Biomedicines

25 pages, 526 KB

Open AccessReview

Gene Therapy in Crohn’s Disease: Current Preclinical Challenges and Future Translational Avenues

by Solafah Abdalla, Antoine Brouquet, Romina Aron-Badin and Pierre Bougnères

Biomedicines 2025, 13(12), 3078; https://doi.org/10.3390/biomedicines13123078 (registering DOI) - 13 Dec 2025

Crohn’s disease (CD) remains a highly complex disorder, and the progress of preclinical gene therapy for CD has been constrained by several significant challenges. These include the identification of optimal therapeutic gene targets, the difficulty of targeting therapy-resistant cells within a chronic inflammatory [...] Read more.

Crohn’s disease (CD) remains a highly complex disorder, and the progress of preclinical gene therapy for CD has been constrained by several significant challenges. These include the identification of optimal therapeutic gene targets, the difficulty of targeting therapy-resistant cells within a chronic inflammatory microenvironment, particularly in the enteric nervous system (ENS), and the lack of robust animal models that faithfully recapitulate human pathology, as classical models largely rely on toxin-induced colitis. This review synthesizes major preclinical studies on gene therapy for CD and related inflammatory bowel diseases (IBD). We critically assess the rationale and biodistribution data for different vector platforms, considering vector type, promoter, and route of administration, in the ileum and colon of both rodent and non-human primate models. Special attention is given to strategies targeting the ENS. Finally, we explore the putative therapeutic aims of these approaches, including direct attenuation of intestinal inflammation and prevention of postoperative recurrence of CD via local intraoperative gene delivery. Although most data derive from chemical colitis models, this review establishes a foundational framework to inform translational research in gene therapy for CD and other IBDs. Full article

(This article belongs to the Special Issue Crohn’s Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (3rd Edition))

12 pages, 416 KB

Open AccessArticle

Impact of Positive Airway Pressure and Mask Leakage on Dry Eye and Glaucoma Risk in Obstructive Sleep Apnea: A Cross-Sectional Analysis

by Wei-Xiang Wang, Ya-Ning Chuang, Chen-Ni Chang, Mei-Chen Yang and Elizabeth P. Shen

Biomedicines 2025, 13(12), 3077; https://doi.org/10.3390/biomedicines13123077 (registering DOI) - 13 Dec 2025

Abstract

Purpose: This study investigates the association between obstructive sleep apnea (OSA), dry eye disease (DED), and glaucoma, focusing on the impact of positive airway pressure (PAP) usage and air leakage. Methods: This retrospective cross-sectional study included 57 adults with polysomnography-confirmed OSA between 2010 [...] Read more.

Purpose: This study investigates the association between obstructive sleep apnea (OSA), dry eye disease (DED), and glaucoma, focusing on the impact of positive airway pressure (PAP) usage and air leakage. Methods: This retrospective cross-sectional study included 57 adults with polysomnography-confirmed OSA between 2010 and 2023. Participants were grouped into PAP users (PAP+, n = 40) and non-users (PAP−, n =17). Ocular assessments included tear film break-up time, Schirmer’s test, Oxford staining, meibomian gland evaluation, intraocular pressure, cup-to-disc (C/D) ratio, and retinal nerve fiber layer thickness. PAP device data (usage duration and air leak rate) and OSA severity metrics were recorded. Group comparisons used chi-square and Student’s t-test, and regression analyses identified associations between PAP leakage and ocular parameters. Results: Among the 57 OSA patients, PAP users showed a trend toward a higher risk of glaucoma (OR = 0.83) and DED (OR = 0.69) compared to non-users, but neither trend was statistically significant. PAP users had significantly more severe OSA, including longer N1 sleep stage (p = 0.0005), higher apnea-hypopnea index (AHI, p = 0.0001), and poorer oxygenation. PAP leakage: 95% (mean = 25.84 L/min) exceeded the 24 L/min threshold specified in ResMed’s clinical guidelines, suggesting suboptimal therapy. Higher PAP leak was significantly associated with a lower Schirmer’s test value (p = 0.031) and a higher C/D ratio (p = 0.040) on regression analysis. However, no significant differences were found in ophthalmic parameters between PAP+ and PAP− groups. Conclusion: Suboptimal PAP therapy as mask leakage or nocturnal hemodynamic changes may worsen evaporative dry eye and affect intraocular pressure. Our findings highlight the association between PAP mask leakage and reduced tear production, and suggest that OSA-related optic nerve stress may persist unless both hypoxia and nocturnal IOP fluctuations are properly managed. However, due to the relatively small sample size and retrospective cross-sectional design, future prospective studies with larger cohorts are needed to confirm these associations. Full article

(This article belongs to the Special Issue Recent Research on Dry Eye)

14 pages, 671 KB

Open AccessArticle

Efficacy and Safety of a Plasma Vaginal Cleanser (WOMEN CARE^®) Using Plasma-Activated Water in Suspected Vaginitis: A Multicenter Randomized Clinical Trial

by Hye-Jin Cho, Min-Kyeong Kim, Yun-Seo Choe, Seo-Yeon Son, Chi-Gu Kang, So-Jung Lim, Sooyong Kim, Hoonseong Choi, Un Suk Jung and Ju-Seop Kang

Biomedicines 2025, 13(12), 3076; https://doi.org/10.3390/biomedicines13123076 (registering DOI) - 12 Dec 2025

Abstract

Background/Objectives: Vaginitis is a prevalent inflammatory disorder of the vaginal mucosa, frequently arising from its anatomical proximity to the anorectal region and a microenvironment conducive to pathogen colonization and dysbiosis. This prospective, multicenter, randomized, third-party-blinded study assessed the efficacy and safety of [...] Read more.

