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32 pages, 20359 KB  
Article
Construction of EGFR-Targeted Triptolide Liposomes Using Uniform Design Optimization and Therapeutic Evaluation in Gliomas
by Huiqing Que, Wei Li, Ziting Li, Lihong Ma, Junyong Han, Shenmin Liu, Xiaomei Xu, Liping Qian, Wenjin Lin and Hongxu Liu
Pharmaceuticals 2026, 19(5), 731; https://doi.org/10.3390/ph19050731 - 6 May 2026
Viewed by 478
Abstract
Background/Objectives: Triptolide (TP), a potent natural diterpenoid, exhibits anti-glioma activity, but faces significant clinical translation challenges, including poor water solubility, systemic toxicity such as hepatotoxicity, and inadequate tumor targeting. This study aimed to develop a novel epidermal growth factor receptor (EGFR)-targeted liposomal formula-tion, [...] Read more.
Background/Objectives: Triptolide (TP), a potent natural diterpenoid, exhibits anti-glioma activity, but faces significant clinical translation challenges, including poor water solubility, systemic toxicity such as hepatotoxicity, and inadequate tumor targeting. This study aimed to develop a novel epidermal growth factor receptor (EGFR)-targeted liposomal formula-tion, designated as TP-CTX-Lip (where CTX denotes cetuximab), to enhance the deliv-ery efficiency and therapeutic window of TP. Methods: The formulation was optimized using a uniform design approach (four factors, six levels) and prepared via thin-film hydra-tion–ultrasonication. The encapsulation of TP was supported by Fourier transform in-frared spectroscopy (FTIR) and thermal analysis (DSC/TGA), which revealed molecu-lar interactions (e.g., hydrogen bonding) with lipid components and a marked en-hancement in thermal stability, consistent with successful incorporation into the lipo-somal bilayer. The physicochemical properties, including the size, polydispersity index (PDI), zeta potential, encapsulation efficiency, and drug loading, were characterized. In vitro release kinetics were evaluated in phosphate buffer (pH 7.4), and cytotoxicity was assessed in high-EGFR (U87-MG) and low-EGFR (SW1088) glioma cells. In vivo efficacy and developmental toxicity were investigated using zebrafish models. The op-timized TP-CTX-Lip demonstrated favorable characteristics: size = 131.3 ± 4.5 nm, PDI = 0.24 ± 0.006, zeta potential = −23.37 ± 0.27 mV, encapsulation efficiency = 85.83% ± 1.81%, and drug loading = 13%. In vitro release followed first-order kinetics dominated by Higuchi diffusion (79.0% ± 4% at 24 h). After 48 h of treatment, TP-CTX-Lip exhib-ited significantly enhanced cytotoxicity in U87-MG cells (IC50 = 10.4 ± 0.2 nM), com-pared with IC50 values of 42.8 nM in SW1088 cells and 45.3 nM for non-targeted lipo-somes. In the 3T3-L1 non-cancerous cell line, the 48 h IC50 value of TP-CTX-Lip (8.433 ± 0.954µM) was higher than that of the TP solution (2.173 ± 0.181µM) but lower than that of TP-Lip (25.78 ± 2.691µM). Specifically, in 3T3-L1 cells, the 48 h IC50 of TP-CTX-Lip (8.43 µM) was approximately 4-fold higher than that of free TP (2.17 µM), confirming its substantially reduced cytotoxicity against non-cancerous cells. Results: In comparison to TP-Lip and free FITC solution, the uptake rate of TP-CTX-Lip in U87-MG cells exhibited a significantly higher level. Specifically, the uptake rate for the TP-CTX-Lip group (57.46 ± 5.44%) was statistically significantly higher than that of TP-Lip (13.7 ± 2.33%) and the free FITC solution group (20.97 ± 1.60%) (p < 0.01). In zebrafish, TP-CTX-Lip reduced developmental toxicity, with LC50 increased 1.26 times to 5.733 μg/mL, and suppressed orthotopic U87-MG xenograft growth (p < 0.001), in-dicating an improved therapeutic window as reflected by the LC50/IC50 ratio. Conclusions: the EGFR-targeted TP-CTX-Lip significantly enhances the tumor selectivity and safety of TP, providing a promising strategy for targeted glioma therapy. Full article
(This article belongs to the Section Pharmacology)
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21 pages, 7080 KB  
Article
Process Optimization of Novel Boronophenylalanine Liposomes Through Box–Behnken Response Surface Design and Preliminary Evaluation in A549 Lung Carcinoma Cells for Boron Neutron Capture Therapy
by Haojie Shi, Qianlong Xu, Fenglin Li, Caiyun Fan and Yi Han
Molecules 2026, 31(9), 1409; https://doi.org/10.3390/molecules31091409 - 24 Apr 2026
Viewed by 417
Abstract
Boron neutron capture therapy (BNCT) is a binary targeted radiotherapy that uses boron agents to treat refractory malignancies. This study developed a novel boronophenylalanine (BPA)-loaded liposome doped with o-carborane (CB) for BNCT. We applied response surface methodology (RSM) to identify factors affecting BPA [...] Read more.
