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20 pages, 4980 KiB  
Article
Quinoa Protein/Sodium Alginate Complex-Stabilized Pickering Emulsion for Sustained Release of Curcumin and Enhanced Anticancer Activity Against HeLa Cells
by Yiqun Zhu, Jianan Li, Shuhong Liu, Hongli Yang, Fei Lu and Minpeng Zhu
Foods 2025, 14(15), 2705; https://doi.org/10.3390/foods14152705 - 1 Aug 2025
Viewed by 284
Abstract
Quinoa protein isolate (QPI) and sodium alginate (SA) have excellent biocompatibility and functional properties, making them promising candidates for food-grade delivery systems. In this study, we developed, for the first time, a QPI/SA complex-stabilized Pickering emulsion for curcumin encapsulation. The coacervation behavior of [...] Read more.
Quinoa protein isolate (QPI) and sodium alginate (SA) have excellent biocompatibility and functional properties, making them promising candidates for food-grade delivery systems. In this study, we developed, for the first time, a QPI/SA complex-stabilized Pickering emulsion for curcumin encapsulation. The coacervation behavior of QPI and SA was investigated from pH 1.6 to 7.5, and the structural and interfacial characteristics of the complexes were analyzed using zeta potential measurements, Fourier-transform infrared spectroscopy, scanning electron microscopy, and contact angle analysis. The results showed that the formation of QPI/SA complexes was primarily driven by electrostatic interactions, hydrogen bonding, and hydrophobic interactions, with enhanced amphiphilicity observed under optimal conditions (QPI/SA = 5:1, pH 5). The QPI/SA-stabilized Pickering emulsions demonstrated excellent emulsification performance and storage stability, maintaining an emulsification index above 90% after 7 d when prepared with 60% oil phase. In vitro digestion studies revealed stage-specific curcumin release, with sustained release in simulated gastric fluid (21.13%) and enhanced release in intestinal fluid (88.21%). Cytotoxicity assays using HeLa cells confirmed the biocompatibility of QPI/SA complexes (≤500 μg/mL), while curcumin-loaded emulsions exhibited dose-dependent anticancer activity. These findings suggest that QPI/SA holds significant potential for applications in functional foods and oral delivery systems. Full article
(This article belongs to the Section Grain)
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13 pages, 272 KiB  
Article
Pleiotropic Effects of Oral Anticoagulant Therapy: Is There a Difference Between VKAs and DOACs?
by Francesco Alfano, Anna Maria Gori, Martina Berteotti, Angela Rogolino, Francesca Cesari, Emilia Salvadori, Benedetta Formelli, Francesca Pescini, Carmen Barbato, Betti Giusti, Anna Poggesi and Rossella Marcucci
Biomedicines 2025, 13(8), 1850; https://doi.org/10.3390/biomedicines13081850 - 30 Jul 2025
Viewed by 192
Abstract
Background: Atrial fibrillation (AF) is one of the most common heart rhythm disorders encountered in clinical practice. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF, but certain questions still remain unanswered, in particular whether AF-related inflammation is [...] Read more.
Background: Atrial fibrillation (AF) is one of the most common heart rhythm disorders encountered in clinical practice. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF, but certain questions still remain unanswered, in particular whether AF-related inflammation is a cause or a consequence of the arrhythmia, and whether inflammation reflects underlying disease or AF itself. At the current state of the art, scientific evidence on the role of oral anticoagulants (OAC) in modulating pro-inflammatory cytokines implicated in the pathogenesis of AF remains scarce. The aim of our study was to evaluate, in a population of AF patients undergoing OAC, the different roles of anticoagulant therapy [Vitamin K antagonists (VKAs) and direct oral anti-coagulants (DOACs)] in modulating the levels of inflammatory biomarkers in AF. Methods: The Strat-AF study is an observational, prospective, single center, hospital-based study enrolling elderly patients with AF. Results refer to 170 subjects with complete clinical and biohumoral assessment. Results: At multivariate logistic regression analysis, adjusted for several covariates, VKA treatment was an independent protective predictor for having a high grade of inflammation not balanced by anti-inflammatory cytokine levels [OR = 0.26 (0.10–0.69), p = 0.007]. Conclusions: These results from the Strat-AF study are “generators of hypotheses” and provide preliminary evidence for the differential effects of VKAs and DOACs on inflammatory biomarkers (e.g., IL-6, TNF-α) in AF patients. These findings suggest that inflammatory biomarkers could enhance stroke risk prediction models, potentially improving a tailored AF management. Full article
(This article belongs to the Special Issue Advanced Research in Atrial Fibrillation)
22 pages, 2677 KiB  
Article
Prevalence of Temporomandibular Disorder Symptoms Among Dental Students at the Faculty of Dental Medicine in Iași: A Self-Reported Study Based on DC/TMD Criteria
by Eugenia Larisa Tarevici, Oana Tanculescu, Alina Mihaela Apostu, Sorina Mihaela Solomon, Alice-Teodora Rotaru-Costin, Adrian Doloca, Petronela Bodnar, Vlad Stefan Proca, Alice-Arina Ciocan-Pendefunda, Monica Tatarciuc, Valeriu Fala and Marina Cristina Iuliana Iordache
Diagnostics 2025, 15(15), 1908; https://doi.org/10.3390/diagnostics15151908 - 30 Jul 2025
Viewed by 258
Abstract
Temporomandibular disorders (TMDs) encompass a heterogeneous group of musculoskeletal and neuromuscular conditions affecting the temporomandibular joint (TMJ) and masticatory system. Due to academic stress and parafunctional habits, dental students may be particularly vulnerable to TMD. Objective: To determine the prevalence of TMD symptoms [...] Read more.