Background/Objectives: Vaginitis is a prevalent inflammatory disorder of the vaginal mucosa, frequently arising from its anatomical proximity to the anorectal region and a microenvironment conducive to pathogen colonization and dysbiosis. This prospective, multicenter, randomized, third-party-blinded study assessed the efficacy and safety of a plasma vaginal cleanser (WOMEN CARE^®) employing plasma-activated water (PAW) as a non-pharmacological alternative to conventional antimicrobials for restoring vaginal homeostasis. Methods: Women aged ≥19 years with clinically suspected vaginitis were assigned to either the experimental group (WOMEN CARE^®) or the control group (standard pharmacotherapy). The primary endpoint was the proportion of participants exhibiting decreased Nugent scores between baseline and Visit 4. Results: Of 144 participants in the experimental group, 125 completed the study. The experimental group showed comparable outcomes to standard pharmacotherapy group across Nugent scores, vaginal pH, and symptoms severity, with pathogen suppression confirmed as non-inferior. Additionally, PAW exerted anti-HPV activity through a potential effect against new genotypic HPV infection. While the control group experienced antibiotic-associated adverse effects (e.g., headache, abdominal discomfort, nausea), no treatment-related adverse events occurred in the WOMEN CARE^® group. Conclusions: These results indicate that PAW vaginal cleansing provides an effective, safe, non-antibiotic approach for managing vaginitis and maintaining vaginal ecological balance. Full article

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

10 pages, 514 KB

Open AccessArticle

Mid- and Long-Term Results of Covered Stents for Iatrogenic Common Femoral Artery Injury

by Francesca Miceli, Giulia Demirxhiu, Alessia Di Girolamo, Antonio Marzano, Andrea Molinari, Rocco Cangiano, Marta Ascione, Francesco Ajmone, Gennaro Sardella, Massimo Mancone, Luca di Marzo and Wassim Mansour

Biomedicines 2025, 13(12), 3075; https://doi.org/10.3390/biomedicines13123075 (registering DOI) - 12 Dec 2025

Abstract

Background/Objectives: The increasing use of endovascular procedures with common femoral artery (CFA) access has led to a rise in iatrogenic arterial injuries at this site. The most frequent injuries are pseudoaneurysms (PSA), retrograde dissections (RD), arteriovenous fistulas (AVF), and arterial perforations. Surgical repair [...] Read more.

Background/Objectives: The increasing use of endovascular procedures with common femoral artery (CFA) access has led to a rise in iatrogenic arterial injuries at this site. The most frequent injuries are pseudoaneurysms (PSA), retrograde dissections (RD), arteriovenous fistulas (AVF), and arterial perforations. Surgical repair is the standard treatment; however, the use of covered stents (CS) may represent a valid alternative, despite current instructions for use (IFU) not recommending CFA implantation. Methods: We conducted a single-center retrospective study on a prospectively maintained database. Patients undergoing transcatheter aortic valve repair (TAVR), endovascular aortic repair EVAR, diagnostic or therapeutic coronary angiography, or peripheral percutaneous transluminal angioplasty, who were subsequently treated for CFA injury with CS implantation between February 2015 and May 2024, were included. Endpoints were technical success (complete arterial repair), 30-day mortality, overall mortality, reintervention rates, and long-term stent patency. Results: A total of 41 patients were included: 10 (24.4%) PSA, 3 (7.3%) AVF, 27 (65.8%) perforations, and 2 (4.9%) RD. Of which 28 (68.3%) were treated with self-expandable CS and 13 (31.7%) with balloon-expandable CS. Additionally, 33 (80.5%) underwent urgent treatment. Technical success was achieved in 97.5%. Thirty-day mortality was 7.3%, with no procedure-related deaths. At a mean follow-up of 50.8 months (range 1–109), survival was 63.4%, with 100% stent patency and no procedure-related reinterventions. Conclusions: CS implantation for CFA iatrogenic injuries achieved high technical success and excellent long-term patency, representing a viable alternative to open repair. Further studies are needed to integrate CS use for CFA injuries into treatment algorithms and to update device IFUs accordingly. Full article

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

25 pages, 1144 KB

Open AccessArticle

Clinical Remission in Severe Asthma: A Comparative Analysis of Patients with and Without Biologics from the Swiss Severe Asthma Registry

by Fabienne Jaun, Maria Boesing, Giorgia Lüthi-Corridori, Pierre-Olivier Bridevaux, Florian Charbonnier, Christian F. Clarenbach, Jean-Marc Fellrath, Pietro Gianella, Anja Jochmann, Lukas Kern, Nikolay Pavlov, Tsogyal Daniela Latshang, Christophe Von Garnier and Joerg Daniel Leuppi

Biomedicines 2025, 13(12), 3074; https://doi.org/10.3390/biomedicines13123074 (registering DOI) - 12 Dec 2025

Abstract

Background: Severe asthma is a complex chronic airway disease. Biologic therapies are targeted monoclonal antibody treatments used in patients with uncontrolled, severe asthma, but real-world data from long-term registries and on patients who remain biologic-naïve are limited. This study compared severe asthma [...] Read more.