Boron neutron capture therapy (BNCT) is a binary targeted radiotherapy that uses boron agents to treat refractory malignancies. This study developed a novel boronophenylalanine (BPA)-loaded liposome doped with o-carborane (CB) for BNCT. We applied response surface methodology (RSM) to identify factors affecting BPA loading and optimized encapsulation efficiency (EE) to minimize BPA loss. In in vitro experiments, these liposomes demonstrated promising characteristics for BNCT. The nanoparticle properties of CB-BPA-Lips remain stable for at least 48 h, and CB-BPA-Lips can effectively reduce the release of the agents loaded within them. Both cell viability assays and apoptosis assays have shown that CB-BPA-Lips have good biocompatibility and a lower inhibitory effect on cell viability than BPA. Cellular boron uptake peaked at 47.3642 ng B/106 cells in A549 lung cancer cells and peaked at 38.8875 ng B/106 cells in Bronchial Epithelium transformed with Ad12-SV40 2B (BEAS-2B) human normal bronchial epithelial cells at 24 h post-treatment, with both exceeding uptake in the BPA control group. Overall, this work presents an optimized liposomal formulation that enhances boron delivery to cancer cells and provides a potential candidate boron agent for BNCT pending in-depth in vivo studies. Full article
(This article belongs to the Section Nanochemistry)
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20 pages, 5419 KB  
Article
Preparation of PSA-DOX/ICG-Lip and Evaluation of Its Efficacy Against Cervical Cancer
by Jingya Bai, Jiamin Huang, Qian Zhang, Wenjun Su, Xiaohui Tang, Mukadaisi Amuti, Guorui Zhu, Qi Shen, Jian Yang and Mei Wang
Pharmaceutics 2026, 18(4), 434; https://doi.org/10.3390/pharmaceutics18040434 - 31 Mar 2026
Viewed by 506
Abstract
Objectives: To fabricate polysialic acid (PSA)-modified liposomes co-loaded with doxorubicin (DOX) and indocyanine green (ICG) for synergistic chemotherapy and photothermal therapy, and to enhance the anti-cervical cancer efficacy of liposomes via neutrophil targeting. Methods: PSA-DOX/ICG liposomes (PSA-DOX/ICG-Lip) were prepared by microfluidic [...] Read more.
Objectives: To fabricate polysialic acid (PSA)-modified liposomes co-loaded with doxorubicin (DOX) and indocyanine green (ICG) for synergistic chemotherapy and photothermal therapy, and to enhance the anti-cervical cancer efficacy of liposomes via neutrophil targeting. Methods: PSA-DOX/ICG liposomes (PSA-DOX/ICG-Lip) were prepared by microfluidic technology. The physicochemical properties, including drug encapsulation efficiency (EE), loading capacity (LC), particle size, polydispersity index (PDI), zeta potential, and stability, were systematically characterized. The in vitro anti-tumor activity was evaluated using cellular uptake, apoptosis assays, reactive oxygen species (ROS) detection, and a cell scratch test in HeLa and C33a cells. The in vivo therapeutic efficacy was verified using a nude mouse xenograft model of cervical cancer combined with histopathological analysis. Results: Microfluidic preparation yielded PSA-DOX/ICG-Lip with favorable physicochemical properties: the EE and LC of DOX were 96.52 ± 0.43% and 8.70 ± 0.04%, respectively, while those of ICG were 90.72 ± 1.10% and 0.82 ± 0.02%. The average particle size was 92.68 ± 1.14 nm with a PDI of 0.04 and a zeta potential of −9.66 ± 0.46 mV. The liposomes maintained good stability in terms of EE, particle size, PDI, and zeta potential after 28 days of storage at 4 °C and room temperature, with PSA modification significantly reducing the drug leakage rate. In vitro drug release studies showed that 808 nm laser irradiation triggered a significant increase in drug release from the liposomes. ICG encapsulated in liposomes mediated localized photothermal heating, and PSA targeting precisely confined the therapeutic effect to the tumor site, minimizing damage to adjacent normal tissues. In vitro experiments demonstrated that PSA-DOX/ICG-Lip, combined with laser irradiation, significantly enhanced cellular uptake, elevated intracellular ROS levels, inhibited cancer cell migration, and induced apoptosis. In vivo studies confirmed that this formulation markedly suppressed tumor growth in nude mice, with a tumor inhibition rate of 81.5%, and exhibited good biocompatibility without obvious organ toxicity. Conclusions: The microfluidically prepared PSA-DOX/ICG-Lip possesses high drug encapsulation efficiency, uniform particle size, good stability and sustained drug release properties. It can efficiently convert light energy into thermal energy, target neutrophils to enhance the affinity for cervical cancer cells, and exert a synergistic anti-tumor effect via the combination of chemotherapy and photothermal therapy, which provides a promising nanoplatform for the precise treatment of cervical cancer. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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17 pages, 1519 KB  
Article
Cell-Free DNA as Biomarker in Oral Squamous Cell Carcinoma: Dynamics, Mutational Landscape and Clinical Implications
by Pedro Veiga, Leonor Barroso, Luís Miguel Pires, Carolina Mano, Francisco Caramelo, Isabel Marques Carreira, Ilda Patrícia Ribeiro and Joana Barbosa de Melo
Cells 2026, 15(6), 568; https://doi.org/10.3390/cells15060568 - 23 Mar 2026
Viewed by 871
Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent form of head and neck cancer that typically develops on the lip or within the oral cavity. Although there have been advances in early detection and treatment, the prognosis for patients, particularly those with advanced-stage [...] Read more.
