Biomedicines

14 pages, 1625 KiB

Open AccessCommunication

Last Resort? Rationale for Comprehensive Molecular Analysis in Treatment-Refractory R/M HNSCC: A Case Report of Remarkable Response to Sacituzumab Govitecan Following Molecular and Functional Characterization

by Henrike Barbara Zech, Philippe Schafhausen, Leonie Ramke, Janna-Lisa Velthaus, Simon Kreutzfeldt, Daniel Hübschmann, Kai Rothkamm, Carsten Bokemeyer, Anna Sophie Hoffmann, Stefan Fröhling, Hanno Glimm, Christian Stephan Betz, Malte Kriegs and Maximilian Christopeit

Biomedicines 2025, 13(5), 1266; https://doi.org/10.3390/biomedicines13051266 - 21 May 2025

Viewed by 573

Abstract

Background/Objectives: In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), the overall prognosis is poor, and systemic treatment options remain limited. While precision therapy approaches have revolutionized treatment strategies in several tumor types, molecularly informed therapies in R/M HNSCC are rare, [...] Read more.

Background/Objectives: In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), the overall prognosis is poor, and systemic treatment options remain limited. While precision therapy approaches have revolutionized treatment strategies in several tumor types, molecularly informed therapies in R/M HNSCC are rare, primarily due to the low number of actionable genetic alterations identified through next-generation sequencing (NGS) panels. There is an urgent need to establish precision therapy approaches in R/M HNSCC using innovative predictive testing. Methods: We report the case of a 43-year-old patient with recurrent oral cancer who was extensively pretreated and comprehensively characterized using both descriptive and functional testing. Results: NGS revealed no targetable alterations. A tumor tissue slice radiosensitivity assay suggested radioresistance, arguing against re-irradiation. Kinome profiling identified upregulated Src-family kinases (SFK), and SFK inhibition reduced kinase activity in vitro. Most notably, mRNA analysis demonstrated high Trop-2 overexpression, confirmed by immunohistochemistry (3+ in 100% of tumor cells). Following six cycles of the Trop-2-directed antibody–drug conjugate Sacituzumab govitecan (SG), the patient had an impressive clinical response. Conclusions: Tumor characterization beyond genetic profiling can identify novel treatment options in therapy-refractory HNSCC. This is the first report of “real-world” data on promising antitumor efficacy of SG in a heavily pretreated oral cancer patient with Trop-2 overexpression. Consistent with the findings of the Basket TROPiCS-03 study, SG appears to be a promising novel therapy option for R/M HNSCC after failure of immunotherapy and chemotherapy, particularly in patients with Trop-2 overexpression. Full article

(This article belongs to the Special Issue Novel Approaches towards Targeted Head and Neck Cancer Therapies)

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13 pages, 831 KiB

Open AccessArticle

Blood Serum from Patients with Acute Leukemia Inhibits the Growth of Bone Marrow Multipotent Mesenchymal Stromal Cells

by Nataliya Petinati, Aleksandra Sadovskaya, Irina Shipounova, Alena Dorofeeva, Nina Drize, Anastasia Vasilyeva, Olga Aleshina, Olga Pokrovskaya, Larisa Kuzmina, Sofia Starchenko, Valeria Surimova, Yulia Chabaeva, Sergey Kulikov and Elena Parovichnikova

Biomedicines 2025, 13(5), 1265; https://doi.org/10.3390/biomedicines13051265 - 21 May 2025

Viewed by 443

Abstract

Background/Objectives: Acute leukemia (AL) alters both hematopoiesis and the bone marrow stromal microenvironment. Attempts to develop a culture of multipotent mesenchymal stromal cells (MSCs) from AL patients’ bone marrow are not always successful, as opposed to healthy donors’ bone marrow. Methods: [...] Read more.

Background/Objectives: Acute leukemia (AL) alters both hematopoiesis and the bone marrow stromal microenvironment. Attempts to develop a culture of multipotent mesenchymal stromal cells (MSCs) from AL patients’ bone marrow are not always successful, as opposed to healthy donors’ bone marrow. Methods: To unveil the reason, healthy donors’ MSCs were cultured in the presence of sera from healthy donors (control group) or AL patients at the onset of the disease, in short- and long-term remission, and before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results: The cell yield in the presence of patient sera was lower than in the control, regardless of the AL stage. It was assumed that the patients either lacked growth factors to sustain MSCs, or there were inhibitors of MSC growth present. The serum’s ability to support MSC growth correlated with platelet count and albumin and calcium concentrations in patients’ blood. Platelet-derived growth factors—PDGFA and PDGFB—are known to induce MSC growth. Their concentration in the serum of AL patients and healthy donors was analyzed. A decrease in PDGFA concentration was found in the sera of patients compared to healthy donors. PDGFB concentration was lower at disease onset, increased during remission and decreased again during relapse. PDGFB concentration correlated with platelet count, while PDGFA concentration did not. AL patients’ sera reflected systemic disturbances affecting MSC growth. So far, decreases in PDGFs, albumin and calcium concentration, as well as platelet count, are the parameters that might be among the causes of this observation. Full article

(This article belongs to the Special Issue Role of Bone Marrow Niche in Haematological Cancers)

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13 pages, 1175 KiB

Open AccessArticle

Gut Microbiota Dysbiosis in Japanese Female Patients with Nontuberculous Mycobacteria-Associated Lung Disease: An Observational Study

by Kanako Kono, Yutaka Kozu, Shun Yokota, Kouta Hatayama, Kenji Mizumura, Shuichiro Maruoka, Hiroaki Masuyama and Yasuhiro Gon

Biomedicines 2025, 13(5), 1264; https://doi.org/10.3390/biomedicines13051264 - 21 May 2025

Viewed by 496

Abstract

Background/Objectives: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated using a combination of multiple antimicrobial agents and prolonged therapy; however, recurrence and reinfection rates remain high. Susceptibility to NTM-PD is not fully understood. We aimed to investigate the association between NTM-PD and gut [...] Read more.

Background/Objectives: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated using a combination of multiple antimicrobial agents and prolonged therapy; however, recurrence and reinfection rates remain high. Susceptibility to NTM-PD is not fully understood. We aimed to investigate the association between NTM-PD and gut microbiota and determine the impact of antimicrobial therapy on the composition of the gut microbiota. Methods: We analyzed the gut microbiota of 20 Japanese females with NTM-PD (mean age: 67.9 years; range: 50–80 years) at different treatment stages—before, during, and at recurrence—alongside 20 healthy individuals, using 16S rRNA gene amplicon sequencing. Results: Subgroup A (pre-treatment) showed a small difference in β-diversity when compared with the healthy control (HC) group, while no significant differences in α-diversity were observed. Subgroup B (during treatment) exhibited a larger difference in β-diversity compared with the HC group, along with a decrease in α-diversity. The α-diversity of the gut microbiota in Subgroup C (at recurrence) was lower than that in Subgroup A but higher than that in Subgroup B. In Subgroups A and C, the bacterial taxa Sutterella, Adlercreutzia, Odoribacter, and Prevotella had decreased relative abundance, while Erysipelatoclostridium, Massilimicrobiota, Flavonifractor, Eggerthella, and Fusobacterium had increased relative abundance compared to those in the HC group. Conclusions: The loss of normal resident gut bacteria may hinder reacquisition. Treatment may be associated with the persistence of a dysbiotic gut microbiota, fostering susceptibility to NTM-PD. Gut microbiota dysbiosis may heighten susceptibility to NTM-PD, complicate treatment outcomes, and increase the risk of microbiological recurrence following therapy. Full article

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

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10 pages, 1460 KiB

Open AccessArticle

Interleukin-37 Suppresses the Function of Type 2 Follicular Helper T in Allergic Rhinitis

by Xi Luo, Yanhui Wen, Xiangqian Qiu, Lifeng Zhou, Qingxiang Zeng and Wenlong Liu

Biomedicines 2025, 13(5), 1263; https://doi.org/10.3390/biomedicines13051263 - 21 May 2025

Viewed by 474

Abstract

Background: Allergic rhinitis (AR) is triggered by immunoglobulin E (IgE)-mediated immune responses to airborne allergens. Recent studies highlight the pivotal role of T follicular helper 2 (Tfh2) cells in IgE production. Interleukin-37 (IL-37) has emerged as an intrinsic modulator of innate immunity and [...] Read more.