Background: Severe asthma is a complex chronic airway disease. Biologic therapies are targeted monoclonal antibody treatments used in patients with uncontrolled, severe asthma, but real-world data from long-term registries and on patients who remain biologic-naïve are limited. This study compared severe asthma patients with and without biologic therapy and identified predictors of key clinical remission components. Methods: In this cross-sectional analysis of adult patients from the Swiss Severe Asthma Registry (SSAR), we compared patients treated with a biologic for ≥6 months to biologic-naïve patients (never exposed to biologics). Baseline characteristics were summarized descriptively. Multivariable logistic regression was used to identify predictors of four remission components: good asthma control (ACT ≥ 20), absence of exacerbations, no maintenance oral corticosteroid (OCS) use, and preserved lung function (FEV₁ > 80% predicted). Results: Of 394 patients, 298 (75.6%) were biologic-treated and 96 (24.4%) were biologic-naïve. Biologic-treated patients more often had allergic asthma and type-2–related comorbidities, and showed better outcomes, including fewer exacerbations (0.49 vs. 1.09/year; p < 0.001) and higher ACT scores (20.0 vs. 17.2; p < 0.001). Biologic therapy was independently associated with higher odds of asthma control (OR 3.96; p = 0.006), no exacerbations (OR 5.11; p = 0.001), no OCS use (OR 6.27; p = 0.002), and FEV₁ > 80% predicted (OR 4.42; p = 0.011). Overall, 24.2% of biologic-treated patients and 6.2% of biologic-naïve patients fulfilled all four remission components. Conclusions: In this real-world registry cohort, biologic-treated patients were more likely to meet individual and composite remission criteria than biologic-naïve patients. The relatively low proportion of patients achieving all four stringent criteria highlights the need to revisit current remission definitions and to adopt individualized, multidimensional treatment goals in severe asthma. Full article

(This article belongs to the Special Issue Asthma and Allergy: New Therapeutic Frontiers and Patient Perspectives in a Changing World)

34 pages, 827 KB

Open AccessReview

Liquid Biopsy and Multi-Omic Biomarkers in Breast Cancer: Innovations in Early Detection, Therapy Guidance, and Disease Monitoring

by Daniel Simancas-Racines, Náthaly Mercedes Román-Galeano, Juan Pablo Vásquez, Dolores Jima Gavilanes, Rupalakshmi Vijayan and Claudia Reytor-González

Biomedicines 2025, 13(12), 3073; https://doi.org/10.3390/biomedicines13123073 (registering DOI) - 12 Dec 2025

Abstract

Liquid biopsy and multi-omic biomarker integration are transforming precision oncology in breast cancer, providing real-time, minimally invasive insights into tumor biology. By analyzing circulating tumor DNA, circulating tumor cells, exosomal non-coding RNAs, and proteomic or metabolomic profiles, clinicians can monitor clonal evolution, therapeutic [...] Read more.

Liquid biopsy and multi-omic biomarker integration are transforming precision oncology in breast cancer, providing real-time, minimally invasive insights into tumor biology. By analyzing circulating tumor DNA, circulating tumor cells, exosomal non-coding RNAs, and proteomic or metabolomic profiles, clinicians can monitor clonal evolution, therapeutic response, and recurrence risk in real time. Recent advances in sequencing technologies, methylation profiling, and artificial intelligence–driven data integration have markedly improved diagnostic sensitivity and predictive accuracy. Multi-omic frameworks combining genomic, transcriptomic, and proteomic data enable early detection of resistance, molecular stratification, and identification of actionable targets, while machine learning models enhance outcome prediction and therapy optimization. Despite these advances, key challenges persist. Pre-analytical variability, lack of standardized protocols, and disparities in access continue to limit reproducibility and clinical adoption. High costs, incomplete regulatory validation, and the absence of definitive evidence for mortality reduction underscore the need for larger, prospective trials. Integrating multi-omic assays into clinical workflows will require robust bioinformatics pipelines, clinician-friendly reporting systems, and interdisciplinary collaboration among molecular scientists, data engineers, and oncologists. In the near future, liquid biopsy is expected to complement, not replace, traditional tissue analysis, serving as a cornerstone of adaptive cancer management. As sequencing becomes faster and more affordable, multi-omic and AI-driven analyses will allow earlier detection, more precise treatment adjustments, and continuous monitoring across the disease course. Ultimately, these innovations herald a shift toward real-time, data-driven oncology that personalizes breast cancer care and improves patient outcomes. Full article

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

20 pages, 704 KB

Open AccessReview

Vascular Smooth Muscle Cell Metabolic Disorders in the Occurrence and Development of Aortic Aneurysms and Dissections: Implications for Therapy

by Yuqing Shi, Xianghuan Xie, Yang Sun, Yanghui Chen and Guangzhi Chen

Biomedicines 2025, 13(12), 3072; https://doi.org/10.3390/biomedicines13123072 - 12 Dec 2025

Abstract

Aortic aneurysm and dissection (AAD) represent a life-threatening aortic disorder, for which current treatment strategies rely predominantly on surgical interventions, with limited pharmacological options targeting the underlying pathophysiology. Vascular smooth muscle cell (VSMC) dysfunction constitutes a central pathological mechanism in the development and [...] Read more.