Oral squamous cell carcinoma (OSCC) is a prevalent form of head and neck cancer that typically develops on the lip or within the oral cavity. Although there have been advances in early detection and treatment, the prognosis for patients, particularly those with advanced-stage disease, remains poor. Liquid biopsy, particularly through the analysis of cell-free DNA (cfDNA) in plasma and urine, has emerged as a promising tool for non-invasive cancer detection and monitoring. This study assessed cfDNA concentration dynamics in plasma and urine samples from 32 OSCC patients, with 5 undergoing genomic characterization by targeted next-generation sequencing (NGS). CfDNA levels were higher in patients compared to healthy controls and showed transient increases following treatment initiation, likely reflecting tumor cell death, followed by a gradual return to baseline. However, cfDNA concentrations were not significantly associated with tumor stage, recurrence, or progression-free survival. Targeted NGS analysis revealed a heterogeneous mutational landscape, identifying 76 variants across tumor tissue and initial cfDNA, with 30.3% shared between both sources. Recurrent hotspot mutations were detected in several important genes, including TP53, PIK3CA, KRAS, APC, and FBXW7. Urine cfDNA also captured several mutations absent from plasma or tissue, supporting its complementary value. These findings demonstrate that cfDNA analysis can dynamically reflect treatment response and capture tumor heterogeneity in OSCC. While informative, cfDNA quantification alone offers limited prognostic reliability, reinforcing the need for a multidimensional approach that includes genomic and clinical evaluation. Overall, this study supports the potential of liquid biopsy as a real-time, non-invasive tool for molecular monitoring and personalized management of OSCC patients. Full article
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17 pages, 1414 KB  
Article
Long-Term Clinical Consequences of Severe Oral Mucositis in Survivors of Lip, Oral Cavity, and Pharynx Cancer Versus Leukemia: A Propensity-Score-Matched Comparative Cohort Study Using Real-World Data
by Poolakkad S. Satheeshkumar, Venu Gopalakrishnan, Joel B. Epstein and Roberto Pili
Med. Sci. 2026, 14(1), 142; https://doi.org/10.3390/medsci14010142 - 18 Mar 2026
Viewed by 851
Abstract
Background/Objectives: Severe oral mucositis is widely viewed as a transient toxicity of antineoplastic therapy. Whether its long-term consequences differ between cancers that directly damage the upper aerodigestive tract (cancers of the lip, oral cavity, pharynx [CLOP]) and systemic hematologic malignancies is unknown. The [...] Read more.
Background/Objectives: Severe oral mucositis is widely viewed as a transient toxicity of antineoplastic therapy. Whether its long-term consequences differ between cancers that directly damage the upper aerodigestive tract (cancers of the lip, oral cavity, pharynx [CLOP]) and systemic hematologic malignancies is unknown. The aim of this study was to compare lifetime risks of mortality, dysphagia, malnutrition, respiratory disease, and cardiovascular disease in propensity-score-matched survivors of CLOP cancer versus leukemia with and without a history of ulcerative oral mucositis. Methods: Population-based retrospective cohort study using the TriNetX US Collaborative Network (90 healthcare organizations, >110 million patients). We identified 80,526 adults with a personal history of CLOP cancer (ICD-10-CM Z85.81) and 43,684 with leukemia (Z85.6) from 2005 to 2024. Cohorts were stratified by presence/absence of severe oral mucositis (K12.31 or K12.33 at any time). Separate 1:1 propensity-score matching was performed within each cancer type on age, sex, race/ethnicity, hypertension, diabetes, BMI, ECOG status, and external causes of morbidity. Exposures included documented severe (ulcerative) oral mucositis. Main outcomes and measures were all-cause mortality and incident dysphagia, malnutrition, respiratory disease (J00–J99), influenza/pneumonia (J09–J18), and circulatory disease (I00–I99) after the index date. Results: After 1:1 matching, 4181 CLOP patients with mucositis were compared with 4181 without, and 2508 leukemia patients with mucositis were compared with 2508 without. In CLOP survivors, mucositis was associated with markedly higher lifetime mortality (adjusted HR 1.94, 95% CI 1.87–2.01), dysphagia (HR 3.42, 95% CI 3.28–3.57), malnutrition (HR 2.81, 95% CI 2.66–2.97), any respiratory disease (HR 1.68, 95% CI 1.63–1.73), and influenza/pneumonia (HR 1.79, 95% CI 1.72–1.86). In leukemia survivors, mucositis conferred only modest or null excess risk (mortality HR 1.12, 95% CI 1.05–1.19; dysphagia HR 1.18, 95% CI 1.07–1.30; malnutrition HR 1.24, 95% CI 1.12–1.37; any respiratory disease HR 1.09, 95% CI 1.03–1.15). Conclusions and Relevance: Severe oral mucositis is a powerful, durable prognostic determinant in cancers of the upper aerodigestive tract, where it identifies patients associated with elevated lifelong risk of swallowing dysfunction, aspiration-related lung disease, malnutrition, and premature death. The markedly attenuated effect in leukemia survivors suggests that direct high-dose radiation-induced structural damage to the pharynx and oral cavity—rather than systemic immunosuppression or chemotherapy intensity alone—is the dominant mechanism. Full article
(This article belongs to the Special Issue Feature Papers in Section “Cancer and Cancer-Related Research”)
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16 pages, 2407 KB  
Article
Discovery of RUVBL1 as a Target of the Marine Alkaloid Caulerpin via MS-Based Functional Proteomics
by Alessandra Capuano, Gilda D’Urso, Lucia Capasso, Emilio Brancaccio, Erica Gazzillo, Marianna Carbone, Ernesto Mollo, Gianluigi Lauro, Maria Giovanna Chini, Giuseppe Bifulco, Angela Nebbioso and Agostino Casapullo
Mar. Drugs 2026, 24(1), 37; https://doi.org/10.3390/md24010037 - 10 Jan 2026
Viewed by 1106
Abstract
Marine flora is a significant source of bioactive metabolites. These compounds have been demonstrated to have outstanding bioactivity and biocompatibility, enabling their use in various therapeutic applications. Therefore, examining the biological potential of marine natural compounds remains important, with particular emphasis on their [...] Read more.