Background: Allergic rhinitis (AR) is triggered by immunoglobulin E (IgE)-mediated immune responses to airborne allergens. Recent studies highlight the pivotal role of T follicular helper 2 (Tfh2) cells in IgE production. Interleukin-37 (IL-37) has emerged as an intrinsic modulator of innate immunity and inflammatory processes. We aimed to investigate the regulatory effect of IL-37 on Tfh2 cells in the pathogenesis of AR. Methods: Blood samples were collected from AR patients and controls. The IL-37 levels and the frequency of Tfh2 cells were detected by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. The isolated Tfh2 cells were cultured or cocultured with naive B cells. The regulatory effects of IL-37 on Tfh2/B cells were assessed using ELISA, quantitative real-time polymerase chain reaction (qRT-PCR). Mouse models of ovalbumin (OVA)-induced AR were established to explore the effect of IL-37 in vivo. Results: IL-37 suppressed the production of IL-4 and IL-21 by Tfh2 cells and downregulated C-X-C chemokine receptor type 5 (CXCR5) and B-cell lymphoma 6 protein (Bcl6) mRNA expression while upregulating B lymphocyte-induced maturation protein 1 (Blimp1) and signal transducers and activators of transduction5 (STAT5) mRNA. IL-37 decreased IgE production by B cells significantly, and the addition of anti-IL-18 receptor α alleviated this effect. In mouse models, IL-37 reduced nasal rubbing, sneezing, eosinophil counts, OVA-specific IgE, and Tfh2 proportions. Conclusions: IL-37 plays a crucial role in modulating Tfh2 cell responses in AR, suggesting a potential therapeutic target for this condition. Full article

(This article belongs to the Special Issue Allergic Rhinitis: From Pathology to Novel Therapeutic Approaches)

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21 pages, 1380 KiB

Open AccessReview

Extracellular Vesicles as Emerging Therapeutic Strategies in Spinal Cord Injury: Ready to Go

by Jiali Jiang, Ziyi Wang, Qinghua Bao, Shenyuan Chen, Wenrong Xu and Jiajia Jiang

Biomedicines 2025, 13(5), 1262; https://doi.org/10.3390/biomedicines13051262 - 21 May 2025

Viewed by 647

Abstract

Spinal cord injury (SCI) is a prevalent central nervous system disorder that causes significant disability and mortality. Unfortunately, due to the complex pathophysiological mechanisms involved, there remains a critical paucity of effective therapeutic interventions capable of achieving neural tissue regeneration and functional recovery [...] Read more.

Spinal cord injury (SCI) is a prevalent central nervous system disorder that causes significant disability and mortality. Unfortunately, due to the complex pathophysiological mechanisms involved, there remains a critical paucity of effective therapeutic interventions capable of achieving neural tissue regeneration and functional recovery enhancement in SCI patients. The advancements in extracellular vesicles (EVs) as a cell-free therapy for SCI have displayed notable benefits. These include their small size, low immunogenicity, capacity to target specific areas, and ability to cross the blood‒brain barrier (BBB). EVs offer the potential to not only repair tissue damage and stimulate regeneration but also effectively deliver and release them at the site of SCI when combined with diverse biomaterials. This review explores the biological role and importance of EVs in treating SCI, highlighting the combined use of modified EVs with different biomaterials and their potential for future applications. It presents new and hopeful treatment approaches for individuals afflicted with SCI. Full article

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

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20 pages, 4500 KiB

Open AccessReview

Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance

by Qiwen Tan, Xiongjing Cao, Falong Zou, Hanwenchen Wang, Lijuan Xiong and Shenghe Deng

Biomedicines 2025, 13(5), 1261; https://doi.org/10.3390/biomedicines13051261 - 21 May 2025

Viewed by 511

Abstract

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with [...] Read more.

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with its distribution patterns influenced by factors such as tumor anatomy, local immune status, and therapeutic interventions. This spatial heterogeneity not only alters the interactions between microbes and the host immune system but may also reshape the immunogenic and immunosuppressive landscapes of tumors. The enrichment or depletion of microbiota in different tumor regions can influence immune cell infiltration patterns, metabolic pathway activities, and immune checkpoint molecule expression, thereby driving the development of resistance to immunotherapy. Moreover, certain bacterial metabolites form concentration gradients between the tumor core and margins, thereby regulating immune cell function. Therefore, understanding and manipulating the spatial distribution of intratumoral microbiota, particularly in resistant patients, holds promise for developing new strategies to overcome immunotherapy resistance. In the future, precise modulation strategies targeting microbial spatial heterogeneity, such as engineered bacterial vectors, probiotic combinations, and phage therapy, may open new avenues for immunotherapy. Full article

(This article belongs to the Special Issue Novel Progress in Cancer Immunotherapy)

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22 pages, 672 KiB

Open AccessReview

Chronic Inflammation and Immune Dysregulation in Metabolic-Dysfunction-Associated Steatotic Liver Disease Progression: From Steatosis to Hepatocellular Carcinoma

by Young-Min Jee, Jeong-Yoon Lee and Tom Ryu

Biomedicines 2025, 13(5), 1260; https://doi.org/10.3390/biomedicines13051260 - 21 May 2025

Viewed by 775

Abstract

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) progresses from hepatic steatosis to hepatocellular carcinoma (HCC) as a result of systemic immunometabolic dysfunction. This review summarizes the key roles of the innate and adaptive immune mechanisms driving hepatic injury, fibrogenesis, and carcinogenesis in MASLD. [...] Read more.

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) progresses from hepatic steatosis to hepatocellular carcinoma (HCC) as a result of systemic immunometabolic dysfunction. This review summarizes the key roles of the innate and adaptive immune mechanisms driving hepatic injury, fibrogenesis, and carcinogenesis in MASLD. Methods: A comprehensive literature review was performed using PubMed to identify relevant published studies. Eligible articles included original research and clinical studies addressing immunological and metabolic mechanisms in MASLD, as well as emerging therapeutic strategies. Results: We highlight the roles of cytokine networks, the gut–liver axis, and immune cell reprogramming. Emerging therapeutic strategies, including cytokine inhibitors, anti-fibrotic agents, metabolic modulators, and nutraceuticals, offer several indications for attenuating MASLD progression and reducing the prevalence of extrahepatic manifestations. Conclusions: Given the heterogeneity of MASLD, personalized combination-based approaches targeting both inflammation and metabolic stress are essential for effective disease management and the prevention of systemic complications. Full article

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

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12 pages, 846 KiB

Open AccessArticle

Beating Heart Coronary Artery Bypass Grafting with Preemptive Impella^™ 5.5 Assist Device in Ischemic Cardiomyopathy

by Francesco Cabrucci, Massimo Baudo, Yoshiyuki Yamashita, Amanda Yakobitis, Courtney Murray and Gianluca Torregrossa

Biomedicines 2025, 13(5), 1259; https://doi.org/10.3390/biomedicines13051259 - 21 May 2025

Viewed by 768

Abstract

Background: Choosing the best surgical approach for coronary revascularization in patients with ischemic cardiomyopathy and low EF is complex. Several strategies have been adopted, including on- and off-pump CABG, the use of IABP, and the combination of ECMO or even LVAD with CABG. [...] Read more.

Background: Choosing the best surgical approach for coronary revascularization in patients with ischemic cardiomyopathy and low EF is complex. Several strategies have been adopted, including on- and off-pump CABG, the use of IABP, and the combination of ECMO or even LVAD with CABG. Recently, the Impella 5.5 micro-axial pump has been used as perioperative temporary left ventricular support in CABG patients. This study aims to report a series of CABG procedures performed with Impella assistance, highlighting its potential benefits in high-risk surgery cases. Methods: Between January 2023 and December 2024, seven consecutive patients underwent on-pump beating CABG with planned central Impella 5.5 support via a 10 mm graft in the ascending aorta. This study focused on assessing perioperative outcomes in patients with reduced ventricular dysfunction (ejection fraction [EF] < 35%) undergoing CABG with Impella-assisted support. Results: Seven patients were included in the study, with a median age of 70 [IQR 57–74.7], and six were male. Hypertension was present in all patients, diabetes in six, and COPD in two, and two were in dialysis. The median preoperative EF was 20% [IQR, 18–29%], and the median STS PROM was 5.5 [IQR: 2.9–8.9]. One patient had preoperative IABP support. Four patients required intraoperative transfusions, but all remained hemodynamically stable upon OR exit. The Impella was removed after an average of 5.6 ± 2.1 days. One patient underwent surgical revision for bleeding. No strokes, myocardial infarctions, repeat revascularizations, or mortality occurred postoperatively. The median postoperative hospital stay was 21 [IQR, 17.5–22] days, with a discharge EF of 38% [IQR 33.5–38%]. One patient died 6 months after the procedure due to sepsis caused by a gangrenous diabetic leg. Conclusions: This initial experience using Impella 5.5 support in CABG patients with reduced EF demonstrated its feasibility in selected cases. The Impella provided effective circulatory support, ensuring stable hemodynamics throughout the postoperative stay without complications. Full article

(This article belongs to the Special Issue Advanced Research on Heart Failure and Heart Transplantation)

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11 pages, 980 KiB

Open AccessArticle

Two-Staged Sequential Management of Post-LASIK Ectasia: Under-Flap Corneal Cross-Linking for Stabilization Followed by Flap Surface Topography-Guided PRK for Visual Optimization

by Avi Wallerstein, Brandon Bellware, Mark Cohen, Pierre Demers and Mathieu Gauvin

Biomedicines 2025, 13(5), 1258; https://doi.org/10.3390/biomedicines13051258 - 21 May 2025

Viewed by 333

Abstract

Background/Objectives: To evaluate the efficacy, accuracy, safety, and long-term stability of topography-guided photorefractive keratectomy (TGPRK) in eyes where post-LASIK (PLE) ectasia progression was stabilized with under-flap corneal crosslinking (ufCXL). Methods: This retrospective interventional case series included six eyes from five patients [...] Read more.