Aortic aneurysm and dissection (AAD) represent a life-threatening aortic disorder, for which current treatment strategies rely predominantly on surgical interventions, with limited pharmacological options targeting the underlying pathophysiology. Vascular smooth muscle cell (VSMC) dysfunction constitutes a central pathological mechanism in the development and progression of AAD. This review outlines the association between VSMCs and AAD, covering their physiological functions and pathological alterations, including phenotypic switching, cell death, and VSMC-mediated extracellular matrix remodeling. It further discusses the impact of epigenetic modifications on VSMC core functions. Additionally, this review addresses normal energy metabolism pathways of VSMCs and the mechanisms of metabolic reprogramming, as well as abnormalities in amino acid metabolism, lipid metabolism, and other metabolic pathways. Signaling mechanisms related to AMPK activation and mitochondrial function are also highlighted. Currently, AAD management is dominated by surgical interventions, while pharmacological therapy remains limited to symptomatic control. Looking ahead, future research should focus on VSMC metabolism-related mechanisms to develop early prevention strategies and novel targeted therapeutics, thereby improving the current treatment landscape for AAD. Full article

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

17 pages, 603 KB

Open AccessArticle

The Impact of Mixing Techniques on PMMA Bone Cement Subjected to Two Different Cooling Techniques: A Pilot Study of Thermal Management Strategies in Orthopedic Applications

by Gergo Tamas Szoradi, Andrei Marian Feier, Octav Marius Russu, Sandor Gyorgy Zuh and Tudor Sorin Pop

Biomedicines 2025, 13(12), 3071; https://doi.org/10.3390/biomedicines13123071 - 12 Dec 2025

Abstract

Objectives: Polymethyl methacrylate (PMMA) bone cement is vital for prosthetic fixation in orthopedic surgery, yet its exothermic polymerization can exceed 80 °C, surpassing the 50 °C threshold for thermal osteonecrosis, risking implant failure. This pilot study assesses two cooling strategies—precooling cement components and [...] Read more.

Objectives: Polymethyl methacrylate (PMMA) bone cement is vital for prosthetic fixation in orthopedic surgery, yet its exothermic polymerization can exceed 80 °C, surpassing the 50 °C threshold for thermal osteonecrosis, risking implant failure. This pilot study assesses two cooling strategies—precooling cement components and saline irrigation on the polymerization temperature and compressive strength of antibiotic-loaded PMMA, comparing hand mixing (HM) and vacuum mixing (VM) to optimize thermal management while preserving mechanical integrity in controlled settings relevant to orthopedic applications. Methods: Antibiotic-loaded Simplex bone cement (Stryker, Kalamazoo, MI, USA) was prepared using HM and VM, per ISO 5833. Each batch was divided into three groups: control, precooled (components at 6 °C overnight), and saline irrigation (8 °C saline during setting). Each group included 20 cylindrical samples (1.5 cm × 3 cm), cured for 24 h. Core temperatures were monitored with embedded thermometers, and compressive strength was measured in megapascals (MPa) using a hydraulic press (C092-06, MATEST). Welch’s t-test was used for statistical analysis. Results: HM controls reached 76.2 °C, precooled 63.6 °C, and saline 66 °C; VM controls hit 71.8 °C, precooled 58.8 °C, and saline 63.6 °C. HM strengths were 16–17 MPa, with precooling reducing to 16.49 MPa (p = 0.051) and saline maintaining 17.07 MPa (p = 0.820). VM strengths were 76–80 MPa, with precooling at 78.45 MPa (p < 0.001) and saline at 76.77 MPa (p = 0.010). Failure modes varied: controls (uniform cracking), precooled (shear failure), and saline (mixed cracking/crumbling). Conclusions: Precooling significantly lowers temperatures but compromises strength in HM samples, limiting its use in load-bearing applications. Saline irrigation offers moderate thermal control while preserving mechanics, particularly in HM, suggesting a viable strategy for reducing thermal necrosis risk. VM ensures superior strength, supporting safe cooling application. Full article

(This article belongs to the Special Issue Biomaterials for Bone Regeneration: 2nd Edition)

16 pages, 1619 KB

Open AccessArticle

Intra-Articular Injection of Adipose-Derived-MSC Exosomes and Hyaluronic Acid in Sheep Knee Osteoarthritic Models Enhances Hyaline Cartilage Regeneration

by Auliya Akbar, Ismail Hadisoebroto Dilogo, Radiana Dhewayani Antarianto, Iqra Kousar, Angela Jennifer Tantry and Anissa Feby Canintika

Biomedicines 2025, 13(12), 3070; https://doi.org/10.3390/biomedicines13123070 - 12 Dec 2025

Abstract

Background: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage damage. The limited regenerative capability of articular cartilage poses a therapeutic challenge. Adipose mesenchymal stem cell (MSC) exosomes have shown potential in regenerating cartilage structure in previous in vivo studies on [...] Read more.