Marine flora is a significant source of bioactive metabolites. These compounds have been demonstrated to have outstanding bioactivity and biocompatibility, enabling their use in various therapeutic applications. Therefore, examining the biological potential of marine natural compounds remains important, with particular emphasis on their interaction profiles to identify the macromolecular partners they can modulate. This study focused on the interactome profiling of the marine alkaloid caulerpin (CAU), isolated from the alga Caulerpa cylindracea. Along with the discovery of its antitumor properties, this metabolite has garnered attention for its potential therapeutic applications, including modulation of MAO-B and PPARs involved in inflammatory responses, as well as the discovery of its antitumor properties. Two complementary MS-based proteomic approaches were used to identify CAU target proteins in cancer cells: DARTS, which enabled proteome-wide screening to identify proteins interacting with the compound, and t-LIP-MRM-MS, which pinpointed the target protein regions involved in ligand binding. RUVB-like 1 (RUVBL1), a protein that regulates the essential mechanism of carcinogenesis, including chromatin remodeling, DNA repair, and transcriptional control, was discovered as an intriguing CAU target. These results were corroborated via in silico and biological investigations that elucidated CAU role in the regulation of RUVBL1 activity, highlighting its promising therapeutic relevance. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 5th Edition)
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12 pages, 4678 KB  
Communication
Expression of Glutamatergic Signaling in Canine Oral Melanocytic Neoplasms
by Alison Masyr, Latticha Pluemhathaikij, Sichao Wang, Tuddow Thaiwong-Nebelung and Rebecca C. Smedley
Vet. Sci. 2025, 12(12), 1149; https://doi.org/10.3390/vetsci12121149 - 2 Dec 2025
Viewed by 609
Abstract
Glutamine addiction in human melanoma is a premier example of the cancer hallmark of metabolic reprogramming. In the present study, we investigate the presence of metabotropic glutamate receptor 1 (mGluR1/GRM1) and glutaminase (GLS1/GLS) in canine oral malignant melanoma (OMM) [...] Read more.
Glutamine addiction in human melanoma is a premier example of the cancer hallmark of metabolic reprogramming. In the present study, we investigate the presence of metabotropic glutamate receptor 1 (mGluR1/GRM1) and glutaminase (GLS1/GLS) in canine oral malignant melanoma (OMM) and those of low malignant potential, termed histologically well-differentiated melanocytic neoplasm of the lips and oral mucosa (HWDMN). We used immunohistochemistry (IHC) and qPCR to evaluate mGluR1 and GLS1 protein expression and RNA expression, respectively. Nearly 20% of OMM cases had an mGluR1 IHC score ≥ 1, while none of the HWDMN cases had any expression. Due to low IHC expression, only 10 cases were selected for determination of GRM1 RNA expression, and none were positive. GLS RNA expression did not differ between OMM and HWDMN. A GLS1 IHC score ≥ 1 was significantly higher in OMM cases and highly specific (95%) for correctly identifying tumors with a Ki67 index ≥ 19.5. These results may have been negatively impacted by use of a brown chromogen for IHC labeling among background pigment, particularly in HWDMN. Ultimately, these findings suggest that canine OMM does not heavily rely on mGluR1 for tumorigenesis or progression. Differential GLS1 protein expression warrants further investigation with protein quantification. Full article
(This article belongs to the Section Anatomy, Histology and Pathology)
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19 pages, 1457 KB  
Article
Development and Evaluation of Hyaluronic Acid-Chitosan Coated Liposomes for Enhanced Delivery of Resveratrol to Breast Cancer Cells
by Yin Yin Myat, Khin Khin Gyi, Pornthida Riangjanapatee, Chuda Chittasupho, Songyot Anuchapreeda and Siriporn Okonogi
Polysaccharides 2025, 6(4), 93; https://doi.org/10.3390/polysaccharides6040093 - 10 Oct 2025
Viewed by 2668
Abstract
Resveratrol (RES), a naturally occurring polyphenolic compound with well-documented anticancer potential, is limited in clinical application due to its poor aqueous solubility and low bioavailability. This study aimed to develop RES-loaded liposomes coated sequentially with chitosan (CS) and hyaluronic acid-chitosan (HA) (RES-HA-CS-Lip) to [...] Read more.