Temporomandibular disorders (TMDs) encompass a heterogeneous group of musculoskeletal and neuromuscular conditions affecting the temporomandibular joint (TMJ) and masticatory system. Due to academic stress and parafunctional habits, dental students may be particularly vulnerable to TMD. Objective: To determine the prevalence of TMD symptoms and their psychosocial and functional correlates among students at the Faculty of Dental Medicine, UMPh Iasi, Romania, using the diagnostic criteria for TMD (DC/TMD) self-report axis and axis II instruments. Methods: In this cross-sectional survey, 356 volunteer students (66.0% female; mean age, 22.9 ± 3.6 years) out of a total population of 1874 completed an online DC/TMD–based questionnaire. Axis I assessed orofacial pain, joint noises, and mandibular locking. Axis II instruments included the Graded Chronic Pain Scale (GCPS), Jaw Functional Limitation Scale (JFLS-20), Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Oral Behaviors Checklist (OBC). Descriptive statistics summarized frequencies, means, and standard deviations; χ2 tests and t-tests compared subgroups by sex; Pearson correlations explored relationships among continuous measures (α = 0.05). Results: A total of 5% of respondents reported orofacial pain in the past 30 days; 41.6% observed TMJ noises; 19.7% experienced locking episodes. Mean JFLS score was 28.3 ± 30.5, with 4.8% scoring > 80 (severe limitation). Mean PHQ-9 was 5.96 ± 5.37 (mild depression); 15.5% scored ≥ 10. Mean GAD-7 was 5.20 ± 4.95 (mild anxiety); 16.0% scored ≥ 10. Mean OBC score was 12.3 ± 8.5; 30.1% scored ≥ 16, indicating frequent parafunctional habits. Symptom prevalence was similar by sex, except temporal headache (43.4% females vs. 24.3% males; p = 0.0008). Females reported higher mean scores for pain intensity (2.09 vs. 1.55; p = 0.0013), JFLS (32.5 vs. 18.0; p < 0.001), PHQ-9 (6.43 vs. 5.16; p = 0.048), and OBC (13.9 vs. 9.7; p = 0.0014). Strong correlation was observed between PHQ-9 and GAD-7 (r = 0.74; p < 0.001); moderate correlations were observed between pain intensity and PHQ-9 (r = 0.31) or GAD-7 (r = 0.30), between JFLS and pain intensity (r = 0.33), and between OBC and PHQ-9 (r = 0.39) (all p < 0.001). Conclusions: Nearly half of dental students reported TMD symptoms, with appreciable functional limitation and psychosocial impact. Parafunctional behaviors and psychological distress were significantly associated with pain and dysfunction. These findings underscore the need for early screening, stress-management interventions, and interdisciplinary care strategies in the dental student population. Full article
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17 pages, 4789 KiB  
Systematic Review
Efficacy of Combined Oral Isotretinoin and Desloratadine or Levocetirizine vs. Isotretinoin Monotherapy in Treating Acne Vulgaris: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
by Julia Woźna, Andrzej Bałoniak, Jan Stępka, Adriana Polańska, Ewa Mojs and Ryszard Żaba
Biomedicines 2025, 13(8), 1847; https://doi.org/10.3390/biomedicines13081847 - 30 Jul 2025
Viewed by 409
Abstract
Background/Objectives: Acne vulgaris is a widespread, chronic inflammatory skin condition that significantly impacts patients’ quality of life. Although oral isotretinoin remains the most effective treatment, recent evidence suggests that H1-antihistamines such as desloratadine and levocetirizine may enhance acne therapy. This study [...] Read more.