Background: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage damage. The limited regenerative capability of articular cartilage poses a therapeutic challenge. Adipose mesenchymal stem cell (MSC) exosomes have shown potential in regenerating cartilage structure in previous in vivo studies on small animals. This study aims to compare the effectiveness of intra-articular injections of adipose-derived MSC exosomes and hyaluronic acid (HA) on cartilage regeneration in a sheep osteoarthritis model. Methods: This in vivo study involved 18 male sheep that were induced to develop OA via meniscectomy. The sheep were randomized and divided into three groups: Group 1 (adipose MSC exosomes + HA), Group 2 (adipose MSC exosomes), and Group 3 (HA). Microscopic evaluation using histological scoring with the Pineda score, cartilage regeneration assessment through histochemical and immunohistochemical examinations, and microtopographic examination using a scanning electron microscope (SEM) were performed 6 weeks post-intervention. Results: Cartilage regeneration in the combination group (Group 1) exhibited a larger area of hyaline cartilage (Group 1 vs. Group 2 [40.38 ± 9.35% vs. 34.93 ± 2.32% vs. 31.08 ± 3.47%; p = 0.034]) and a smaller area of fibrocartilage compared to adipose MSC exosomes (Group 2) or HA alone (Group 3) (13.06 ± 2.21% vs. 18.67 ± 3.13% vs. 28.14 ± 3.67%; p = 0.037). Microtopographic examination also showed a more homogeneous and smoother cartilage surface in the combination group (Group 1) of adipose MSC exosomes and HA. Conclusions: In a sheep knee osteoarthritis model, intra-articular injection of a combination of adipose-derived MSC exosomes and HA significantly enhances cartilage regeneration compared to injections of adipose-derived MSC exosomes or HA alone. Full article

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

16 pages, 429 KB

Open AccessArticle

Multivariate Profiles of Female Sexual Function: A Cluster Analysis of FSFI Domains in Women with and Without PCOS

by Andrei Daescu, Ana-Maria Cristina Daescu, Liana Dehelean, Dan-Bogdan Navolan, Alexandru-Ioan Gaitoane and Dana Stoian

Biomedicines 2025, 13(12), 3069; https://doi.org/10.3390/biomedicines13123069 - 12 Dec 2025

Abstract

Background/Objectives: Female sexual dysfunction (FSD) is common in PCOS, yet mean group comparisons can mask variability at the individual level. We aimed to identify and characterize person-centered profiles of sexual function from the six FSFI (Female Sexual Function Index) domains, and secondarily to [...] Read more.

Background/Objectives: Female sexual dysfunction (FSD) is common in PCOS, yet mean group comparisons can mask variability at the individual level. We aimed to identify and characterize person-centered profiles of sexual function from the six FSFI (Female Sexual Function Index) domains, and secondarily to describe the distribution of PCOS across profiles. Methods: In an age- and anthropometry-matched case–control sample, unsupervised clustering on FSFI domains was performed; clinical and psychosocial correlates were compared, and logistic regression tested prediction of FSFI-defined FSD. Results: Two profiles emerged—Sexual Dysfunction vs. Preserved Function—with clear multivariate separation. Dysfunction showed lower FSFI, higher adiposity, and worse body-image discomfort. PCOS was more frequent in Dysfunction but not significantly. Cluster membership predicted FSD. Conclusions: Person-centered profiling reveals clinically meaningful heterogeneity that transcends diagnosis and highlights adiposity and body-image distress as salient, potentially modifiable correlates. Full article

(This article belongs to the Special Issue Ovarian Physiology and Reproduction)

17 pages, 696 KB

Open AccessSystematic Review

Effects of Transcranial Neuromodulation on Rehabilitation Outcomes After Anterior Cruciate Ligament Injury: A Systematic Review of Randomized Controlled Trials

by Juan Vicente-Mampel, Mariola Belda-Antolí, Eloy Jaenada-Carrilero, Andrés Pascual-Leone, Luís Baraja-Vegas, Nicolás Pascual-Leone, Javier Ferrer-Torregrosa, Francisco J. Falaguera-Vera, Álvaro Pascual-Leone and José María Tormos-Muñoz

Biomedicines 2025, 13(12), 3068; https://doi.org/10.3390/biomedicines13123068 - 12 Dec 2025

Abstract

Background/Objectives: Anterior cruciate ligament (ACL) injuries frequently lead to long-term quadriceps impairments despite surgical repair. There is growing evidence that these deficits are caused in part by alterations in the central nervous system. Thus, transcranial neuromodulation (TNM) could be valuable in ACL [...] Read more.

Background/Objectives: Anterior cruciate ligament (ACL) injuries frequently lead to long-term quadriceps impairments despite surgical repair. There is growing evidence that these deficits are caused in part by alterations in the central nervous system. Thus, transcranial neuromodulation (TNM) could be valuable in ACL rehabilitation. To systematically review randomized controlled trials (RCTs) assessing the effects of TNM on neurophysiological, functional, and safety outcomes in patients with ACL injury or reconstruction. Methods: We conducted searches on PubMed, Scopus, Web of Science, and Cochrane. We considered all original studies evaluating TNM, including transcranial current stimulation (tCS) and transcranial magnetic stimulation (TMS), in patients with ACL reconstruction or injury. Measures of corticospinal excitability, safety, balance, and muscle strength were assessed. We employed the Cochrane RoB 2 method to assess the risk of bias. Results: Seven studies comprising 129 participants (64 TNM, 65 controls) were included. Most studies applied transcranial direct current stimulation (tDCS) over the primary motor cortex contralateral to the ACL injury in conjunction with physical rehabilitation. Single-session protocols demonstrated minimal effects, whereas repeated sessions resulted in improvements in corticospinal excitability, quadriceps strength, and balance. No serious adverse events were reported; minor effects included transient headache or scalp tingling. The risk of bias was assessed as low to moderate across the studies. Conclusions: TNM appears to be safe and may enhance functional recovery in individuals with ACL injuries when administered in multiple sessions alongside standard rehabilitation. Further high-quality trials are necessary to determine optimal protocols and long-term outcomes. Full article

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

17 pages, 1049 KB

Open AccessReview

Adipose-Specific Cytokines as Modulators of Reproductive Activity

by Marcelo Martinez-Barbitta, Andrea Biagini, Egidia Costanzi, Margherita Maranesi, Juan García-Díez, Cristina Saraiva, Beniamino Cenci Goga and Massimo Zerani

Biomedicines 2025, 13(12), 3067; https://doi.org/10.3390/biomedicines13123067 - 12 Dec 2025

Abstract

Adipose tissue is characterized by specialized lipid handling cells called adipocytes, which function as the primary energy reservoir. Like many other cell types, adipocytes have highly plastic properties, such as the conversion of white adipocytes into brown or beige adipocytes, which produce heat, [...] Read more.