Resveratrol (RES), a naturally occurring polyphenolic compound with well-documented anticancer potential, is limited in clinical application due to its poor aqueous solubility and low bioavailability. This study aimed to develop RES-loaded liposomes coated sequentially with chitosan (CS) and hyaluronic acid-chitosan (HA) (RES-HA-CS-Lip) to enhance RES stability, delivery, and anticancer efficacy in breast cancer cells. HA-CS-coated liposomes were prepared using a thin-film hydration technique. Their physicochemical characteristics were thoroughly investigated through dynamic light scattering, transmission electron microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. The optimized RES-HA-CS-Lip exhibited spherical morphology with an average particle size of 212 nm, a narrow polydispersity index (<0.4), a zeta potential of +9.04 ± 1.0 mV, and high entrapment efficiency of 82.16%. Stability studies demonstrated superior retention of size, surface charge, and encapsulation efficiency over 28 days at both 4 °C and 25 °C. In vitro release profiles at physiological and acidic pH revealed sustained drug release, with enhanced release under acidic conditions mimicking the tumor microenvironment. Antioxidant activity, assessed via DPPH and ABTS radical-scavenging assays, indicated that RES retained its radical-scavenging potential upon encapsulation. Cytotoxicity assays demonstrated markedly improved anticancer activity against MCF-7 breast cancer cells, with an IC50 of 13.08 μg/mL at 48 h, while maintaining high biocompatibility toward normal HaCaT keratinocytes. RES-HA-CS-Lip demonstrated excellent stability against degradation and aggregation. Overall, these findings highlight HA-CS-coated liposomes as a promising polysaccharide-based nanocarrier that enhances stability, bioactivity, and therapeutic efficacy of RES, representing a potential strategy for targeted breast cancer therapy. Full article
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15 pages, 2459 KB  
Article
The Effect of Liposomal DMU-212 on the Differentiation of Human Ovarian Granulosa Cells in a Primary 3D Culture Model
by Małgorzata Jόzkowiak, Dariusz Wawrzyniak, Alicja Kawczyńska, Paulina Skupin-Mrugalska, Mikołaj Czajkowski, Paul Mozdziak, Marta Podralska, Marek Żywicki, Bartosz Kempisty, Robert Z. Spaczyński and Hanna Piotrowska-Kempisty
Pharmaceuticals 2025, 18(10), 1460; https://doi.org/10.3390/ph18101460 - 28 Sep 2025
Viewed by 917
Abstract
Background/Objectives: Human ovarian granulosa cells (hGCs) are crucial to ovarian follicle development and function, exhibiting multipotency and the ability to differentiate into neuronal cells, chondrocytes, and osteoblasts in vitro. 3,4,5,4′-tetramethoxystilbene (DMU-212) is a methylated derivative of resveratrol, a natural polyphenol found in grapes [...] Read more.
Background/Objectives: Human ovarian granulosa cells (hGCs) are crucial to ovarian follicle development and function, exhibiting multipotency and the ability to differentiate into neuronal cells, chondrocytes, and osteoblasts in vitro. 3,4,5,4′-tetramethoxystilbene (DMU-212) is a methylated derivative of resveratrol, a natural polyphenol found in grapes and berries, with a wide spectrum of biological activities, including notable anticancer properties. Interestingly, DMU-212 exhibits cytotoxic effects predominantly on cancer cells while sparing non-cancerous ones, and evidence suggests that similar to resveratrol, it may also promote hGC differentiation. This study aimed to investigate the effects of the liposomal formulation of this methylated resveratrol analog—lipDMU-212—on the osteogenic differentiation ability of hGCs in a primary three-dimensional cell culture model. Methods: lipDMU-212 was formulated using the thin-film hydration method. GC spheroids’ viability was evaluated after exposure to lipDMU-212, an osteoinductive medium, or both. Osteogenic differentiation was confirmed using Alizarin Red staining and quantified by measuring Alkaline Phosphatase (ALP) activity on days 1, 7, and 15. RNA sequencing (RNA-seq) was performed to explore molecular mechanisms underlying lipDMU-212-induced differentiation. Results: lipDMU-212 promoted osteogenic differentiation of hGCs in the 3D cell culture model, as evidenced by increased mineralization and a ~4-fold increase in ALP activity compared with the control. RNA-seq revealed up-regulation of genes related to cell differentiation and cellular identity. Furthermore, JUN (+2.82, p = 0.003), LRP1 (+2.06, p = 0.05), AXIN1 (+3.02, p = 0.03), and FYN (+3.30, p = 0.01) were up-regulated, indicating modulation of the Wnt/β-catenin signaling pathway, a key regulator of osteoblast differentiation. Conclusions: The ability of GCs to differentiate into diverse tissue-specific cell types underscores their potential in regenerative medicine. This study contributes to the understanding of lipDMU-212’s role in osteogenic differentiation and highlights its potential in developing future therapies for degenerative bone diseases. Full article
(This article belongs to the Section Pharmacology)
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11 pages, 986 KB  
Article
The Burden of Lip and Oral Cavity Cancer Among Women Across 204 Countries and Territories in the Context of the Framework Convention on Tobacco Control: An Interrupted Time Series Analysis
by Laila Menezes Hagen, Larissa Rodrigues Gasparini, Bruna Machado da Silva, Amanda Ramos da Cunha, Fernando Neves Hugo and José Miguel Amenábar
Int. J. Environ. Res. Public Health 2025, 22(10), 1464; https://doi.org/10.3390/ijerph22101464 - 23 Sep 2025
Viewed by 1263
Abstract
Background: Historically, lip and oral cavity cancer (LOC) has been more prevalent among men, largely due to higher tobacco use in this group. However, over the past decades, smoking rates among women have risen and, in some regions, are approaching those of men. [...] Read more.
