...] Read more.

Background: Retinoblastoma (RB) is the most common pediatric ocular tumor that occurs due to the biallelic inactivation of the RB1 tumor suppressor gene. RB may be unilateral or bilateral and is hereditary in 50% of cases. An inactivation of the RB1 gene may occur due to gross rearrangements (20%) or due to small-length changes (80%): single nucleotide substitutions (SNVs) and insertions/deletions (INDELs). Objectives: Our objective was to study the frequency of the different RB1 variants present in patients with retinoblastoma and to correlate them with the functional domains of the pRb protein and with the clinical presentation. Methods: For this purpose, we analyzed all the clinically validated germline SNVs and INDELs annotated in the database. They were grouped into the pRb domains; contingency tables were made, and figures were constructed to compare the types of variants in the different domains between bilateral and unilateral patients. Results: The number of variants analyzed was 2103; 34% of them were nonsense, 34% INDELs, 22% splice-site and 10% missense. All these variants mainly gave rise to bilateral RB (88%); their frequency and distribution in relation to pRb domains varied between bilateral (Bi) and unilateral hereditary (Ug) RB. Nonsense variants occurred more frequently in Bi vs. Ug, whereas missense variants were more frequent in Ug vs. Bi. Indels and splice-site variants were not significantly different between Bi and Ug. The most frequent pRB location of variants was in the Pocket domain (the binding site of the E2F transcription factor). The slice-site of the consensus sequence most mutated was the first nucleotide of the donor, which is the driver of the splicing process. Conclusions: The highest percentage of variants in RB corresponded to nonsense substitutions and indels, mainly affecting the Pocket domain, which is the major functional site for the pRb regulatory process. These results indicate the predominance of the most pathogenic variants related to the bilateral presentation of retinoblastoma. Full article

(This article belongs to the Special Issue Pediatric Tumors: Diagnosis, Pathogenesis, Treatment, and Outcome)

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19 pages, 8412 KB

Open AccessArticle

A Thymus-Independent Artificial Organoid System Supports Complete Thymopoiesis from Rhesus Macaque-Derived Hematopoietic Stem and Progenitor Cells

by Callie Wilde, Saleem Anwar, Yu-Tim Yau, Sunil Badve, Yesim Gokmen Polar, John D. Roback, Rama Rao Amara, R. Paul Johnson and Sheikh Abdul Rahman

Biomedicines 2025, 13(11), 2692; https://doi.org/10.3390/biomedicines13112692 - 1 Nov 2025

Abstract

Background: T cell regeneration in the thymus is intrinsically linked to the T cell-biased lineage differentiation of hematopoietic stem and progenitor cells (HSPCs). Although nonhuman primates (NHPs) serve as indispensable models for studying thymic output under physiological and pathological conditions, a non-animal technology [...] Read more.

Background: T cell regeneration in the thymus is intrinsically linked to the T cell-biased lineage differentiation of hematopoietic stem and progenitor cells (HSPCs). Although nonhuman primates (NHPs) serve as indispensable models for studying thymic output under physiological and pathological conditions, a non-animal technology facilitating efficient TCR-selected T cell development and evaluating T cell output from NHP-derived HSPCs has been lacking. To address this gap, we established a rhesus macaque-specific artificial thymic organoid (RhATO) modeling primary thymus-tissue-free thymopoiesis. Methods: The RhATO was developed by expressing Rhesus macaque (RM) Delta-like Notch ligand 1 in mouse bone marrow stromal cell line (MS5-RhDLL1). The bone marrow-derived HSPCs were aggregated with MS5-RhDLL1 and cultured forming 3D artificial thymic organoids. These organoids were maintained under defined cytokine conditions to support complete T cell developmental ontogeny. T cell developmental progression was assessed by flow cytometry, and TCR-selected subsets were analyzed for phenotypic and functional properties. Results: RhATOs recapitulated the complete spectrum of thymopoietic events, including emergence of thymus-seeding progenitors, CD4⁺CD3⁻ immature single-positive and CD4⁺CD8⁺ double-positive early thymocytes, and mature CD4⁺ or CD8⁺ single-positive subsets. These subsets expressed CD38, consistent with the recent thymic emigrant phenotype, and closely mirrored canonical T cell ontogeny described in humans. RhATO-derived T cells were TCR-selected and demonstrated cytokine expression upon stimulation. Conclusions: This study provides the first demonstration of an NHP-specific artificial thymic technology that faithfully models thymopoiesis. RhATO represents a versatile ex vivo platform for studying T cell development, immunopathogenesis, and generating TCR selected T cells. Full article

(This article belongs to the Special Issue Immune Cell Reprogramming: Molecular Mechanisms and Therapeutic Approaches)

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16 pages, 841 KB

Open AccessReview

Deep Brain Stimulation: Mechanisms, Cost-Effectiveness, and Precision Applications Across Neurology and Psychiatry

by Horia Petre Costin, Felix-Mircea Brehar, Antonio-Daniel Corlatescu and Viorel Mihai Pruna

Biomedicines 2025, 13(11), 2691; https://doi.org/10.3390/biomedicines13112691 - 1 Nov 2025

Abstract

In less than 30 years, Deep Brain Stimulation (DBS) has evolved from an antiparkinsonian rescue intervention into a flexible neuromodulatory therapy with the potential for personalized, adaptive, and enhancement-focused interventions. In this review we collected evidence from seven areas: (i) modern eligibility criteria, [...] Read more.

In less than 30 years, Deep Brain Stimulation (DBS) has evolved from an antiparkinsonian rescue intervention into a flexible neuromodulatory therapy with the potential for personalized, adaptive, and enhancement-focused interventions. In this review we collected evidence from seven areas: (i) modern eligibility criteria, and ways to practically improve on these, outside of ‘Core Assessment Program of Surgical Interventional Therapies in Parkinson’s Disease’ (CAPSIT-PD); (ii) cost-effectiveness, where long-horizon models now show positive incremental net monetary benefit for Parkinson’s disease, and rechargeable-devices lead the way in treatment-resistant depression and obsessive–compulsive disorder; (iii) anatomical targets, from canonical subthalamic nucleus (STN) / globus pallidus internus (GPi) sites, to new dual-node and cortical targets; (iv) mechanistic theories from informational lesions, antidromic cortical drive, and state-dependent network modulation made possible by optogenetics and computational modeling; (v) psychiatric and metabolic indications, and early successes in subcallosal and nucleus-accumbens stimulation for depression, obsessive–compulsive disorder (OCD), anorexia nervosa, and schizophrenia; (vi) procedure- and hardware-related safety, summarized through five reviews, showing that the risks were around 4% for infection, 4–5% for revision surgery, 3% for lead malposition or fracture, and 2% for intracranial hemorrhage; and (vii) future directions in connectomics, closed-loop sensing, and explainable machine learning pipelines, which may change patient selection, programming, and long-term stewardship. Overall, the DBS is entering a “third wave” focused on a better understanding of neural circuits, the integration of AI-based adaptive technologies, and an emphasis on cost-effectiveness, in order to extend the benefits of DBS beyond the treatment of movement disorders, while remaining sustainable for healthcare systems. Full article

(This article belongs to the Special Issue Nervous System Diseases: From Pathophysiology to Novel Therapeutic Approaches)

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