Adipose tissue is characterized by specialized lipid handling cells called adipocytes, which function as the primary energy reservoir. Like many other cell types, adipocytes have highly plastic properties, such as the conversion of white adipocytes into brown or beige adipocytes, which produce heat, and pink adipocytes into mammary cells synthesizing and secreting milk. Highly specialized adipose tissue depots are present in various species, such as male orangutans with prominent fat-filled facial flanges indicating hierarchical status, or cetaceans with the melon, a specialized adipose tissue for echolocation. Adipose tissue is now considered a true endocrine organ that regulates various physiological mechanisms through the hormonal secretion of adipokines, which modulate systemic metabolism and physiological processes. In particular, the role of adipokines in the control of the reproductive axis and their participation in the regulation of fertility have been widely reported. This review summarizes the current state of research on the effects of adipose-specific cytokines on the male and female reproductive systems. Full article

(This article belongs to the Special Issue Recent Advances in Adipokines (3nd Edition))

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42 pages, 1086 KB

Open AccessReview

Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1

by Elizaveta Plotnikova, Tatyana Ageeva, Albert Sufianov, Galina Sufianova, Albert Rizvanov and Yana Mukhamedshina

Biomedicines 2025, 13(12), 3066; https://doi.org/10.3390/biomedicines13123066 - 12 Dec 2025

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative dis-ease caused by the expansion of cytosine–adenine–guanine (CAG) repeats in the ataxin-1 (ATXN1) gene, leading to toxic gain-of-function of the ataxin-1 (ATXN1) protein. This narrative review systematizes the clinical and genetic [...] Read more.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative dis-ease caused by the expansion of cytosine–adenine–guanine (CAG) repeats in the ataxin-1 (ATXN1) gene, leading to toxic gain-of-function of the ataxin-1 (ATXN1) protein. This narrative review systematizes the clinical and genetic aspects of SCA1 and discusses key molecular and cellular mechanisms: the ATXN1-CIC ataxin-1-Capicua complex (ATXN1-CIC), the role of serine 776 (Ser776) phosphorylation, interactions with 14-3-3 proteins, transcriptional dysregulation, and critically analyzes experimental models of the disease in vivo and in vitro. In addition, it presents a descriptive quantitative analysis of the literature on in vivo SCA1 models, conducted using a defined search methodology with a cut-off date of 23 November 2025. For each model, phenotypic markers, molecular signatures, and applicability to preclinical testing tasks are summarized. A comparison of the models reveals their complementarity and outlines optimal research trajectories, including omics approaches and prospects for targeted antisense oligonucleotide (ASO) therapy, RNA interference (RNAi), and genome editing. The result is a practical guide for selecting a model in accordance with specific hypotheses and translational objectives. Full article

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

22 pages, 1928 KB

Open AccessArticle

Subtype-Independent Dysregulation of the Notch Signaling Pathway and Its miRNA Regulators in Breast Cancer

by Elżbieta Mitka-Krysiak, Katarzyna Król-Jatręga, Piotr Ossowski, Nikola Zmarzły, Krzysztof Bereza, Paweł Ordon, Wojciech Kulej, Tomasz Sirek, Agata Sirek, Kacper Boroń, Maciej Boroń, Dariusz Boroń and Beniamin Oskar Grabarek

Biomedicines 2025, 13(12), 3065; https://doi.org/10.3390/biomedicines13123065 - 12 Dec 2025

Abstract

Background/Objectives: The Notch signaling pathway regulates cell fate, proliferation, and differentiation, and its dysregulation has been implicated in various cancers, including breast cancer. MicroRNAs (miRNAs) are critical post-transcriptional regulators that can modulate Notch pathway components. The aim of this study was to [...] Read more.

Background/Objectives: The Notch signaling pathway regulates cell fate, proliferation, and differentiation, and its dysregulation has been implicated in various cancers, including breast cancer. MicroRNAs (miRNAs) are critical post-transcriptional regulators that can modulate Notch pathway components. The aim of this study was to identify miRNAs that may potentially regulate the expression of Notch pathway-related genes across five molecular subtypes of breast cancer in Polish women. Methods: Tumor and adjacent normal tissue samples were collected from 405 patients with five breast cancer subtypes: luminal A (n = 130), HER2-negative luminal B (n = 100), HER2-positive luminal B (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (n = 43). Gene expression was profiled using mRNA microarrays and validated with RT-qPCR and ELISA. Candidate regulatory miRNAs were identified by miRNA microarrays and confirmed using the miRDB database. Results: APH1A, CTBP1, DTX1, HEY1, HEY2, JAG2, NOTCH4, TLE2, and TLE4 were consistently dysregulated across all breast cancer subtypes. Overexpression of HEY1 and JAG2 may be driven by decreased levels of miR-145, miR-98, and miR-381. Conversely, downregulation of TLE4 may be associated with elevated expression of miR-196a and miR-155. No regulatory miRNAs meeting the selection criteria were identified for APH1A, CTBP1, DTX1, HEY2, NOTCH4, or TLE2. Conclusions: The consistent alterations suggest the presence of a shared Notch-driven oncogenic signature in breast cancer, potentially driving cell proliferation, stemness, and resistance to therapy. These findings enhance our understanding of Notch signaling in breast cancer and propose novel miRNA–Notch interactions as candidate targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer: From Biomarkers to Targeted Therapy)