Background/Objectives: To evaluate the efficacy, accuracy, safety, and long-term stability of topography-guided photorefractive keratectomy (TGPRK) in eyes where post-LASIK (PLE) ectasia progression was stabilized with under-flap corneal crosslinking (ufCXL). Methods: This retrospective interventional case series included six eyes from five patients with PLE after microkeratome LASIK. All eyes underwent ufCXL to halt ectatic progression. A shallow TGPRK enhancement was performed on the LASIK flap surface after corneal and refractive stability was confirmed (18 months median) post ufCXL Outcome measures included uncorrected and corrected distance visual acuity (UDVA, CDVA), spherical equivalent (SEQ), refractive astigmatism, keratometry, and corneal irregularity indices over a mean follow-up of 47 months. Results: ufCXL stabilized ectatic progression but left residual refractive errors, limiting UDVA. TGPRK performed subsequently significantly improved UDVA, from 0.38 to 0.10 LogMAR (p = 0.017), and increased the LASIK efficacy index from 0.46 to 0.83 (p = 0.0087). Refractive astigmatism was reduced in all eyes achieving a SEQ within ±1.00 D of the target. Long-term stability was maintained, with no ectasia progression, no change in SEQ, no change in corneal irregularity indices, and no increase in maximal keratometry. Conclusions: TGPRK performed in ufCXL stabilized corneas can safely correct residual refractive errors, resulting in significant and sustained improvements in both refractive and visual outcomes in PLE. Full article

(This article belongs to the Special Issue New Insights and Latest Advances in Corneal and Ocular Surface Diseases)

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16 pages, 263 KiB

Open AccessReview

Platelet-Rich Plasma (PRP) in Reproductive Medicine: A Critical Review of PRP Therapy in Low-Reserve and Premature Ovarian Insufficiency

by Efthalia Moustakli, Anastasios Potiris, Athanasios Zikopoulos, Athanasios Zachariou, Spyridon Topis, Periklis Panagopoulos, Ekaterini Domali, Peter Drakakis and Sofoklis Stavros

Biomedicines 2025, 13(5), 1257; https://doi.org/10.3390/biomedicines13051257 - 21 May 2025

Viewed by 976

Abstract

Background: Intraovarian platelet-rich plasma (PRP) has emerged as a novel intervention at the intersection of reproductive medicine and regenerative biology. As women with diminished ovarian reserve (DOR), poor response to stimulation, or premature ovarian insufficiency (POI) seek fertility solutions, PRP provides a scientifically [...] Read more.

Background: Intraovarian platelet-rich plasma (PRP) has emerged as a novel intervention at the intersection of reproductive medicine and regenerative biology. As women with diminished ovarian reserve (DOR), poor response to stimulation, or premature ovarian insufficiency (POI) seek fertility solutions, PRP provides a scientifically plausible—yet exploratory—strategy to restore or augment ovarian function. The proposed pathways include the stimulation of local stem cells, tissue remodeling, neoangiogenesis, and the potential reawakening of dormant follicles. Methods: This narrative review critically synthesizes the existing literature on intraovarian PRP therapy. It draws from published case series, pilot studies, and preclinical data to evaluate the biological rationale, clinical outcomes, and current limitations of PRP use in women with DOR and POI. Results: Early clinical findings, albeit limited to modest case series and pilot investigations, reveal promising outcomes such as improved ovarian reserve markers, menstrual restoration, and infrequent spontaneous pregnancies in women who had previously been unresponsive to treatment. However, the variability in preparation techniques, patient selection criteria, and outcome measures limits the generalizability of these results. Conclusions: While intraovarian PRP presents an exciting frontier in reproductive medicine, the absence of defined protocols, controlled trials, and long-term safety data underscores its experimental nature. Future research should focus on standardizing methodologies, conducting randomized controlled trials, and elucidating the molecular mechanisms underlying observed clinical effects to establish PRP’s role in managing poor ovarian response and POI. Full article

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

24 pages, 2711 KiB

Open AccessReview

Integrative Approaches in the Management of Hypertrophic Cardiomyopathy: A Comprehensive Review of Current Therapeutic Modalities

by Marco Maria Dicorato, Gaetano Citarelli, Francesco Mangini, Rossella Alemanni, Miriam Albanese, Sebastiano Cicco, Cosimo Angelo Greco, Cinzia Forleo, Paolo Basile, Maria Cristina Carella, Marco Matteo Ciccone, Andrea Igoren Guaricci and Ilaria Dentamaro

Biomedicines 2025, 13(5), 1256; https://doi.org/10.3390/biomedicines13051256 - 21 May 2025

Viewed by 834

Abstract

Hypertrophic cardiomyopathy (HCM) is often associated with left ventricular outflow tract (LVOT) obstruction, which affects a substantial proportion of patients. This obstruction results from a range of anatomical abnormalities involving both the valvular and subvalvular structures. Pharmacological therapies play a pivotal role in [...] Read more.

Hypertrophic cardiomyopathy (HCM) is often associated with left ventricular outflow tract (LVOT) obstruction, which affects a substantial proportion of patients. This obstruction results from a range of anatomical abnormalities involving both the valvular and subvalvular structures. Pharmacological therapies play a pivotal role in the management of LVOT obstruction, with a range of drug classes exhibiting distinct mechanisms of action. Beta-blockers, including atenolol and nadolol, are considered the first-line treatment due to their ability to reduce heart rate and myocardial contractility and enhance diastolic filling. Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, are utilized as second-line agents when beta-blockers are ineffective or contraindicated. Disopyramid, a Class 1A antiarrhythmic agent, is employed for patients who do not respond to initial therapeutic interventions and can reduce LVOT gradients. Recent advancements in cardiac myosin modulators, such as Mavacamten and Aficamten, offer targeted therapies by modulating myosin–actin interactions to reduce LVOT gradients and improve symptoms, with promising results from clinical trials. Although gene therapy is still in its nascent stages, it has the potential to address the genetic basis of HCM by employing techniques such as genome editing, gene replacement, and the modulation of signaling pathways. For patients exhibiting severe symptoms or demonstrating unresponsiveness to medical treatment, invasive therapies, such as septal reduction therapy and alcohol septal ablation, are considered. Ultimately, the treatment and prevention of atrial fibrillation and sudden cardiac death are two key points of HCM management in both obstructive and non-obstructive forms. This review aims to provide an overview of current pharmacological and invasive strategies, as well as emerging therapies, in the management of HCM. Full article

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

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14 pages, 2973 KiB

Open AccessArticle

The Presence and Significance of Bacteria and Fungi in Bile Aspirated During ERC—A Retrospective Analysis

by Sylvia Weigand, Arne Kandulski, Ina Zuber-Jerger, Marcus Scherer, Jens Werner, Jan Bornschein and Kilian Weigand

Biomedicines 2025, 13(5), 1255; https://doi.org/10.3390/biomedicines13051255 - 21 May 2025

Viewed by 334

Abstract

Background: Infections of the biliary tract are found frequently in pathologically or surgically altered bile ducts. Mostly these infections result from the ascent of bacteria or fungi from the small bowel, although hematogeneous infections of the biliary system may also occur. The biliary [...] Read more.