Background/Objectives: Acne vulgaris is a widespread, chronic inflammatory skin condition that significantly impacts patients’ quality of life. Although oral isotretinoin remains the most effective treatment, recent evidence suggests that H1-antihistamines such as desloratadine and levocetirizine may enhance acne therapy. This study assesses whether combining H1-antihistamines to isotretinoin enhances treatment efficacy in acne vulgaris compared to isotretinoin alone. Methods: Our analysis included 10 randomized controlled trials involving 675 patients collectively, predominantly from Asia and the Middle East. Data were extracted by two independent reviewers, with discrepancies resolved by a third. Risk of bias was assessed using the Cochrane RoB 2 tool. Analyses were performed using RevMan 5.4 with random-effects models, and heterogeneity was evaluated via I2 and Q tests. Sensitivity analyses were conducted to assess result robustness. Results: Combination therapy with isotretinoin and desloratadine showed a significantly greater reduction in GAGS (Global Acne Grading Scale) score by week 12 (p < 0.00001; MD 2.68, 95% CI 1.60 to 3.75; I2 = 0%) while earlier timepoints showed non-significant or borderline results. For inflammatory lesions, significant improvements with desloratadine emerged at weeks 4, 8, and 12 after excluding an influential outlier, with low heterogeneity and consistent direction of effect. Non-inflammatory lesions did not differ significantly at weeks 4 or 8. At week 12, a significant reduction was seen in the desloratadine subgroup (OR 2.61, p = 0.003, I2 = 11%) and in overall pooled analysis (OR 2.77, p < 0.0001, I2 = 2%). Among side effects, acne flare-ups, pruritus, and cheilitis were significantly reduced in the desloratadine group, as well as in pooled analysis. Xerosis did not consistently differ between groups. Overall, desloratadine improved tolerability and reduced mucocutaneous adverse events more than levocetirizine. Conclusions: Current evidence suggests that combining oral antihistamines with isotretinoin may offer therapeutic benefits in acne management, particularly in enhancing tolerability and potentially improving clinical outcomes, as reflected by significant reductions in GAGS scores and mucocutaneous adverse effects such as cheilitis, pruritus, and acne flare-ups. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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17 pages, 1908 KiB  
Article
BDE-47 Disrupts Gut Microbiota and Exacerbates Prediabetic Conditions in Mice: Therapeutic Potential of Grape Exosomes and Antioxidants
by Zaoling Liu, Fang Cao, Aerna Qiayimaerdan, Nilupaer Aisikaer, Zulipiya Zunong, Xiaodie Ma and Yale Yu
Toxics 2025, 13(8), 640; https://doi.org/10.3390/toxics13080640 - 29 Jul 2025
Viewed by 222
Abstract
Background: BDE-47, a pervasive environmental pollutant detected in >90% of human serum samples, is increasingly linked to metabolic disorders. This study investigates the specific impact of BDE-47 exposure on the gut microbiota in prediabetic mice and evaluates the efficacy of therapeutic interventions [...] Read more.
Background: BDE-47, a pervasive environmental pollutant detected in >90% of human serum samples, is increasingly linked to metabolic disorders. This study investigates the specific impact of BDE-47 exposure on the gut microbiota in prediabetic mice and evaluates the efficacy of therapeutic interventions in mitigating these effects. Objectives: To determine whether BDE-47 exposure induces diabetogenic dysbiosis in prediabetic mice and to assess whether dietary interventions, such as grape exosomes and an antioxidant cocktail, can restore a healthy microbiota composition and mitigate diabetes risk. Methods: In this study, a prediabetic mouse model was established in 54 male SPF-grade C57BL/6J mice through a combination of high-sugar and high-fat diet feeding with streptozotocin injection. Oral glucose tolerance tests (OGTT) were conducted on day 7 and day 21 post-modeling to assess the establishment of the model. The criteria for successful model induction were defined as fasting blood glucose levels below 7.8 mmol/L and 2 h postprandial glucose levels between 7.8 and 11.1 mmol/L. Following confirmation of model success, a 3 × 3 factorial design was applied to allocate the experimental animals into groups based on two independent factors: BDE-47 exposure and exosome intervention. The BDE-47 exposure factor consisted of three dose levels—none, high-dose, and medium-dose—while the exosome intervention factor included three modalities—none, Antioxidant Nutrients Intervention, and Grape Exosomes Intervention. Fresh fecal samples were collected from mice two days prior to sacrifice. Cecal contents and segments of the small intestine were collected and transferred into 1.5 mL cryotubes. All sequences were clustered into operational taxonomic units (OTUs) based on defined similarity thresholds. To compare means across multiple groups, a two-way analysis of variance (ANOVA) was employed. The significance level was predefined at α = 0.05, and p-values < 0.05 were considered statistically significant. Bar charts and line graphs were generated using GraphPad Prism version 9.0 software, while statistical analyses were performed using SPSS version 20.0 software. Results: The results of 16S rDNA sequencing analysis of the microbiome showed that there was no difference in the α diversity of the intestinal microbiota in each group of mice (p > 0.05), but there was a difference in the Beta diversity (p < 0.05). At the gate level, the abundances of Proteobacteria, Campylobacterota, Desulfobacterota, and Fusobacteriota in the medium-dose BDE-7 group were higher than those in the model control group (p < 0.05). The abundance of Patellar bacteria was lower than that of the model control group (p < 0.05). The abundances of Proteobacteria and Campylobacterota in the high-dose BDE-7 group were higher than those in the model control group (p < 0.05). The abundance of Planctomycetota and Patescibacteria was lower than that of the model control group (p < 0.05), while the abundance of Campylobacterota in the grape exosome group was higher than that of the model control group (p < 0.05). The abundance of Patescibacteria was lower than that of the model control group (p < 0.05), while the abundance of Firmicutes and Fusobacteriota in the antioxidant nutrient group was higher than that of the model control group (p < 0.05). However, the abundance of Verrucomicrobiota and Patescibacteria was lower than that of the model control group (p < 0.05). At the genus level, the abundances of Bacteroides and unclassified Lachnospiraceae in the high-dose BDE-7 group were higher than those in the model control group (p < 0.05). The abundance of Lachnospiraceae NK4A136_group and Lactobacillus was lower than that of the model control group (p < 0.05). The abundance of Veillonella and Helicobacter in the medium-dose BDE-7 group was higher than that in the model control group (p < 0.05), while the abundance of Lactobacillus was lower (p < 0.05). The abundance of genera such as Lentilactobacillus and Faecalibacterium in the grape exosome group was higher than that in the model control group (p < 0.05). The abundance of Alloprevotella and Bacteroides was lower than that of the model control group (p < 0.05). In the antioxidant nutrient group, the abundance of Lachnospiraceae and Hydrogenophaga was higher than that in the model control group (p < 0.05). However, the abundance of Akkermansia and Coriobacteriaceae UCG-002 was significantly lower than that of the model control group (p < 0.05). Conclusions: BDE-47 induces diabetogenic dysbiosis in prediabetic mice, which is reversible by dietary interventions. These findings suggest that microbiota-targeted strategies may effectively mitigate the diabetes risk associated with environmental pollutant exposure. Future studies should further explore the mechanisms underlying these microbiota changes and the long-term health benefits of such interventions. Full article
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24 pages, 4347 KiB  
Article
Diatomaceous Earth Supplementation as a Bioavailable Silicon Source Modulates Postprandial Lipid Metabolism in Healthy Female Rats
by Rocío Redondo-Castillejo, Marina Hernández-Martín, Jousef Ángel Issa-García, Aránzazu Bocanegra, Alba Garcimartín, Adrián Macho-González, Sara Bastida, Francisco J. Sánchez-Muniz, Juana Benedí and M. Elvira López-Oliva
Nutrients 2025, 17(15), 2452; https://doi.org/10.3390/nu17152452 - 28 Jul 2025
Viewed by 347
Abstract
Background/Objectives: Diatomaceous earth (DE), a natural substance rich in amorphous silica and recognized as a food additive, is gaining attention as a dietary silicon supplement. However, its bioavailability and impact on lipid digestion and absorption remain poorly characterized. This study aimed to investigate [...] Read more.
Background/Objectives: Diatomaceous earth (DE), a natural substance rich in amorphous silica and recognized as a food additive, is gaining attention as a dietary silicon supplement. However, its bioavailability and impact on lipid digestion and absorption remain poorly characterized. This study aimed to investigate silicon bioavailability after short-term DE supplementation and its effects on postprandial glycemia and triglyceridemia, the expression of lipid metabolism-related proteins, and the modulation of the intestinal mucosal barrier. Methods: Female Wistar rats received daily oral supplementation of DE (equivalent to 2 or 4 mg silicon/kg body weight) for one week. Silicon digestibility, excretion, and hepatic accumulation were quantified. Postprandial glycemia and triglyceridemia were monitored. Lipid profile was analyzed by HPSEC in gastric and intestinal contents. Jejunal morphology and mucin-secreting cells were assessed histologically. Lipid metabolism markers were evaluated by immunohistochemistry and Western blot in both intestinal and hepatic tissues. Results: DE supplementation enhanced silicon absorption and increased hepatic levels. Fecal output and moisture content were also elevated, especially at the higher dose. DE significantly reduced postprandial triglyceridemia and consequently increased luminal triglyceride retention. These changes were associated with decreased jejunal levels of IFABP, ACAT2, and MTP, as well as reduced hepatic levels of MTP and LDLr, alongside increased levels of ABCG5/G8 and LXRα/β, indicating a partial blockage of lipid absorption and enhanced cholesterol efflux. The effects on the intestinal barrier were evidenced by villi shortening and an increase in mucin-producing cells. Conclusion: Food-grade DE is a bioavailable source of silicon with hypolipidemic potential, mainly by reducing intestinal lipid absorption. This is supported by lower postprandial triglycerides, increased luminal lipid retention, and decreased expression of lipid transport proteins. The study in healthy female rats underscores the importance of sex-specific responses and supports DE as a dietary strategy to improve lipid metabolism. Full article
(This article belongs to the Section Lipids)
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29 pages, 1209 KiB  
Review
The Oral–Gut Microbiota Axis as a Mediator of Frailty and Sarcopenia
by Domenico Azzolino, Margherita Carnevale-Schianca, Lucrezia Bottalico, Marica Colella, Alessia Felicetti, Simone Perna, Leonardo Terranova, Franklin Garcia-Godoy, Mariangela Rondanelli, Pier Carmine Passarelli and Tiziano Lucchi
Nutrients 2025, 17(15), 2408; https://doi.org/10.3390/nu17152408 - 23 Jul 2025
Viewed by 622
Abstract
Traditionally studied in isolation, the oral and gut microbiota are now being recognized as interconnected through anatomical and physiological pathways forming a dynamic “oral–gut microbiota axis”. Both oral and gut microbiota undergo changes with aging, characterized by a decline in microbial diversity and [...] Read more.