18 pages, 1051 KB

Open AccessArticle

Inflammatory–Thrombotic Phenotypes and Outcomes in COVID-19-Associated Pulmonary Embolism: A Single-Center Cohort Study

by Aneta-Rada Dobrin, Voichita Elena Lazureanu, Cristian Oancea, Livia Stanga, Alexandra Herlo, Silvia Alda, Diana Utu, Lucian Flavius Herlo and Monica Licker

Biomedicines 2025, 13(12), 3064; https://doi.org/10.3390/biomedicines13123064 - 12 Dec 2025

Abstract

Background and Objectives: Pulmonary embolism (PE) complicating COVID-19 combines viral pneumonia with immunothrombosis, but the relative prognostic value of comorbidities, embolic burden, lung involvement, and inflammatory markers is uncertain. We aimed to characterize clinical profiles and identify independent predictors of respiratory failure [...] Read more.

Background and Objectives: Pulmonary embolism (PE) complicating COVID-19 combines viral pneumonia with immunothrombosis, but the relative prognostic value of comorbidities, embolic burden, lung involvement, and inflammatory markers is uncertain. We aimed to characterize clinical profiles and identify independent predictors of respiratory failure and in-hospital mortality in COVID-19–associated PE. Materials and Methods: We performed an observational single-center study including 161 adults with RT-PCR–confirmed COVID-19 and CTPA-confirmed acute PE. Demographic data, comorbidities, CT lung involvement, biomarkers, and treatments were compared across outcomes, and multivariable logistic regression and principal component analysis (PCA) were used to model risk. Results: In-hospital mortality was 24.8% (40/161), and invasive mechanical ventilation was 18.6% (30/161). Classical PE variables (Wells score, PESI, thrombus location, D-dimer) and comorbidities showed limited discrimination, whereas severe CT lung involvement independently predicted death (OR 4.46; 95% CI 1.55–12.86) and intubation (OR 8.88; 95% CI 2.92–27.04). Each 50 mg/L increase in CRP increased mortality odds by 41% (OR 1.41; 95% CI 1.02–1.96), and a 10-fold rise in IL-6 (log10 IL-6) was associated with six-fold higher mortality (OR 6.10; 95% CI 1.84–20.18). PCA identified a hyperinflammatory–thrombotic component (PC1); per 1-SD increase in standardized PC1, the odds of intubation or death rose 3.5-fold (OR 3.50; 95% CI 2.05–5.99), and event rates across PC1 tertiles were 7.4%, 20.8%, and 57.4%. Conclusions: In COVID-19–related PE, integrated immunothrombotic activation and extent of lung involvement, rather than embolic burden alone, drive early critical outcomes and may support refined risk stratification. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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23 pages, 1908 KB

Open AccessReview

Spinal Cord Stimulation in Painful Diabetic Neuropathy: Advances, Outcomes, and Future Directions

by Roberto Gazzeri, Jacopo Mosca, Felice Occhigrossi, Marcelo Galarza, Riccardo Schiaffini, Giustino Varrassi, Marco Mercieri and Matteo Luigi Giuseppe Leoni

Biomedicines 2025, 13(12), 3063; https://doi.org/10.3390/biomedicines13123063 - 12 Dec 2025

Abstract

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus, often inadequately managed by conventional pharmacological therapies. Alternative interventions, including spinal cord stimulation (SCS), have garnered increasing attention for their potential effectiveness. This narrative review evaluates the efficacy, safety, mechanisms of action, [...] Read more.

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus, often inadequately managed by conventional pharmacological therapies. Alternative interventions, including spinal cord stimulation (SCS), have garnered increasing attention for their potential effectiveness. This narrative review evaluates the efficacy, safety, mechanisms of action, and impact on quality of life of SCS in the management of PDN. A systematic search was conducted covering the last 15 years (from January 2010 to April 2025), using the keywords “diabetic neuropathy,” “spinal cord stimulation,” “neuropathic pain,” and “neuromodulation” with Boolean operators. Eligible studies included randomized controlled trials (RCTs), observational studies, systematic reviews, and meta-analyses involving adult populations and published in English. Study selection and data extraction were performed independently by two authors. Multiple RCTs and observational studies (involving over 500 patients) were identified. RCTs consistently demonstrated that SCS significantly reduces neuropathic pain intensity compared to conventional medical therapy (CMT). The most recent study, with the largest sample size (216 patients), reported that high-frequency SCS achieved ≥50% pain relief in 79% of patients at 6 months, compared to only 5% in the CMT group. Observational studies confirmed sustained pain relief (≥50% reduction) in approximately 55–80% of patients over 5–10 years. Significant improvements in sleep, neurological function, and quality of life were also consistently observed. The complication rate was low, with infections requiring explantation in approximately 2–3% of cases. Rare serious adverse events, such as spinal hematoma, were reported. Current evidence underlines the efficacy and safety of SCS, particularly newer waveform paradigms, for the treatment of PDN refractory to medical management. Given its durable effects on pain relief, functional improvement, and quality of life, SCS should be considered an option within the treatment algorithm for carefully selected patients with severe, refractory PDN. Full article