Background: Infections of the biliary tract are found frequently in pathologically or surgically altered bile ducts. Mostly these infections result from the ascent of bacteria or fungi from the small bowel, although hematogeneous infections of the biliary system may also occur. The biliary sphincter and the continuous flow of bile are thought to prevent or limit ascending infections. Obstructive alterations in the biliary system are the most frequent indication of endoscopic retrograde cholangiography (ERC). The aim of this study was to analyze the spectrum and frequency of microbes within the bile, and discover the influence of earlier sphincterotomy. Methods: In our department, we routinely aspirate bile for microbiologic culture during ERC. For this study, all ERC performed in 2014–2018 were retrospectively analyzed, including all microbiological reports. Indications for the endoscopic examination were also recorded. In addition, the findings were correlated with whether or not a sphincterotomy had been previously performed, and whether or not there had been antibiotic treatment prior to the examination. Results: A total of 2253 successful standard ERC procedures were performed between 2014 and 2016. In 486 cases, bile was aspirated and sent for microbiologic culture. In total, 1220 bile samples were analyzed, and bacteria or fungi were found in 1029 (86.0%). Enterococci and Enterobacter were found most commonly, but E. coli, streptococci, klebsiella, and staphylococci were also found. In 11.2% of positive cultures, multiresistant pathogens were identified. In up to 29% Candida spp., most commonly, Candida albicans (68%) were also found, either alone or in conjunction with bacteria. Neither prior sphincterotomy nor the use of peri-interventional antibiotics had a major influence on the frequency with which positive bile cultures were detected. Conclusions: Aspiration of bile during ERC is of high clinical relevance, because microbiological analysis reveals the frequent presence of bacteria and fungi, knowledge of which may be useful for deciding on anti-infective treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Hepatic and Gastrointestinal Diseases in Germany)

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11 pages, 844 KiB

Open AccessArticle

Influence of Constipation in the Behavior of Circulating Alpha- and Beta-CGRP Levels in Chronic/High-Frequency Migraine Patients After CGRP Monoclonal Antibodies

by Gabriel Gárate, Marcos Polanco, Jorge Madera, María Muñoz-San Martín, Marta Pascual-Mato, Vicente González-Quintanilla and Julio Pascual

Biomedicines 2025, 13(5), 1254; https://doi.org/10.3390/biomedicines13051254 - 21 May 2025

Viewed by 396

Abstract

Background/Objectives: Migraines contain neurological and gastrointestinal manifestations. The first specific migraine preventive drugs, CGRP monoclonal antibodies (mAbs), though efficacious and very well-tolerated in general, induce constipation as their main adverse event. Our goal was to analyze the role of the two isoforms [...] Read more.

Background/Objectives: Migraines contain neurological and gastrointestinal manifestations. The first specific migraine preventive drugs, CGRP monoclonal antibodies (mAbs), though efficacious and very well-tolerated in general, induce constipation as their main adverse event. Our goal was to analyze the role of the two isoforms of CGRP in the development of constipation in patients treated with mABs. Methods: We prospectively measured by ELISA circulating alpha- and beta-CGRP levels in 133 high-frequency episodic/chronic migraine patients before and three months after mAbs treatment and correlated these levels with a number of clinical variables, including the development of constipation during this treatment. Results: Twelve patients (9.0%) noticed de novo constipation with mAbs. Demographics, efficacy end-points, profile of preventive treatment, and comorbidities, with the exception of anxiety/depression, were superimposable between patients with or without emergent constipation. Basal alpha-CGRP levels (49.5 [29.2–73.8] pg/mL) significantly decreased at month three of treatment (40.5 [20.4–61.0] pg/mL; p < 0.0001), both in patients with and without emergent constipation. Pre-treatment circulating beta-CGRP levels (4.0 [2.1–6.2] pg/mL) remained unchanged after three months of treatment (4.3 [2.5–6.0] pg/mL; p = 0.574) in the whole series but were selectively reduced in patients with emergent constipation (p = 0.034). Conclusions: This is the first work exploring the role of the two isoforms of CGRP in the pathophysiology of constipation with mAbs. Our results suggest that the antagonism on the alpha-CGRP isoform plays a relevant role in the antimigraine action of mABs but not in the development of constipation. By contrast, the specific reduction in beta-CGRP levels in patients with emergent constipation supports the role of beta-CGRP antagonism in the development of this adverse event. Full article

(This article belongs to the Special Issue Bench-to-Bedside Approach to Migraine: How Pathophysiology Could Influence Novel Therapeutic Approaches and Back)

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18 pages, 3639 KiB

Open AccessArticle

Therapeutic Potential of Chick Early Amniotic Fluid in Mitigating Ionizing-Radiation-Induced Damage

by Ke Zhang, Hai Yang, Yueyue Wu, Yining Zhao, Wenxu Xin, Deshen Han, Ning Sun and Chao Ye

Biomedicines 2025, 13(5), 1253; https://doi.org/10.3390/biomedicines13051253 - 21 May 2025

Viewed by 382

Abstract

Background: Clinical data indicate that at least half of patients with malignancies receive radiotherapy. While radiotherapy effectively kills tumor cells, it is also associated with significant ionizing radiation (IR) damage. Moreover, the increasing emissions of nuclear pollutants raise concerns about the potential exposure [...] Read more.

Background: Clinical data indicate that at least half of patients with malignancies receive radiotherapy. While radiotherapy effectively kills tumor cells, it is also associated with significant ionizing radiation (IR) damage. Moreover, the increasing emissions of nuclear pollutants raise concerns about the potential exposure of more individuals to the risks associated with IR. The Chinese term for amniotic fluid (AF) is rooted in the Yin–Yang theory of traditional Chinese medicine, where it symbolizes the inception of human life. Chick early AF (ceAF), a natural product, has shown promise in the field of regenerative medicine. There have been no studies investigating the potential efficacy of ceAF in the treatment of IR-induced damage. This study aims to assess the therapeutic potential of ceAF in alleviating IR-induced damage and elucidate its potential molecular mechanism. Methods: In vivo experiments were conducted on 8-week-old male C57BL/6J mice to investigate the effects of ceAF in a radiation injury model induced by whole-body irradiation with X-rays (6 Gy) for 5 min. The ceAF was extracted from chicken embryos aged 7–9 days. Results: We found that the supplementation of ceAF reduces mortality induced by IR, improves exercise capacity in IR mice, and reverses IR-induced skin damage. IR leads to varying degrees of volume atrophy and weight loss in the major internal organs of mice. However, ceAF intervention effectively mitigates IR-induced organ damage, with a notable impact on the spleen. The supplementation of ceAF enhances spleen hematopoietic and immune functions by reducing oxidative stress, alleviating inflammatory responses, and preventing splenic DNA damage from IR exposure, ultimately leading to an overall improvement in health. Conclusions: ceAF effectively alleviates body damage induced by IR, and our findings provide new perspectives and therapeutic strategies for mitigating IR-induced damage. Full article

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

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13 pages, 256 KiB

Open AccessArticle

Prevalence and Clinical Impact of Obstructive Sleep Apnea in Patients with Severe Aortic Stenosis Undergoing Valve Replacement

by Hilary Miranda-Mendoza, Luis M. Amezcua-Guerra, Gustavo Rojas-Velasco, Daniel Manzur-Sandoval, Jennifer Escobar-Alvarado, Luis Chávez-Sánchez, Wendy G. Vázquez-González, Laura L. Rodríguez Chávez, Humberto Martínez Hernández and Malinalli Brianza-Padilla

Biomedicines 2025, 13(5), 1252; https://doi.org/10.3390/biomedicines13051252 - 21 May 2025

Viewed by 546

Abstract

Background/Objectives: Aortic stenosis (AS) is the most prevalent valvular disease among older adults. Although obstructive sleep apnea (OSA) has been linked to adverse cardiovascular outcomes, its specific impact on patients with severe AS remains unclear. This study aimed to determine the prevalence [...] Read more.

Background/Objectives: Aortic stenosis (AS) is the most prevalent valvular disease among older adults. Although obstructive sleep apnea (OSA) has been linked to adverse cardiovascular outcomes, its specific impact on patients with severe AS remains unclear. This study aimed to determine the prevalence of OSA and its influence on postoperative recovery following aortic valve replacement. Methods: A prospective case-control study was conducted at the Instituto Nacional de Cardiología Ignacio Chávez. Patients aged 40–80 years with echocardiographically confirmed severe AS were categorized into groups with and without OSA, based on respiratory polygraphy (Apnea–Hypopnea Index [AHI] threshold of >15 events per hour). Clinical, biochemical, echocardiographic, body composition, and hemodynamic parameters were assessed. Daytime sleepiness and sleep quality were evaluated using validated questionnaires. Inflammatory biomarkers were also analyzed. This study was approved by the institutional ethics committee. Results: Of the 30 patients included, 66.6% were diagnosed with OSA. Compared to non-OSA patients, those with OSA had a higher left ventricular mass index (160 vs. 108; p = 0.001), greater postoperative increases in central venous pressure [8 (8–10) vs. 8 (6–8); p = 0.037], and lower mixed venous oxygen saturation within the first 24 h (69.2 vs. 76; p = 0.027). OSA patients also had longer hospital stays (11 vs. 8 days; p = 0.014). Trends toward a heightened subclinical inflammatory state were noted in the OSA group. Conclusions: OSA is frequent and underdiagnosed in patients with severe AS and is associated with more complicated postoperative recovery. Systematic OSA screening is recommended for candidates undergoing aortic valve surgery. Full article

(This article belongs to the Special Issue Molecular and Translational Research in Cardiovascular Disease)

11 pages, 411 KiB

Open AccessArticle

HD-OCT Angiography and SD-OCT in Patients with Mild or No Clinically Apparent Diabetic Retinopathy

by Maja Vinković, Andrijana Kopić, Tvrtka Benašić, Dubravka Biuk, Ivanka Maduna and Stela Vujosevic

Biomedicines 2025, 13(5), 1251; https://doi.org/10.3390/biomedicines13051251 - 20 May 2025

Viewed by 345

Abstract

Purpose: To analyze the retinal and choriocapillaris changes in diabetic patients with no or with early signs of diabetic retinopathy using high-definition (HD) angio optical coherence tomography angiography (OCTA) software and spectral-domain (SD) OCT. Methods: A total of 112 eyes (54 eyes from [...] Read more.