Traditionally studied in isolation, the oral and gut microbiota are now being recognized as interconnected through anatomical and physiological pathways forming a dynamic “oral–gut microbiota axis”. Both oral and gut microbiota undergo changes with aging, characterized by a decline in microbial diversity and a shift toward potentially harmful species. The aim of this review is, therefore, to provide an overview of oral–gut communications in mediating frailty and sarcopenia. PubMed, EMBASE and Scopus databases were searched for relevant articles. We limited our search to manuscripts published in the English language. Interactions between oral and gut microbiota occur mainly through three pathways namely the enteral, the bloodstream and the fecal-oral routes. Alterations in the oral–gut microbiota axis contribute to chronic low-grade inflammation (i.e., “inflamm-ageing”) and mitochondrial dysfunction, key mechanisms underlying frailty and sarcopenia. Microbial metabolites, such as short-chain fatty acids and modified bile acids, appear to play an emerging role in influencing microbial homeostasis and muscle metabolism. Furthermore, poor oral health associated with microbial dysbiosis may contribute to altered eating patterns that negatively impact gut microbiota eubiosis, further exacerbating muscle decline and the degree of frailty. Strategies aimed at modulating the microbiota, such as healthy dietary patterns with reduced consumption of ultra-processed foods, refined carbohydrates and alcohol, ensuring an adequate protein intake combined with physical exercise, as well as supplementation with prebiotics, probiotics, and omega-3 polyunsaturated fatty acids, are increasingly recognized as promising interventions to improve both oral and gut microbiota health, with beneficial effects on frailty and sarcopenia. A better understanding of the oral–gut microbiota axis offers promising insights into nutritional interventions and therapeutic strategies for the age-related muscle decline, frailty and systemic health maintenance. Full article
(This article belongs to the Special Issue Addressing Malnutrition in the Aging Population)
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14 pages, 690 KiB  
Article
Ibrutinib in Combination with Lenalidomide Revlimid/Dexamethasone in Relapsed/Refractory Multiple Myeloma (AFT-15)
by Yvonne Efebera, Vera Suman, Shira Dinner, Taylor O’Donnell, Ashley Rosko, John Mckay, Peter Barth, Patrick Hagen, Saad Usmani, Paul Richardson and Jacob Laubach
Cancers 2025, 17(15), 2433; https://doi.org/10.3390/cancers17152433 - 23 Jul 2025
Viewed by 282
Abstract
Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the [...] Read more.
Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least one prior line of therapy. Three dose levels (DLs) were planned. The cycle length was 28 days. IBR was administered orally daily in doses of 560 mg on DL1-2 and 840 mg on DL3, LEN was administered orally on days 1–21 in doses of 15 mg on DL1 and 25 mg on DL2-3, and DEX was administered orally on days 1, 8, 15, and 22 in a dose of 40 mg if age < 75 years or in a dose of 20 mg if it was ≥75 years for DL1-3. Patients with a glomerular filtration rate (GFR) <60 but ≥30 mL/min were treated in accordance with the manufacturer’s instructions with LEN 10 mg. Dose-limiting toxicities (DLTs) included the following: grade 4 neutropenia lasting more than 5 days, thrombocytopenia, febrile neutropenia, nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; and grade 3–4 hyperglycemia or a thrombotic/embolic event, and other nonhematologic toxicities. The overall response rate (ORR) was defined as the percentage of patients with a partial response (PR), very good partial response (VGPR), or complete response (CR) according to IMWG criteria on two consecutive evaluations at least 4 weeks apart. The clinical benefit rate (CBR) was defined as the percentage of patients with stable disease (SD) or a better outcome on two consecutive evaluations at weeks apart. Results: Fourteen patients (DL1: six patients; DL2: three patients; DL3: five patients) were registered for the study from March 2019 to May 2023, prior to its closure due to limited accrual. Thirteen patients are included in the summary of toxicities and response as one patient on DL3 halted participation prior to the start of the treatment. Two patients on DL3 were excluded from the determination of MTD: one having discontinued cycle 1 treatment due to COVID-19 infection and the another having mistakenly taken 280 mg/day of IBR instead of the assigned 840 mg/day dose during cycle 1. Only one patient developed a DLT, on DL1 with grade 3 non-viral hepatitis. The median number of cycles administered was 4 (range: 1–56). Severe toxicities reported included grade 4 lymphocytopenia (1), grade 4 thrombocytopenia (1), and grade 5 sepsis in the setting of PD (1). Disease responses included a VGPR on DL1 and CR on DL3. Thus, the ORR was 15.4% (90% CI: 2.8–41.0%). One patient on DL1 maintained SD for 4.6 years before discontinuing the treatment to undergo an alternative therapy. Another five patients maintained SD for ≥ 2 consecutive cycles. Thus, the CBR was 61.5% (90% CI: 35.5–83.4%). Conclusions: The combination of LEN with IBR in RR MM proved feasible, with manageable toxicities and the majority of discontinuations being due to disease progression. Full article
(This article belongs to the Special Issue Multiple Myeloma: Diagnosis and Therapy)
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14 pages, 9728 KiB  
Article
Combined Model of Tumor–Stroma Ratio and Tumor Budding Are Not Associated with Tumor Recurrence or Metastasis in Oral Squamous Cell Carcinoma Patients
by Drago Boščić, Emili Dragaš, Andro Košec, Goran Geber, Čedna Tomasović-Lončarić and Davor Vagić
Diagnostics 2025, 15(15), 1844; https://doi.org/10.3390/diagnostics15151844 - 22 Jul 2025
Viewed by 285
Abstract
Histopathological grading of oral squamous cell carcinoma is currently based on differentiation of cells, while additional histological parameters, such as the tumor–stroma ratio (TSR), tumor budding (TB), or the combined TSR/tumor budding model could better assess tumor biological behavior and monitoring of patients. [...] Read more.