(This article belongs to the Special Issue Novel Biomarker and Treatments for Diabetic Neuropathy)

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32 pages, 4758 KB

Open AccessReview

Hypertrophic Cardiomyopathy Phenocopies: Classification, Key Features, and Differential Diagnosis

by Lucio Teresi, Giancarlo Trimarchi, Roberto Licordari, Davide Restelli, Giovanni Taverna, Paolo Liotta, Antonino Micari, Ignazio Smecca, Gregory Dendramis, Dario Turturiello, Alessia Chiara Latini, Giulio Falasconi, Cesare de Gregorio, Pasquale Crea, Giuseppe Dattilo, Antonio Berruezo, Antonio Micari and Gianluca Di Bella

Biomedicines 2025, 13(12), 3062; https://doi.org/10.3390/biomedicines13123062 - 12 Dec 2025

Abstract

Among cardiomyopathies, the hypertrophic phenotype is the most common, and hypertrophic cardiomyopathy (HCM) phenocopies represent a heterogeneous group of conditions. They are defined by a left ventricular wall thickness ≥15 mm in the absence of other causes such as loading conditions, ischemia, or [...] Read more.

Among cardiomyopathies, the hypertrophic phenotype is the most common, and hypertrophic cardiomyopathy (HCM) phenocopies represent a heterogeneous group of conditions. They are defined by a left ventricular wall thickness ≥15 mm in the absence of other causes such as loading conditions, ischemia, or valvular disease. Although they mimic similar clinical and morphological features, their etiologies are distinct and include genetic, metabolic, and infiltrative mechanisms. Therefore, accurate classification and differential diagnosis are crucial for effective management and treatment. Sarcomeric HCM is the most frequent form, accounting for up to 60% of cases. However, numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases. Clinical and imaging findings are essential to distinguish these entities from sarcomeric HCM. Electrocardiography, echocardiography, advanced modalities such as cardiac magnetic resonance (CMR), and specific laboratory tests all play a central role in guiding diagnosis. Genetic testing provides key insights into mutations and inheritance patterns, further supporting definitive diagnosis. Correct identification of an HCM phenocopy carries important therapeutic implications, as disease-specific treatments can significantly improve prognosis. For example, targeted therapies exist for amyloidosis, Fabry disease, and certain metabolic or mitochondrial disorders, underlining the clinical relevance of an accurate diagnosis. This review aims to provide an overview of HCM phenocopies and assist clinicians in diagnostic reasoning. The first part addresses classification according to pathophysiological mechanisms, clinical features, and genetic background. The second part focuses on the stepwise approach to differential diagnosis, integrating clinical assessment, laboratory evaluation, ECG, echocardiography, and CMR findings. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis and Treatment of Cardiomyopathy and Cardiac Arrhythmias (3rd Edition))

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23 pages, 2060 KB

Open AccessReview

Targeting the JAK/STAT Signaling Pathway in Breast Cancer: Leaps and Hurdles

by Simon Aho, Clio Coste, Luiza Purcari, Olivier Trédan, Coralie Poulard, Benoite Mery, François-Michel Boisvert and Muriel Le Romancer

Biomedicines 2025, 13(12), 3061; https://doi.org/10.3390/biomedicines13123061 - 12 Dec 2025

Abstract

The JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway transfers signals at the surface of cell membranes to the nucleus, triggering the expression of a myriad of factors implicated in immunity, cell proliferation, and apoptosis. Owing to this central role in [...] Read more.

The JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway transfers signals at the surface of cell membranes to the nucleus, triggering the expression of a myriad of factors implicated in immunity, cell proliferation, and apoptosis. Owing to this central role in cell homeostasis, its dysregulation is extensively reported in tumorigenesis, particularly in hematological cancers, justifying the development of specific inhibitors. It has more recently also been implicated in the development of solid cancers, including breast cancer. However, so far, clinical trials testing drugs targeting actors of JAK/STAT signaling yielded disappointing results, advocating in favor of a better understanding of this pathway in breast cancer. Herein, we exhaustively reviewed the current tools available to target this pathway in clinical trials and we offer several perspectives to gain further insight into the role of JAK2 in breast cancer and more particularly in the resistance to endocrine therapy in hormone-dependent breast cancers. Full article

(This article belongs to the Special Issue Breast Cancer Research: Charting Future Directions)

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15 pages, 3176 KB

Open AccessArticle

Quantitative Measures of Time to Loss of 15% Vital Capacity and Survival Extension in Slowly Progressive Amyotrophic Lateral Sclerosis (ALS) Patients Treated with the Immune Regulator NP001 Suggests an Immunopathogenic Subset of ALS

by Namita A. Goyal, Jinsy A. Andrews, Björn E. Oskarsson, Martina H. Wiedau, Edward J. Kasarskis, Bruce D. Forrest, Rongzhen Zhang, Paige M. Bracci, Matthew W. Davis, Ari Azhir and Michael S. McGrath

Biomedicines 2025, 13(12), 3060; https://doi.org/10.3390/biomedicines13123060 - 12 Dec 2025

Abstract

Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would [...] Read more.

Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. Methods: In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. Results: Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months (p = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed (p < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. Conclusions: These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients. Full article

(This article belongs to the Special Issue New Advances in Neuropharmacology)

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