Purpose: To analyze the retinal and choriocapillaris changes in diabetic patients with no or with early signs of diabetic retinopathy using high-definition (HD) angio optical coherence tomography angiography (OCTA) software and spectral-domain (SD) OCT. Methods: A total of 112 eyes (54 eyes from 27 diabetic patients and 58 eyes from 29 control subjects) were included in this retrospective cross-sectional study of healthy and diabetic adults. Retinal microvascular changes were assessed by using HD-OCTA software to calculate vascular density (VD) and foveal avascular zone (FAZ). SD-OCT was used to assess retinal thickness and volume in parafovea as well as ganglion cell complex (GCC) parameters. Results: The VD-whole image was significantly higher in the healthy control group (MW z = 1109.5, p = 0.012; t = 2.611, p = 0.010). Also, VD-parafovea was significantly higher in the healthy subjects (MW z = 1053.5, p = 0.004; t = 3.207, p = 0.002). GCC focal loss volume (FLV) was significantly decreased in diabetic patients (p = 0.051). Non-flow FAZ did not show a statistically significant difference between groups, although the FAZ was larger in the diabetic patients. Conclusions: Diabetic patients with no or early signs of diabetic retinopathy have decreased VD compared to healthy individuals. They also present retinal changes at the GCC that are correlated with initial neurodegeneration. HD-OCTA and SD-OCT can detect vascular changes and structural signs of retinal neurodegeneration before clinically apparent diabetic retinopathy. Potentially, these methods may offer new biomarkers for monitoring disease progression and visual prognosis. Full article

(This article belongs to the Special Issue Emerging Issues in Retinal Degeneration)

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16 pages, 4129 KiB

Open AccessArticle

Effective Management of Chronic Low Back Pain in the Elderly: A One-Year Cohort Study of Oxygen–Ozone Therapy Under CT Guidance Combined with Alpha Lipoic Acid, Palmitoylethanolamide, and Myrrh

by Matteo Bonetti, Michele Frigerio, Gian Maria Ottaviani, Giannantonio Pellicanò, Alessio Zambello, Mario Muto, Francesco Carinci and Federico Maffezzoni

Biomedicines 2025, 13(5), 1250; https://doi.org/10.3390/biomedicines13051250 - 20 May 2025

Viewed by 593

Abstract

Background and Objective: This observational study aimed to evaluate the clinical efficacy of combined oxygen–ozone (O₂-O₃) therapy under CT guidance with the oral administration of alpha-lipoic acid (ALA), palmitoylethanolamine (PEA), and myrrh in elderly patients suffering from chronic low [...] Read more.

Background and Objective: This observational study aimed to evaluate the clinical efficacy of combined oxygen–ozone (O₂-O₃) therapy under CT guidance with the oral administration of alpha-lipoic acid (ALA), palmitoylethanolamine (PEA), and myrrh in elderly patients suffering from chronic low back pain (LBP). Given the rising prevalence of degenerative spinal diseases in older adults, this study addresses the need for effective, minimally invasive treatment options. Methods: A total of 276 patients aged 65 to 92 years, with chronic unilateral or bilateral LBP, underwent CT-guided paravertebral infiltrations with an O₂-O₃ gas mixture. This treatment was complemented with a 30-day regimen of ALA (800 mg/day), PEA (600 mg/day), and myrrh (200 mg/day). Clinical outcomes were assessed at one month and one year post-treatment using the Visual Analog Scale (VAS) and the modified McNab method. Results: At one month, 32.94% of patients reported an excellent improvement, with the mean VAS score dropping from 8.17 to 2.81. At the one-year follow-up, 68.15% cumulatively experienced positive outcomes, with 17.78% reporting the complete resolution of pain. In this occasion, the mean VAS score was 3.57. Conclusions: The study demonstrates that the combination of oxygen–ozone therapy and oral ALA, PEA, and myrrh is a promising alternative for managing chronic low back pain in the elderly, leading to significant pain reduction and improved quality of life. Findings emphasize the need for further research to validate these results and explore the long-term benefits. Full article

(This article belongs to the Special Issue Mechanisms and Pharmacological Targets for Pain)

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17 pages, 6775 KiB

Open AccessArticle

Bioinformatics-Guided Experimental Validation Identifies NQO1 as a Senescence-Ferroptosis Hub in Liver Fibrosis

by Xinying Zhang, Chunmeng Fu, Ziyue Yang, Yue Tan, Huan Li, Xiangqian Zhang, Mengru Chen, Fang Peng and Ning Li

Biomedicines 2025, 13(5), 1249; https://doi.org/10.3390/biomedicines13051249 - 20 May 2025

Viewed by 903

Abstract

Background: As a pivotal point for the development of liver diseases, liver fibrosis (LF) is closely associated with cellular senescence and ferroptosis. However, there is a lack of effective markers that accurately predict LF status. This study aims to identify key genes involved [...] Read more.

Background: As a pivotal point for the development of liver diseases, liver fibrosis (LF) is closely associated with cellular senescence and ferroptosis. However, there is a lack of effective markers that accurately predict LF status. This study aims to identify key genes involved in LF through bioinformatics analysis and experimental validation. Methods: We used bioinformatics analysis of Gene Expression Omnibus (GEO) data to investigate the gene functions, prognostic value, and immune associations of characteristic genes in LF. Functional enrichment analysis of DEGs was performed using GO and KEGG. Immune cell types and their proportions were estimated with CIBERSORTx. In addition, we analyzed the role of NQO1 in LF using IHC, WB, PCR, and flow cytometry. Results: Bioinformatics analysis identified 10 hub genes, including AR, CDKN1A, GJA1, CTSB, HIF1A, HMGB1, NQO1, PARP1, PTEN, and TXN. Among them, NQO1 was strongly correlated with immune cell activity. Experimental validation confirmed that NQO1 is upregulated and promotes αSMA and COL1A1 expression in hepatic stellate cells (HSCs). Knockdown of NQO1 significantly affected the proliferation of HSCs. Conclusions: NQO1 plays a critical role in HSC senescence and ferroptosis, promoting HSC activation and contributing to LF progression. Our findings suggest that NQO1 may serve as a potential biomarker for LF. Full article

(This article belongs to the Special Issue Liver Disease: Etiology, Pathology, and Treatment)

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17 pages, 4197 KiB

Open AccessArticle

Systemic Ozone Therapy Improves Oral Hard and Soft Tissue Healing in Medication-Related Osteonecrosis of the Jaw (MRONJ): A Study in Senescent Female Rats

by Leonardo Alan Delanora, Tiburtino José de Lima Neto, Tiago Esgalha da Rocha, Glauco Rodrigues Carmo Silveira, Liran Levin, Jamil Awad Shibli, Edilson Ervolino, Carlos Fernando Mourão and Leonardo P. Faverani

Biomedicines 2025, 13(5), 1248; https://doi.org/10.3390/biomedicines13051248 - 20 May 2025

Cited by 1 | Viewed by 455

Abstract

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a challenging condition often associated with bisphosphonate use, leading to impaired bone healing and difficult clinical management. Given the lack of predictable therapeutic options, this study investigated the effects of systemic ozone therapy on [...] Read more.