Histopathological grading of oral squamous cell carcinoma is currently based on differentiation of cells, while additional histological parameters, such as the tumor–stroma ratio (TSR), tumor budding (TB), or the combined TSR/tumor budding model could better assess tumor biological behavior and monitoring of patients. Background/Objectives: To integrate risk factors associated with tumor progression: the TSR, TB and TSR/tumor budding model, whose prognostic significance in oral cancer has not yet been evaluated. Methods: An observational cohort retrospective study assembled according to STROBE guidelines on histological materials from 196 patients with invasive squamous cell carcinoma of the oral cavity. The goal of the analysis was to evaluate the association between the tumor stroma ratio, tumor budding, and the combined model of TSR/TB with the clinical and pathologic features of patients with squamous cell carcinoma of the oral cavity and to determine the prognostic value of this model in relation to disease-free survival (DFS) Results: The analysis did not show that the tumor stroma ratio (TSR), tumor budding, and the combined model of TSR/tumor budding were statistically significantly associated with the occurrence of metastatic disease at the start of treatment or during postoperative follow-up, but confirmed the value of depth-of-invasion (DOI) as a negative prognostic factor (HR 15.3, p < 0.001). Conclusions: The TSR, TB, and the combined TSR/TB model were not found to be statistically significant predictors for the disease progression in the Cox regression survival analysis but were found to have a significant correlation with known negative prognostic factors: DOI, neural invasion, and T category. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Management of Oral Disorders)
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16 pages, 2557 KiB  
Article
Explainable AI for Oral Cancer Diagnosis: Multiclass Classification of Histopathology Images and Grad-CAM Visualization
by Jelena Štifanić, Daniel Štifanić, Nikola Anđelić and Zlatan Car
Biology 2025, 14(8), 909; https://doi.org/10.3390/biology14080909 - 22 Jul 2025
Viewed by 362
Abstract
Oral cancer is typically diagnosed through histological examination; however, the primary issue with this type of procedure is tumor heterogeneity, where a subjective aspect of the examination may have a direct effect on the treatment plan for a patient. To reduce inter- and [...] Read more.
Oral cancer is typically diagnosed through histological examination; however, the primary issue with this type of procedure is tumor heterogeneity, where a subjective aspect of the examination may have a direct effect on the treatment plan for a patient. To reduce inter- and intra-observer variability, artificial intelligence algorithms are often used as computational aids in tumor classification and diagnosis. This research proposes a two-step approach for automatic multiclass grading using oral histopathology images (the first step) and Grad-CAM visualization (the second step) to assist clinicians in diagnosing oral squamous cell carcinoma. The Xception architecture achieved the highest classification values of 0.929 (±σ = 0.087) AUCmacro and 0.942 (±σ = 0.074) AUCmicro. Additionally, Grad-CAM provided visual explanations of the model’s predictions by highlighting the precise areas of histopathology images that influenced the model’s decision. These results emphasize the potential of integrated AI algorithms in medical diagnostics, offering a more precise, dependable, and effective method for disease analysis. Full article
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12 pages, 3331 KiB  
Article
Oral Undifferentiated Pleomorphic Sarcoma: A Novel SPECC1L::TERT Gene Fusion and a Comprehensive Literature Review
by Mario Della Mura, Joana Sorino, Eugenio Maiorano, Gerardo Cazzato, Anna Colagrande, Alfonso Manfuso, Concetta Caporusso, Chiara Copelli and Eliano Cascardi
Genes 2025, 16(7), 830; https://doi.org/10.3390/genes16070830 - 17 Jul 2025
Viewed by 340
Abstract
Background: Undifferentiated pleomorphic sarcoma (UPS) is a rare, high-grade soft-tissue sarcoma characterized by a patternless proliferation of bizarre pleomorphic tumor cells lacking identifiable lineage differentiation. Its occurrence in the oral cavity is exceptionally uncommon and poses significant diagnostic challenges due to its morphological [...] Read more.