Background: Historically, lip and oral cavity cancer (LOC) has been more prevalent among men, largely due to higher tobacco use in this group. However, over the past decades, smoking rates among women have risen and, in some regions, are approaching those of men. This shift highlights the urgent need to analyze the burden of LOC specifically in women, as they may respond differently to tobacco control policies. This study assessed whether the World Health Organization Framework Convention on Tobacco Control (WHO-FCTC), launched in 2003, and the implementation of MPOWER measures have influenced LOC trends among women. Methods: A controlled interrupted time series was conducted from 1990 to 2021, with the launch of the WHO-FCTC considered the intervention point. A total of 204 countries and territories were initially categorized into two groups: those without (G1) and with (G2) MPOWER coverage. G2 was further subdivided based on the median MPOWER score from 2007 to 2020 into G2A (equal to or below the median) and G2B (above the median). Analyses were also stratified by Socio-Demographic Index (SDI) levels. Female LOC rates were obtained from the Global Burden of Disease Study 2021. Prais-Winsten segmented regression was applied to estimate annual percent changes (APCs) in LOC rates before and after the WHO-FCTC. Results: Prior to the WHO-FCTC, most trends for G1 and G2A were stable, while all trends for G2B were increasing. After 2003, LOC rates increased across all groups, especially in G2B. In high-SDI settings, rising trends in G2B remained unchanged post-intervention, whereas G1 and G2A shifted from stable to increasing. Among low-SDI groups, slopes were mostly not statistically significant. Conclusions: These findings suggest that the WHO-FCTC has had no measurable impact on reducing LOC burden among women so far. Instead, rates have continued to rise in many regions, signaling a concerning trend for women’s global health. Full article
(This article belongs to the Section Global Health)
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19 pages, 11762 KB  
Article
Metastatic Head and Neck Non-Melanoma Skin Cancer: A Retrospective Analysis of Clinico-Pathologic Features and Reconstructive Approach
by Victor Vlad Costan, Otilia Boișteanu, Delia Gabriela Ciobanu Apostol, Ștefan Vasile Toader, Cristina Colac Boțoc, Alin Gabriel Colac, Mihai-Liviu Ciofu and Mihaela Paula Toader
J. Clin. Med. 2025, 14(18), 6650; https://doi.org/10.3390/jcm14186650 - 21 Sep 2025
Viewed by 1348
Abstract
Background/Objectives: Non-melanoma skin cancer (NMSC) is the most common malignancy globally, with cutaneous squamous cell carcinoma (cSCC) posing a significant risk of regional metastasis, especially in high-risk anatomical areas such as the head and neck. While general risk factors for metastasis are well [...] Read more.
Background/Objectives: Non-melanoma skin cancer (NMSC) is the most common malignancy globally, with cutaneous squamous cell carcinoma (cSCC) posing a significant risk of regional metastasis, especially in high-risk anatomical areas such as the head and neck. While general risk factors for metastasis are well known, few studies have directly compared the clinical and pathological features of synchronous versus metachronous metastatic behavior. This study aimed to evaluate the clinicopathological characteristics and reconstructive implications associated with these two metastatic patterns in head and neck NMSC. Methods: We conducted a retrospective observational study of 46 patients with histologically confirmed metastatic NMSC of the head and neck, treated between January 2022 and May 2024 at a tertiary care center. Patients were stratified into synchronous or metachronous metastasis groups. Clinical data, histopathological features, metastatic sites, and surgical approaches were analyzed. Comparative statistics were applied using chi-square and t-tests, with significance set at p < 0.05. Results: Of the 46 patients, 50% had synchronous and 50% had metachronous metastases. The lower lip was the most common primary tumor site in both groups. Perineural and lymphovascular invasion were more frequent in synchronous metastases. Metachronous cases often required more complex reconstructive procedures, including free flap reconstructions and mandibular resections. Patients with metachronous metastases were significantly older (p = 0.024), and approximately one-third developed metastases more than four years after initial treatment. Conclusions: Head and neck NMSC, particularly involving the lower lip, may exhibit late-onset metastatic potential. Risk-adapted surveillance extending beyond current guidelines is warranted to improve long-term outcomes in high-risk patients. Full article
(This article belongs to the Special Issue Clinical Advances in Skin Cancer: A Closer Look at Non-Melanoma Types)
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23 pages, 1279 KB  
Review
Head and Neck Malignancies in Autoimmune Polyendocrine Syndrome Type 1 (APS-1/APECED): A Scoping Review of Molecular Pathogenesis, Clinical Features, and Outcomes
by Marko Tarle, Marina Raguž and Ivica Lukšić
Int. J. Mol. Sci. 2025, 26(18), 8969; https://doi.org/10.3390/ijms26188969 - 15 Sep 2025
Cited by 1 | Viewed by 1650
Abstract
Autoimmune polyendocrine syndrome type 1 (APS-1, APECED) is a rare monogenic disorder caused by biallelic AIRE mutations and is classically associated with chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. Apart from the autoimmune manifestations, APS-1 is associated with an increased risk of [...] Read more.