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a challenging condition often associated with bisphosphonate use, leading to impaired bone healing and difficult clinical management. Given the lack of predictable therapeutic options, this study investigated the effects of systemic ozone therapy on MRONJ healing. This study aimed to analyze the effects of systemic ozone therapy on oral hard and soft tissue healing in senescent rats with medication-related osteonecrosis of the jaw (MRONJ) induced by antiresorptive therapy. Methods: Twenty-eight senescent Wistar rats, aged eighteen months and weighing ~350 g, were used for this study. The animals were divided into four groups. The negative control (SAL) group received saline applications, while the control-treated (SAL+OZ) group received saline applications and ozone therapy (0.7 mg/kg). The MRONJ (ZOL) group received Zoledronate, an intravenous antiresorptive drug (100 μg/kg), and the MRONJ-treated (ZOL+OZ) group received zoledronate application and was treated with systemic ozone therapy (0.7 mg/kg). All rats underwent molar extraction in the third week of the experiment and were euthanized in the seventh week of the experiment. The mandibles were resected, reduced, and prepared for microtomographic analysis, histopathological/histometric analysis, and immunohistochemistry. Results: The ZOL group presented characteristics of vitreous, non-vital, and dense bone, poor vascularization, and high values of inflammation markers compatible with MRONJ. In contrast, the ZOL+OZ group exhibited improvement in alveolar bone and soft tissue healing, a decrease in nonvital bone area, and modulation of local inflammation. Conclusions: It can be concluded that Ozone therapy improved oral hard and soft tissue healing of MRONJ in senescent female rats subjected to antiresorptive drugs and might be considered for future clinical applications. Full article

(This article belongs to the Collection Feature Papers in Biomedical Materials)

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19 pages, 16275 KiB

Open AccessArticle

Targeting the ZMYM2-ANXA9 Axis with FLT3 Inhibitor G749 Overcomes Oxaliplatin Resistance in Colorectal Cancer

by Dezheng Lin, Yucheng Xu, Huanmiao Zhan, Yufan Liang, Riyun Liu, Jun Liu, Dandong Luo, Xiaochuan Chen, Jiawei Cai and Yifeng Zou

Biomedicines 2025, 13(5), 1247; https://doi.org/10.3390/biomedicines13051247 - 20 May 2025

Viewed by 551

Abstract

Background: Chemoresistance and tumor recurrence remain major obstacles in colorectal cancer (CRC) therapy. Elucidating the molecular mechanisms underlying treatment resistance is critical for improving therapeutic outcomes. Methods: We analyzed transcriptomic profiles from public datasets (TCGA and GSE39582) to identify differentially expressed genes [...] Read more.

Background: Chemoresistance and tumor recurrence remain major obstacles in colorectal cancer (CRC) therapy. Elucidating the molecular mechanisms underlying treatment resistance is critical for improving therapeutic outcomes. Methods: We analyzed transcriptomic profiles from public datasets (TCGA and GSE39582) to identify differentially expressed genes associated with a poor response to neoadjuvant chemotherapy in CRC patients. Among 298 candidate genes, ANXA9 emerged as significantly overexpressed in chemoresistant tumors and associated with a poor prognosis. These findings were further validated in an independent cohort of 146 Stage III CRC patients using immunohistochemistry and survival analysis. The expression of ANXA9 was evaluated in oxaliplatin acquired-resistant CRC cell lines via qPCR and Western blot. Functional studies, including RNA interference, colony formation, apoptosis assays, and drug sensitivity testing, were performed in vitro and in vivo to assess the role of ANXA9. A high-throughput drug screen identified G749, a FLT3 inhibitor, as a potential therapeutic agent. Results: ANXA9 expression was significantly elevated in non-responders to chemotherapy and oxaliplatin-resistant CRC cell lines. The knockdown of ANXA9 reduced proliferation and enhanced oxaliplatin sensitivity. G749 was found to suppress ANXA9 expression in a dose-dependent manner and inhibit CRC cell growth in vitro and in patient-derived organoids. In a CRC xenograft mouse model, G749 reduced the tumor burden without observable toxicity. Mechanistically, we identified ZMYM2 as a transcriptional regulator of ANXA9. ChIP-qPCR confirmed ZMYM2 binding to the ANXA9 promoter, especially in resistant cells. Silencing ZMYM2 suppressed tumor cell growth and restored chemosensitivity. Conclusions: The ZMYM2-ANXA9 signaling axis drives chemoresistance and tumor progression in CRC. FLT3 inhibition by G749 effectively downregulates ANXA9 and sensitizes tumors to chemotherapy, highlighting a novel therapeutic approach for chemoresistant CRC. Full article

(This article belongs to the Special Issue Progress in Immunopharmacy)

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12 pages, 1280 KiB

Open AccessArticle

Structured Early Follow-Up in Head and Neck Squamous Cell Carcinomas: A Retrospective Cohort Study

by Philipp Dittmann, Bernhard Lehnert, Friedrich Ihler, Chia-Jung Busch and Markus Blaurock

Biomedicines 2025, 13(5), 1246; https://doi.org/10.3390/biomedicines13051246 - 20 May 2025

Viewed by 576

Abstract

Background/Objectives: The various head and neck squamous cell carcinoma (HNSCC) subtypes are among the most common cancers globally, with significant recurrence rates within the first two years post-treatment. Despite advancements in treatment, structured early follow-up remains crucial for timely diagnosis and effective salvage [...] Read more.

Background/Objectives: The various head and neck squamous cell carcinoma (HNSCC) subtypes are among the most common cancers globally, with significant recurrence rates within the first two years post-treatment. Despite advancements in treatment, structured early follow-up remains crucial for timely diagnosis and effective salvage treatment. Methods: This retrospective study examines the impact of implementing a structured initial restaging between three and six months after the conclusion of initial treatment. The study population included 532 patients treated with curative intent at the University Medicine of Greifswald, Germany, between 2010 and 2019. Patients were divided into two groups: standard follow-up (SF) and adapted follow-up (AF). The AF group received standardized post-treatment restaging, including imaging and panendoscopy or PET-CT exams. Results: We found a trend towards earlier diagnosis and a reduction in recurrences, although these differences were not statistically significant. Secondary cancers were observed more frequently in the AF group, significantly affecting overall survival. Conclusions: Our cohort supports structured initial cancer follow-up in HNSCC. Although not significant, an initial multimodal exam after treatment was well tolerated and showed a trend toward earlier diagnosis. Full article

(This article belongs to the Special Issue Head and Neck Tumors, 4th Edition)

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13 pages, 4321 KiB

Open AccessArticle

ML210 Antagonizes ABCB1- Not ABCG2-Mediated Multidrug Resistance in Colorectal Cancer

by Yan-Chi Li, Yu-Meng Xiong, Ze-Ping Long, Yi-Ping Huang, Yu-Bin Shu, Ke He, Hong-Yan Sun and Zhi Shi

Biomedicines 2025, 13(5), 1245; https://doi.org/10.3390/biomedicines13051245 - 20 May 2025

Viewed by 555

Abstract

Objectives: ABCB1-mediated multidrug resistance (MDR) compromises chemotherapy efficacy in colorectal cancer (CRC). Despite decades of research, no selective ABCB1 inhibitor has achieved clinical success. This study investigates ML210 as a novel ABCB1-specific inhibitor to reverse ABCB1-driven MDR. Methods: Cytotoxicity assays (MTT) were performed [...] Read more.

Objectives: ABCB1-mediated multidrug resistance (MDR) compromises chemotherapy efficacy in colorectal cancer (CRC). Despite decades of research, no selective ABCB1 inhibitor has achieved clinical success. This study investigates ML210 as a novel ABCB1-specific inhibitor to reverse ABCB1-driven MDR. Methods: Cytotoxicity assays (MTT) were performed on ABCB1-overexpressing HCT-8/V and ABCG2-overexpressing S1-M1-80 CRC cells. Drug accumulation (doxorubicin/mitoxantrone) was quantified via flow cytometry, and cell cycle effects were analyzed using propidium iodide staining. Molecular docking utilized the ABCB1 crystal structure. Results: ML210 selectively reversed ABCB1-mediated resistance to doxorubicin and vincristine in HCT-8/V cells, enhancing intracellular drug accumulation without affecting ABCG2 activity. It induced cell cycle arrest in ABCB1-overexpressing cells and did not alter ABCB1 protein expression. Molecular docking revealed stable binding of ML210 within the ABCB1 substrate pocket through hydrophobic interactions and hydrogen bonding. Conclusions: ML210 is a selective ABCB1 inhibitor that circumvents MDR via direct transport blockade, offering a targeted strategy against ABCB1-mediated chemoresistance in CRC. Its specificity for ABCB1 over ABCG2 highlights potential clinical advantages. Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

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15 pages, 618 KiB

Open AccessReview

New Insights into the Diagnosis and Treatment of Hepatocellular Carcinoma

by Chengbo Li, Bingjiu Lu and Baocheng Deng

Biomedicines 2025, 13(5), 1244; https://doi.org/10.3390/biomedicines13051244 - 20 May 2025

Viewed by 728

Abstract

Hepatocellular carcinoma remains one of the leading contributors to global cancer mortality, frequently stemming from chronic liver conditions, such as viral hepatitis, non-alcoholic fatty liver disease, and alcohol-induced cirrhosis. While antiviral treatments have made significant strides, the rising prevalence of hepatocellular carcinoma linked [...] Read more.