Background: Undifferentiated pleomorphic sarcoma (UPS) is a rare, high-grade soft-tissue sarcoma characterized by a patternless proliferation of bizarre pleomorphic tumor cells lacking identifiable lineage differentiation. Its occurrence in the oral cavity is exceptionally uncommon and poses significant diagnostic challenges due to its morphological overlap with a wide spectrum of other malignancies. Material and Methods: We report a novel case of oral UPS in a 54-year-old woman, characterized by an exceptionally large size and a rapidly progressive clinical course. The diagnostic evaluation included clinical, radiological, histopathological, immunohistochemical, and molecular analyses conducted within a multidisciplinary framework. A comprehensive review of the literature on oral UPS was also performed. Results: The patient underwent an aggressive demolitive surgical approach due to the extent of the lesion. Molecular analysis revealed a previously unreported SPECC1L::TERT gene fusion. The literature review highlighted the rarity of oral UPS, its geographic predilection for Central and East Asia, possible associations with traumatic events, and its heterogeneous clinical and histopathological presentations. Conclusions: This case underscores the critical importance of a thorough diagnostic workup to ensure the accurate diagnosis and appropriate management of this rare and aggressive tumor. Multidisciplinary evaluation is essential, especially in anatomically complex and diagnostically challenging presentations such as oral UPS. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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13 pages, 6081 KiB  
Article
TrkA Expression as a Novel Prognostic Biomarker in Oral Squamous Cell Carcinoma
by Aleksandra Ciarka, Filip Skowronek, Przemysław Miłosz, Michał Kunc, Robert Burdach, Monika Sakowicz-Burkiewicz, Barbara Jereczek-Fossa, Anna Starzyńska and Rafał Pęksa
Int. J. Mol. Sci. 2025, 26(14), 6847; https://doi.org/10.3390/ijms26146847 - 16 Jul 2025
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Abstract
Oral squamous cell carcinoma (OSCC) remains a significant global health challenge, representing 90% of oral malignancies. Despite therapeutic advances, patient outcomes remain poor, highlighting the need for novel prognostic biomarkers and treatment targets. We investigated the expression patterns of NTRK genes and their [...] Read more.
Oral squamous cell carcinoma (OSCC) remains a significant global health challenge, representing 90% of oral malignancies. Despite therapeutic advances, patient outcomes remain poor, highlighting the need for novel prognostic biomarkers and treatment targets. We investigated the expression patterns of NTRK genes and their corresponding proteins (TrkA, TrkB, and TrkC) in OSCC, analyzing their relationships with clinical outcomes and potential as therapeutic targets. We examined 93 OSCC tissue samples using immunohistochemistry and quantitative real-time PCR. Protein expression was quantified using the H-score method. We analyzed correlations between Trk expression, clinicopathological parameters, and 2-year survival rates using chi-square tests, Mann–Whitney U tests, and Kaplan–Meier survival analysis. TrkA showed near-universal expression (97.8%—91 patients) in OSCC samples, with high expression levels significantly correlating with lower tumor grade (p = 0.014) and improved 2-year survival (p = 0.011). While TrkB and TrkC were expressed in 65.5% and 84.9% of cases, respectively, neither showed significant associations with clinical parameters. NTRK2 and NTRK3 mRNA levels demonstrated a strong positive correlation (R = 0.64, p = 0.002), suggesting coordinated regulation. Our findings establish TrkA as a promising positive prognostic marker in OSCC, warranting investigation as a therapeutic target. The strong correlation between NTRK2 and NTRK3 expression suggests shared regulatory mechanisms in OSCC pathogenesis. Further studies with larger cohorts and longer follow-up periods are needed to validate these findings and explore their therapeutic implications. Full article
(This article belongs to the Special Issue Biology of Oral Cancer)
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15 pages, 745 KiB  
Systematic Review
Relationship Between Bruxism and Obstructive Sleep Apnea: A Systematic Review of the Literature
by Natalia García Doblado, José María Barrera Mora, Francisco Pastor Dorado, Juan C. Rodríguez Fernández, Guillem Ballestero Ordeix and Eduardo Espinar Escalona
J. Clin. Med. 2025, 14(14), 5013; https://doi.org/10.3390/jcm14145013 - 15 Jul 2025
Viewed by 602
Abstract
Background and objectives: The interest in studying the relationship between bruxism and sleep apnea has increased over the past decade, given its prevalence and its implications for both oral and overall health. Bruxism occurs in a significant portion of the population, with [...] Read more.