Autoimmune polyendocrine syndrome type 1 (APS-1, APECED) is a rare monogenic disorder caused by biallelic AIRE mutations and is classically associated with chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. Apart from the autoimmune manifestations, APS-1 is associated with an increased risk of squamous cell carcinoma (SCC), particularly in the oral cavity and esophagus. However, the evidence is patchy and has not yet been systematically reviewed. We conducted a scoping review according to the PRISMA-ScR guidelines. Pub-Med, Scopus, and Web of Science were searched using the terms APS-1/APECED and malignancy until July 2025. Eligible studies reported on APS-1 patients with histologically confirmed head, neck or esophageal cancer. Clinical, pathological, genetic and outcome data were summarized narratively. Nine publications described 19 APS-1 patients with 26 tumors. The mean age at cancer diagnosis was 35 years, with a latency period of ~24 years from the onset of APS-1. Tumors occurred most frequently in the oral cavity (65%), followed by the lip (19%) and esophagus (15%). In 96% of cases, the tumors were SCC. The grade of the tumor varied, and almost half of the cases were diagnosed at an advanced stage. As far as reported, the usual risk factors were not particularly pronounced; many patients did not smoke or drink alcohol. The main treatment consisted of surgery, often in combination with radiotherapy or chemoradiotherapy, alongside long-term antifungal therapy. Despite the multimodal treatment, outcomes were poor: the overall survival rate was ~50%, with recurrence occurring in 38% of cases and a second primary tumor in 26%. A further 14 cases were reported from another Italian cohort, which together with the national cohort dana suggest a risk of approximately ~10% with APS-1; however, the true lifetime risk remains uncertain. Head and neck malignancies in APS-1 occur early, often without classic risk factors, and have a high recurrence and mortality rate. Lifelong surveillance, antifungal stewardship and increased clinical awareness, ideally as part of multidisciplinary treatment pathways, are critical to improving outcomes in this rare but high-risk population. Full article
(This article belongs to the Special Issue Pathogenesis and Treatments of Head and Neck Cancer: 2nd Edition)
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33 pages, 2526 KB  
Systematic Review
Global Prevalence and Modifiers of Human Papillomavirus Positivity in Oral Cavity Cancer: A Systematic Review and Meta-Analysis of Prevalence (1995–2024)
by Areeb Iraqui, Alaa Safia, Mohamad Mahameed, Uday Abd Elhadi and Shlomo Merchavy
Cancers 2025, 17(17), 2870; https://doi.org/10.3390/cancers17172870 - 31 Aug 2025
Cited by 5 | Viewed by 4617
Abstract
Background/Objectives: Human papillomavirus (HPV) is a known etiologic agent in oropharyngeal cancers, but its role in oral cavity squamous cell carcinoma (OCSCC) remains unclear. This systematic review and meta-analysis aimed to estimate the global prevalence of HPV in OCSCC and explore variation [...] Read more.