Hepatocellular carcinoma remains one of the leading contributors to global cancer mortality, frequently stemming from chronic liver conditions, such as viral hepatitis, non-alcoholic fatty liver disease, and alcohol-induced cirrhosis. While antiviral treatments have made significant strides, the rising prevalence of hepatocellular carcinoma linked to non-infectious causes underscores the pressing demand for more effective diagnostic tools and therapeutic interventions. Advances in imaging and liquid biopsy technologies have facilitated early detection and diagnosis, and treatment strategies are diversifying to include immune checkpoint inhibitors, tyrosine kinase inhibitors, and interventional therapies. Translational therapies for advanced hepatocellular carcinoma have improved surgical opportunities and patient survival. Artificial intelligence has played a transformative role in the diagnosis and treatment of hepatocellular carcinoma, in terms of image analysis, histopathologic classification, drug development, and targeted therapy. The future of hepatocellular carcinoma treatment lies in precision oncology and the collaboration of multidisciplinary teams, as well as in early detection. The ultimate goal is to keep patients alive longer and reduce the global burden of this complex malignancy. Full article

(This article belongs to the Special Issue New Insights into the Diagnosis and Treatment of Hepatocellular Carcinoma)

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20 pages, 10972 KiB

Open AccessArticle

Renalase Overexpression-Mediated Excessive Metabolism of Peripheral Dopamine, DOPAL Accumulation, and α-Synuclein Aggregation in Baroreflex Afferents Contribute to Neuronal Degeneration and Autonomic Dysfunction

by Xue Xiong, Yin-Zhi Xu, Yan Zhang, Hong-Fei Zhang, Tian-Min Dou, Xing-Yu Li, Zhao-Yuan Xu, Chang-Peng Cui, Xue-Lian Li and Bai-Yan Li

Biomedicines 2025, 13(5), 1243; https://doi.org/10.3390/biomedicines13051243 - 20 May 2025

Viewed by 454

Abstract

Background/Objectives: Increasing evidence reveals the likely peripheral etiology of Parkinson’s disease; however, the mechanistic insight into α-Synuclein aggregation in the periphery remains unclear. This study aimed to explore the effect of abnormal expression of renalase on dopamine metabolism, toxic DOPAL generation, and [...] Read more.

Background/Objectives: Increasing evidence reveals the likely peripheral etiology of Parkinson’s disease; however, the mechanistic insight into α-Synuclein aggregation in the periphery remains unclear. This study aimed to explore the effect of abnormal expression of renalase on dopamine metabolism, toxic DOPAL generation, and subsequently, α-Synuclein aggregation. Methods: Blood pressure (BP) was monitored while changing the body position of rats; the serum level of renalase was detected by ELISA; the mRNA/protein of renalase and α-Synuclein were determined by qRT-PCR/Western blot; DOPAL was measured using HPLC; renalase distribution was explored by immunostaining; cell viability and ultrastructure were examined by TUNEL and electron microscopy, respectively. Results: The results showed that, in PD model rats, the serum level of renalase was increased time-dependently with up-regulated renalase gene/protein expression in the nodose ganglia, nucleus tractus solitarius, and heart; a reduced dopamine content was also detected by the renalase overexpression in PC12 cells. Strikingly, up-regulated renalase and orthostatic BP changes were observed before the behavioral changes in the model rats. Meanwhile, the levels of DOPAL and α-Synuclein were increased time-dependently. Intriguingly, the low molecular weight of α-Synuclein declined coordinately with the increase in the higher molecular weight of α-Synuclein. Clear ultrastructure damage at the cellular level supported the notion of molecular findings. Notably, the α-Synuclein aggregation-induced impairment of the axonal transport function predates neuronal degeneration mediated by renalase overexpression. Conclusions: Our results demonstrate that abnormal peripheral dopamine metabolism mediated by overexpressed renalase promotes the DOPAL-induced α-Synuclein and leads to baroreflex afferent neuronal degeneration and early autonomic failure. Full article

(This article belongs to the Special Issue Challenges in the Diagnosis and Treatment of Parkinson’s Disease)

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10 pages, 1127 KiB

Open AccessBrief Report

Significant Microvascular Abnormalities Present in Autonomic Nervous System Dysfunction: Results of a Cross-Sectional Study

by Sehreen Mumtaz, Karissa Arca, Vikas Majithia, William Cheshire, David Hodge and Florentina Berianu

Biomedicines 2025, 13(5), 1242; https://doi.org/10.3390/biomedicines13051242 - 20 May 2025

Viewed by 459

Abstract

Purpose: The prevalence and phenotype of capillaroscopic abnormalities in patients with autonomic nervous system dysfunction have not yet been investigated. Multiorgan involvement in dysautonomia entails abnormal vasoreactivity. We aim to correlate the diagnosis of autonomic dysfunction with certain clinical manifestations, which may provide [...] Read more.

Purpose: The prevalence and phenotype of capillaroscopic abnormalities in patients with autonomic nervous system dysfunction have not yet been investigated. Multiorgan involvement in dysautonomia entails abnormal vasoreactivity. We aim to correlate the diagnosis of autonomic dysfunction with certain clinical manifestations, which may provide prognostic or diagnostic information using a noninvasive technique, i.e., nailfold video capillaroscopy (NVC). Methods: Patients with autonomic nervous system dysfunction were recruited from rheumatology and neurology clinics with voluntary NVC procedures from 31 January 2024 to 10 January 2024, and a comparison with normal controls was performed. Additional recorded information include demographics and diagnoses of autonomic dysfunction types by autonomic testing, including, but not limited to, the following: reflex screen, sweat test, Valsalva maneuver, nerve fiber density, electromyography (EMG), serology, and history of autoimmune diseases. NVC was performed on a total of 27 patients. This study was approved by the Mayo Clinic Institutional Review Board. Results: The autonomic dysfunction group consisted of small-fiber neuropathy (37%), orthostatic hypotension (48%), autonomic neuropathy (30%), limited autonomic neuropathy (7%), postural orthostatic tachycardia syndrome (POTS) (7%), and connective tissue disease (7%), among other types. Patients with autonomic dysfunction had statistically significant increases in microhemorrhages, dilated capillaries, and ramifications when compared to controls. Conclusions: Autonomic dysfunction was associated with statistically significant microvascular abnormalities compared to normal controls with a distinct NVC pattern. There was a statistically significant correlation between age and BMI with microvascular abnormalities. Here, we demonstrate the diagnostic potential of NVC in autonomic dysfunction and advocate for further study of capillary structures in autonomic dysfunction. Full article

(This article belongs to the Special Issue Neurovascular Dysfunction: Mechanisms and Therapeutic Strategies)

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11 pages, 1521 KiB

Open AccessCommunication

The Chemokine (C-C Motif) Receptor 1 Antagonist BX471 Improves Fluid Resuscitation in Rat Models of Hemorrhagic Shock

by Elizabeth A. Cook, Ololade Ogunsina, Xianlong Gao and Matthias Majetschak

Biomedicines 2025, 13(5), 1241; https://doi.org/10.3390/biomedicines13051241 - 20 May 2025

Viewed by 358

Abstract

Background/Objectives: We reported previously that antagonists at chemokine receptors CCR2 and CCR3 have fluid-sparing effects during resuscitation from hemorrhagic shock. Because CCR1 shares several chemokine ligands with CCR2/3, we tested whether the CCR1 antagonist BX471 also reduces fluid requirements to maintain hemodynamics. [...] Read more.

Background/Objectives: We reported previously that antagonists at chemokine receptors CCR2 and CCR3 have fluid-sparing effects during resuscitation from hemorrhagic shock. Because CCR1 shares several chemokine ligands with CCR2/3, we tested whether the CCR1 antagonist BX471 also reduces fluid requirements to maintain hemodynamics. Methods: Sprague Dawley rats were hemorrhaged for 30 min, followed by fluid resuscitation to maintain blood pressure for 60 min (series 1) and 180 min (series 2). Series 1: Animals received vehicle (n = 5), 0.05 μmol/kg (n = 5), or 0.5 μmol/kg (n = 4) BX471 at t = 30 min. Series 2: Animals received vehicle (n = 8) or 0.5 μmol/kg (n = 7) BX471 at t = 30 min. Hemodynamics, fluid requirements, blood gases, and lactate were monitored. Serum concentrations of CCR1 ligands (CCL3/4/5/7) were determined at baseline and at the conclusion of the experiments. Tissue (small/large intestine, lung) wet/dry (W/D) weight ratios, lung myeloperoxidase activity, and a panel of inflammation markers in tissue extracts were measured. Results: All animals could be resuscitated to target blood pressures. Series 1: A total of 0.5 μmol/kg BX471 reduced fluid requirements by more than 60% (p < 0.05 vs. vehicle and 0.05 μmol/kg BX471). Series 2: Systemic CCL3/5/7 levels increased during the experiment (p < 0.05). BX471-treatment reduced fluid requirements by more than 60% (p < 0.05) and prevented increases in CCL3/7. W/D ratios of large intestine and of the sum of all tissues were lower with BX471 treatment (p < 0.05). BX471-treatment reduced TNFα and IL6 concentrations in large intestine extracts (p < 0.05). Conclusions: Our findings suggest CCR1 as a new therapeutic target to reduce fluid requirements during resuscitation from hemorrhagic shock. Full article

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

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18 pages, 2924 KiB

Open AccessArticle

The Potential Role of SP-G and PLUNC in Tumor Pathogenesis and Wound Healing in the Human Larynx

by Aurelius Scheer, Lars Bräuer, Markus Eckstein, Heinrich Iro, Friedrich Paulsen, Fabian Garreis, Martin Schicht and Antoniu-Oreste Gostian

Biomedicines 2025, 13(5), 1240; https://doi.org/10.3390/biomedicines13051240 - 20 May 2025

Viewed by 422

Abstract

Background: Immunological and rheological properties are important factors of the surfactant protein (SP) family, whose impact on tumorigenesis is not yet known, although some SPs have been identified as tumor marker candidates for various malignancies. This study describes the detection of the two [...] Read more.