Background and objectives: The interest in studying the relationship between bruxism and sleep apnea has increased over the past decade, given its prevalence and its implications for both oral and overall health. Bruxism occurs in a significant portion of the population, with an overall incidence ranging between 8 and 31%. Obstructive sleep apnea affects 4–6% of middle-aged men and 2–4% of middle-aged women, and it is associated with diminished quality of life, hypertension, increased cardiovascular risks, traffic accidents, and a higher mortality rate. Although a possible association has been suggested, the causal relationship remains unclear. This review aimed to systematically evaluate the available evidence on the association between SB and OSA, focusing on potential shared risk factors and underlying mechanisms. Methods: An electronic literature search was conducted in PubMed, Scopus, Web of Science, and the Cochrane Library for studies published between 2020 and 2025. Inclusion criteria encompassed observational studies and clinical trials involving adults with SB and/or OSA. Risk of bias was assessed using ROBINS-I, and the certainty of evidence was evaluated using GRADE. The review protocol was not registered. Results: A total of 11 studies met the inclusion criteria. The prevalence of SB was consistently higher in individuals with OSA compared to the general population. Several studies suggest a potential link through autonomic arousals and neurotransmitter dysregulation. However, inconsistencies in diagnostic criteria and moderate methodological quality limited the strength of the findings. Conclusions: There is a notable prevalence of bruxism in patients with OSA, suggesting possible shared pathophysiological mechanisms; however, it is necessary to standardize diagnostic criteria and conduct larger, more standardized studies to clarify the relationship. No funding was received, and the authors declare no conflicts of interest. Full article
(This article belongs to the Section Respiratory Medicine)
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16 pages, 3666 KiB  
Article
Horse Meat Hydrolysate Ameliorates Dexamethasone-Induced Muscle Atrophy in C57BL/6 Mice via the AKT/FoxO3a/mTOR Pathway
by Hee-Jeong Lee, Dongwook Kim, Yousung Jung, Soomin Oh, Cho Hee Kim and Aera Jang
Cells 2025, 14(14), 1050; https://doi.org/10.3390/cells14141050 - 9 Jul 2025
Viewed by 501
Abstract
As life expectancy increases, muscle atrophy, characterized by a decline in muscle mass and strength that can impair mobility, has become a growing concern, highlighting the potential of protein supplementation as a promising intervention strategy. A horse meat hydrolysate, with a molecular weight [...] Read more.
As life expectancy increases, muscle atrophy, characterized by a decline in muscle mass and strength that can impair mobility, has become a growing concern, highlighting the potential of protein supplementation as a promising intervention strategy. A horse meat hydrolysate, with a molecular weight of less than 3 kDa, derived from m. biceps femoris and produced using the food-grade enzyme Alcalase® (A4 < 3kDa) was evaluated for its efficacy in mitigating dexamethasone-induced muscle atrophy, a widely accepted model for studying catabolic muscle loss. Administered orally to C57BL/6 mice at dosages of 200 mg/kg or 500 mg/kg body weight for 35 days, A4 < 3kDa effectively countered the weight loss induced by dexamethasone in the whole body, quadriceps, tibialis anterior, and gastrocnemius muscles. Moreover, it increased muscle fiber cross-sectional area and grip strength. These effects were attributed to increased protein synthesis via the protein kinase B (AKT)/forkhead box O3 (FoxO3a)/mammalian target of rapamycin (mTOR) signaling pathway. A4 < 3kDa augmented the phosphorylation of key components of the signaling pathways associated with muscle atrophy, resulting in reduced mRNA expression of Atrogin-1 and MuRF-1. These findings demonstrate the potential of A4 < 3kDa as a functional food ingredient for preventing muscle atrophy. Full article
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11 pages, 566 KiB  
Article
Reliability and Sources of Variation of Preclinical OSCEs at a Large US Osteopathic Medical School
by Martin Schmidt, Sarah Parrott and Maurice Blodgett
Int. Med. Educ. 2025, 4(3), 25; https://doi.org/10.3390/ime4030025 - 5 Jul 2025
Viewed by 256
Abstract
The objective structured clinical examination (OSCE) is a well-established tool for assessing clinical skills, providing reliability, validity, and generalizability for high-stakes examinations. Des Moines University College of Osteopathic Medicine (DMU-COM) adapted the OSCE for formative assessments in undergraduate medical education, focusing on interpersonal [...] Read more.
The objective structured clinical examination (OSCE) is a well-established tool for assessing clinical skills, providing reliability, validity, and generalizability for high-stakes examinations. Des Moines University College of Osteopathic Medicine (DMU-COM) adapted the OSCE for formative assessments in undergraduate medical education, focusing on interpersonal aspects in the primary care setting. Students are graded by standardized patients and faculty observers on interpersonal skills, history/physical examination, oral case presentation, and documentation. The purpose of the study is to establish the reliability and to identify sources of variation in the DMU-COM OSCE to aid medical educators in their understanding of the accuracy of clinical skills. We examined student performance data across five OSCE domains. We assessed intra- and inter-OSCE reliability by calculating KR20 values, determined sources of variation by multivariate regression analysis, and described relationships among observed variables through factor analysis. The results indicate that the OSCE captures student performance in three dimensions with low intra-OSCE reliability but acceptable longitudinal inter-OSCE reliability. Variance analysis shows significant measurement error in rubric-graded scores but negligible error in checklist-graded portions. Physical exam scores from patients and faculty showed no correlation, indicating value in having two different observers. We conclude that a series of formative OSCEs is a valid tool for assessing clinical skills in preclinical medical students. However, the low intra-assessment reliability cautions against using a single OSCE for summative clinical skills competency assessments. Full article
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