Background/Objectives: Human papillomavirus (HPV) is a known etiologic agent in oropharyngeal cancers, but its role in oral cavity squamous cell carcinoma (OCSCC) remains unclear. This systematic review and meta-analysis aimed to estimate the global prevalence of HPV in OCSCC and explore variation by clinicodemographic and tumor characteristics. Methods: We systematically searched multiple databases for studies reporting HPV prevalence in OCSCC. Pooled prevalence estimates were calculated, and subgroup analyses examined differences by age, gender, cancer stage, anatomical site, histologic subtype, region, and HPV type (HPV-16 and HPV-18). Heterogeneity and publication bias were assessed using standard meta-analytic techniques. Results: A total of 122 studies involving 16,311 patients were included. The pooled HPV prevalence in OCSCC was 25.8% (95% CI: 20.4–31.2), with HPV-16 and HPV-18 detected in 52.4% and 30.3% of positive cases, respectively. Prevalence varied geographically, from 73% in Singapore to 7.7% in South Korea. Younger patients (<40 years) had higher HPV positivity (29.7%) than older patients (>70 years, 23.8%). Early-stage cancers (stage I) showed higher HPV prevalence (41.8%) than advanced-stage cancers (stage IV, 10.4%). Verrucous carcinoma had the highest HPV positivity (34.1%), and moderately differentiated tumors the lowest (23.4%). HPV prevalence was highest in the lower alveolus (29.5%) and lips (25%), and lowest in the upper gingiva (3.9%). Conclusions: HPV prevalence in OCSCC demonstrates significant heterogeneity across regions and clinical subgroups. These findings emphasize the need for standardized diagnostic approaches and further research into the role of HPV in OCSCC pathogenesis and treatment. Full article
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
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7 pages, 746 KB  
Communication
Exploring Laser-Induced Plasma Spectroscopy for Skin Cancer Patients: A Preliminary Study
by Dimitrios Sgouros, Emmanouil Karampinis, Melpomeni Theofili, Georgia Pappa, Panagiotis Theofilis, Sofia Theotokoglou, Anna Syrmali and Alexander Katoulis
Diagnostics 2025, 15(16), 2116; https://doi.org/10.3390/diagnostics15162116 - 21 Aug 2025
Viewed by 1092
Abstract
Skin cancer is the most frequently diagnosed form of cancer worldwide. Diagnostic uncertainty can arise when macroscopic or dermoscopic evaluations do not clearly differentiate between benign and malignant lesions. Laser-induced plasma spectroscopy (LIPS), traditionally used in fields like materials science and environmental analysis, [...] Read more.
Skin cancer is the most frequently diagnosed form of cancer worldwide. Diagnostic uncertainty can arise when macroscopic or dermoscopic evaluations do not clearly differentiate between benign and malignant lesions. Laser-induced plasma spectroscopy (LIPS), traditionally used in fields like materials science and environmental analysis, has recently gained attention for its applications in human tissue assessment. LIPS works by generating a (micro)plasma when a laser interacts with tissue, producing element-specific light emissions that can be analyzed in real time. In this study, we explored the potential of LIPS to differentiate between benign and malignant skin lesions using the Spectra-Scope® Score (SSS). Our results revealed a clear distinction: benign lesions showed a median SSS of 1.7, while suspicious and malignant lesions had a significantly higher median score of 8.1 (p < 0.001). Receiver operating characteristic (ROC) curve analysis demonstrated strong diagnostic performance, with an area under the curve (AUC) of 0.82 (p < 0.001). The findings of this preliminary study support the high accuracy of LIPS in identifying malignancy and underscore its promise as a non-invasive, real-time diagnostic aid. Integrating SSS into clinical workflows could enhance the early detection of skin cancer and reduce reliance on invasive diagnostic procedures. However, further validation is needed to fully establish its role in routine dermatological practice. Full article
(This article belongs to the Special Issue Noninvasive Diagnosis in Dermatology)
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13 pages, 2087 KB  
Article
Liposome-Loaded Mesenchymal Stem Cells Enhance Tumor Accumulation and Anti-Tumor Efficacy of Doxorubicin in Mouse Tumor Models of Melanoma
by Yusuke Kono, Himi Kanbara, Saki Danjo, Aiga Yoshikawa, Yoshihiro Iwayama and Ken-ichi Ogawara
Pharmaceutics 2025, 17(8), 947; https://doi.org/10.3390/pharmaceutics17080947 - 22 Jul 2025
Viewed by 1332
Abstract
Background: Mesenchymal stem cells (MSCs) possess an intrinsic tumor-tropic ability, and therefore, MSCs may potentially be used as biomimetic carriers for active drug delivery systems targeting tumors. We previously developed a method to efficiently load liposomes onto the surface of MSCs via [...] Read more.
Background: Mesenchymal stem cells (MSCs) possess an intrinsic tumor-tropic ability, and therefore, MSCs may potentially be used as biomimetic carriers for active drug delivery systems targeting tumors. We previously developed a method to efficiently load liposomes onto the surface of MSCs via electrostatic interactions. The prepared liposome-loaded MSCs (Lip-MSCs) spontaneously accumulated in solid melanoma tumors with low vascular permeability while stably carrying liposomes. Methods: To explore Lip-MSC applications in cancer chemotherapy, doxorubicin (DOX)-encapsulated liposomes (DOX-Lip) were prepared and loaded onto MSCs. The cell viability, DOX-releasing properties, tumor-homing capacity, and anti-tumor efficacy of DOX-Lip-MSCs were analyzed. Results: Small liposomes (100 nm) retained DOX, whereas significant leakage of DOX was observed from 600 nm-sized liposomes. Based on this result, we used 100 nm DOX-Lip for the preparation of DOX-Lip-MSCs. Compared with MSCs loaded with DOX by incubation with DOX solution, DOX-Lip-MSCs could load a larger amount of DOX with minimal cytotoxicity. DOX-Lip-MSCs also showed sustained DOX release. DOX-Lip-MSCs efficiently migrated toward the conditioned medium of B16/BL6 melanoma cells in vitro and accumulated in B16/BL6 tumors in vivo, leading to a significant inhibitory effect on tumor growth. Conclusions: Lip-MSCs can serve as an efficient carrier to deliver anti-cancer drugs into solid tumors. Full article
(This article belongs to the Special Issue Cell-Mediated Delivery Systems)
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