Background: Immunological and rheological properties are important factors of the surfactant protein (SP) family, whose impact on tumorigenesis is not yet known, although some SPs have been identified as tumor marker candidates for various malignancies. This study describes the detection of the two surfactant family proteins SP-G and PLUNC in healthy glottis, the presence of SP-G in glottic cancer, and the in vitro tissue regeneration potential of SP-G and PLUNC on epithelial cells. Methods: The expression and distribution of SP-G and PLUNC were investigated immunohistochemically in squamous cell carcinomas of the vocal folds. The expression of both proteins was analyzed by Western blot in micro-dissected healthy vocal fold mucosa from body donors. The hypopharyngeal squamous carcinoma cell line (FaDu) was used as an in vitro model for wound healing experiments with Electric cell–substrate impedance sensing (ECIS). Results: The results show the presence of SP-G and PLUNC in epithelial cells of the healthy vocal folds and the submucosal glands of the vestibular folds. SP-G was detected in squamous cell carcinomas of the vocal folds. SP-G and PLUNC show accelerated wound healing of FaDu cells in vitro. Conclusions: SP-G and PLUNC were first detected in the vocal fold of the human larynx. SP-G shows a distinct presence in glottic carcinoma, whose relevance needs to be determined in future studies. SP-G and PLUNC exhibit a positive influence on the repair mechanisms of epithelial lesions of the glottis. The data presented form the basis for follow-up studies focusing on the impact of SP-G in glottic cancer development and the potentially meaningful clinical effect of SP-G and PLUNC on tissue repair of the human vocal fold. Full article

(This article belongs to the Special Issue Head and Neck Tumors, 4th Edition)

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16 pages, 1321 KiB

Open AccessArticle

In Vitro Evaluation of the PMN Reaction on a Collagen-Based Purified Reconstituted Bilayer Matrix (PRBM) Using the Autologous Blood Concentrate PRF

by Eva Dohle, Hongyu Zuo, Büşra Bayrak, Anja Heselich, Birgit Schäfer, Robert Sader and Shahram Ghanaati

Biomedicines 2025, 13(5), 1239; https://doi.org/10.3390/biomedicines13051239 - 20 May 2025

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Abstract

Background/Objectives: The body’s reaction after the implantation of a biomaterial is a non-specific inflammatory response that is mainly initiated via the recruitment of polymorphonuclear cells (PMNs) to the implant site secreting cytokines and growth factors, followed by activation of monocytes/macrophages, finally leading [...] Read more.

Background/Objectives: The body’s reaction after the implantation of a biomaterial is a non-specific inflammatory response that is mainly initiated via the recruitment of polymorphonuclear cells (PMNs) to the implant site secreting cytokines and growth factors, followed by activation of monocytes/macrophages, finally leading to wound healing. The wound healing process is dependent on the priming of the PMNs that can be guided towards an inflammatory or a regenerative phenotype with the associated characteristic PMN cytokine profiles. Since the collagen-based Purified Reconstituted Bilayer Matrix (PRBM) triggers the wound healing process at the implant site in vivo, it is hypothesized that this positive effect might be due to a material-mediated priming of the PMNs towards the regenerative phenotype. With the use of the blood concentrate platelet-rich fibrin (PRF) containing high concentrations of leukocytes, including PMNs, the natural environment of the body after the implantation of a material can be mimicked in vitro. The aim of the present study was to characterize the phenotype of native blood-derived PMNs within PRF in response to the PRBM. Methods: PMNs within PRF gained from different relative centrifugal forces were characterized in a first step before PRF was combined with the PRBM for 4 h. Supernatants were harvested to analyze the phenotype of the PMNs via the evaluation of eight different cytokines using the ELISA. Results: Analysis of the PMN phenotype could assess cytokines commonly associated with neutrophils of the proinflammatory phenotype, such as TNFα, IL15, and IL1, as lower in supernatants when PRF was incubated in the presence of the PRBM and compared to the control PRF. On the other hand, cytokines related to the PMN regenerative phenotype, like TGFβ and IL10, could be detected as higher when PRF was incubated in the presence of the PRBM. Conclusions: This might suggest that PRBM significantly activates and primes neutrophils to the regenerative phenotype, leading to the resolution of inflammation. This might trigger the process of wound healing and tissue regeneration, making the PRBM a beneficial material for therapeutic applications. Full article

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

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1 pages, 142 KiB

Open AccessCorrection

Correction: Kim et al. Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study. Biomedicines 2023, 11, 2308

by Jung Sun Kim, Sak Lee, Jeong Yee, Kyemyung Park, Eun Jeong Jang, Byung Chul Chang and Hye Sun Gwak

Biomedicines 2025, 13(5), 1238; https://doi.org/10.3390/biomedicines13051238 - 20 May 2025

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Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

18 pages, 5017 KiB

Open AccessArticle

A CECT-Based Radiomics Nomogram Predicts the Overall Survival of Patients with Hepatocellular Carcinoma After Surgical Resection

by Peng Zhang, Yue Shi, Maoting Zhou, Qi Mao, Yunyun Tao, Lin Yang and Xiaoming Zhang

Biomedicines 2025, 13(5), 1237; https://doi.org/10.3390/biomedicines13051237 - 19 May 2025

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Abstract

Objective: The primary objective of this study was to develop and validate a predictive nomogram that integrates radiomic features derived from contrast-enhanced computed tomography (CECT) images with clinical variables to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC) after surgical [...] Read more.

Objective: The primary objective of this study was to develop and validate a predictive nomogram that integrates radiomic features derived from contrast-enhanced computed tomography (CECT) images with clinical variables to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC) after surgical resection. Methods: This retrospective study analyzed the preoperative enhanced CT images and clinical data of 202 patients with HCC who underwent surgical resection at the Affiliated Hospital of North Sichuan Medical College (Institution 1) from June 2017 to June 2021 and at Nanchong Central Hospital (Institution 2) from June 2020 to June 2022. Among these patients, 162 patients from Institution 1 were randomly divided into a training cohort (112 patients) and an internal validation cohort (50 patients) at a 7:3 ratio, whereas 40 patients from Institution 2 were assigned as an independent external validation cohort. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify clinical risk factors associated with OS after HCC resection. Using 3D-Slicer software, tumor lesions were manually delineated slice by slice on preoperative non-contrast-enhanced (NCE) CT, arterial phase (AP), and portal venous phase (PVP) images to generate volumetric regions of interest (VOIs). Radiomic features were subsequently extracted from these VOIs. LASSO Cox regression analysis was employed for dimensionality reduction and feature selection, culminating in the construction of a radiomic signature (Radscore). Cox proportional hazards regression models, including a clinical model, a radiomic model, and a radiomic–clinical model, were subsequently developed for OS prediction. The predictive performance of these models was assessed via the concordance index (C-index) and time–ROC curves. The optimal performance model was further visualized as a nomogram, and its predictive accuracy was evaluated via calibration curves and decision curve analysis (DCA). Finally, the risk factors in the optimal performance model were interpreted via Shapley additive explanations (SHAP). Results: Univariate and multivariate Cox regression analyses revealed that BCLC stage, the albumin–bilirubin index (ALBI), and the NLR–PLR score were independent predictors of OS after HCC resection. Among these three models, the radiomic–clinical model exhibited the highest predictive performance, with C-indices of 0.789, 0.726, and 0.764 in the training, internal and external validation cohorts, respectively. Furthermore, the time–ROC curves for the radiomic–clinical model showed 1-year and 3-year AUCs of 0.837 and 0.845 in the training cohort, 0.801 and 0.880 in the internal validation cohort, and 0.773 and 0.840 in the external validation cohort. Calibration curves and DCA demonstrated the model’s excellent calibration and clinical applicability. Conclusions: The nomogram combining CECT radiomic features and clinical variables provides an accurate prediction of OS after HCC resection. This model is beneficial for clinicians in developing individualized treatment strategies for patients with HCC. Full article

(This article belongs to the Special Issue New Insights into the Diagnosis and Treatment of Hepatocellular Carcinoma)

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Biomedicines, Volume 13, Issue 5 (May 2025) – 258 articles

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