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15 pages, 2737 KiB  
Article
Thermogenic Activation of Adipose Tissue by Caffeine During Strenuous Exercising and Recovery: A Double-Blind Crossover Study
by Dany Alexis Sobarzo Soto, Diego Ignácio Valenzuela Pérez, Mateus Rossow de Souza, Milena Leite Garcia Reis, Naiara Ribeiro Almeida, Bianca Miarka, Esteban Aedo-Muñoz, Armin Isael Alvarado Oyarzo, Manuel Sillero-Quintana, Andreia Cristiane Carrenho Queiroz and Ciro José Brito
Metabolites 2025, 15(8), 517; https://doi.org/10.3390/metabo15080517 (registering DOI) - 1 Aug 2025
Viewed by 162
Abstract
Background/Objectives: To investigate acute caffeine (CAF: 375 mg, ≈4.8 mg/kg body mass) effects on energy expenditure (EE) and substrate kinetics during high-intensity interval exercise in individuals with high (HBAT) versus low (LBAT) brown adipose tissue activity using time-trend polynomial modeling. Methods: This [...] Read more.
Background/Objectives: To investigate acute caffeine (CAF: 375 mg, ≈4.8 mg/kg body mass) effects on energy expenditure (EE) and substrate kinetics during high-intensity interval exercise in individuals with high (HBAT) versus low (LBAT) brown adipose tissue activity using time-trend polynomial modeling. Methods: This is a randomized, double-blind crossover study in which 35 highly-trained males [HBAT-CAF, HBAT-PLA (Placebo), LBAT-CAF, LBAT-PLA] performed 30-min treadmill HIIE. Infrared thermography (IRT) assessed BAT activity by measuring supraclavicular skin temperature (SST). Breath-by-breath ergospirometry measured EE (kcal/min) and carbohydrate (CHO), lipid (LIP), and protein (PTN) oxidation. We applied second- and third-order polynomial regression models to depict the temporal trajectories of metabolic responses. Results: HBAT groups showed 25% higher sustained EE versus LBAT (p < 0.001), amplified by CAF. CHO oxidation exhibited biphasic kinetics: HBAT had 40% higher initial rates (0.75 ± 0.05 vs. 0.45 ± 0.04 g/min; p < 0.001) with accelerated decline (k = −0.21 vs. −0.15/min; p = 0.01). LIP oxidation peaked later in LBAT (40 vs. 20 min in HBAT), with CAF increasing oxidation by 18% in LBAT (p = 0.01). HBAT-CAF uniquely showed transient PTN catabolism (peak: 0.045 g/min at 10 min; k = −0.0033/min; p < 0.001). Conclusions: BAT status determines EE magnitude and substrate-specific kinetic patterns, while CAF exerts divergent modulation, potentiating early glycogenolysis in HBAT and lipolysis in LBAT. The HBAT-CAF synergy triggers acute proteolysis, revealing BAT-mediated metabolic switching. Full article
(This article belongs to the Special Issue Energy Metabolism in Brown Adipose Tissue)
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17 pages, 902 KiB  
Review
Cancer Stem Cells in Melanoma: Drivers of Tumor Plasticity and Emerging Therapeutic Strategies
by Adrian-Horațiu Sabău, Andreea-Cătălina Tinca, Raluca Niculescu, Iuliu Gabriel Cocuz, Andreea Raluca Cozac-Szöke, Bianca Andreea Lazar, Diana Maria Chiorean, Corina Eugenia Budin and Ovidiu Simion Cotoi
Int. J. Mol. Sci. 2025, 26(15), 7419; https://doi.org/10.3390/ijms26157419 (registering DOI) - 1 Aug 2025
Viewed by 116
Abstract
Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack [...] Read more.
Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article
(This article belongs to the Special Issue Mechanisms of Resistance to Melanoma Immunotherapy)
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16 pages, 2243 KiB  
Article
Comparative Effectiveness of Tunneling vs. Coronally Advanced Flap Techniques for Root Coverage: A 6–12-Month Randomized Clinical Trial
by Luis Chauca-Bajaña, Pedro Samuel Vásquez González, María José Alban Guijarro, Carlos Andrés Guim Martínez, Byron Velásquez Ron, Patricio Proaño Yela, Alejandro Ismael Lorenzo-Pouso, Alba Pérez-Jardón and Andrea Ordoñez Balladares
Bioengineering 2025, 12(8), 824; https://doi.org/10.3390/bioengineering12080824 (registering DOI) - 30 Jul 2025
Viewed by 252
Abstract
Background: Gingival recession is a common condition involving apical displacement of the gingival margin, leading to root surface exposure and associated complications such as dentin hypersensitivity and root caries. Among the most effective treatment options are the tunneling technique (TUN) and the coronally [...] Read more.
Background: Gingival recession is a common condition involving apical displacement of the gingival margin, leading to root surface exposure and associated complications such as dentin hypersensitivity and root caries. Among the most effective treatment options are the tunneling technique (TUN) and the coronally advanced flap (CAF), both combined with connective tissue grafts (CTGs). This study aimed to evaluate and compare the clinical outcomes of TUN + CTG and CAF + CTG in terms of root coverage and keratinized tissue width (KTW) over a 6–12-month follow-up. Methods: A randomized, double-blind clinical trial was conducted following CONSORT guidelines (ClinicalTrials.gov ID: NCT06228534). Participants were randomly assigned to receive either TUN + CTG or CAF + CTG. Clinical parameters, including gingival recession depth (REC) and KTW, were assessed at baseline as well as 6 months and 12 months postoperatively using a calibrated periodontal probe. Statistical analysis was performed using descriptive statistics and linear mixed models to compare outcomes over time, with a significance level set at 5%. Results: Both techniques demonstrated significant clinical improvements. At 6 months, mean root coverage was 100% in CAF + CTG cases and 97% in TUN + CTG cases, while complete root coverage (REC = 0) was observed in 100% and 89% of cases, respectively. At 12 months, root coverage remained stable, at 99% in the CAF + CTG group and 97% in the TUN + CTG group. KTW increased in both groups, with higher values observed in the CAF + CTG group (3.53 mm vs. 3.11 mm in TUN + CTG at 12 months). No significant postoperative complications were reported. Conclusions: Both TUN + CTG and CAF + CTG are safe and effective techniques for treating RT1 and RT2 gingival recession, offering high percentages of root coverage and increased KTW. While CAF + CTG achieved slightly superior coverage and tissue gain, the TUN was associated with better aesthetic outcomes and faster recovery, making it a valuable alternative in clinical practice. Full article
(This article belongs to the Special Issue Biomaterials and Technology for Oral and Dental Health)
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32 pages, 1740 KiB  
Review
Cancer-Associated Fibroblasts: Immunosuppressive Crosstalk with Tumor-Infiltrating Immune Cells and Implications for Therapeutic Resistance
by Jogendra Singh Pawar, Md. Abdus Salam, Md. Shalman Uddin Dipto, Md. Yusuf Al-Amin, Moushumi Tabassoom Salam, Sagnik Sengupta, Smita Kumari, Lohitha Gujjari and Ganesh Yadagiri
Cancers 2025, 17(15), 2484; https://doi.org/10.3390/cancers17152484 - 28 Jul 2025
Viewed by 449
Abstract
Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within [...] Read more.
Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within the complex ecosystem of TME, with significant heterogeneity and plasticity in origin and functional phenotypes. Very enigmatic cells, CAFs determine the progress and outcomes of tumors through extensive reciprocal signaling with different tumors infiltrating immune cells in the TME. In their biological drive, CAFs release numerous chemical mediators and utilize various signaling pathways to recruit and modulate tumor-infiltrating immune cells. The CAF-induced secretome and exosomes render immune cells ineffective for their antitumor activities. Moreover, by upregulating immune inhibitory checkpoints, CAFs create an immunosuppressive TME that impedes the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs). Further, by depositing and remodeling extracellular matrix (ECM), CAFs reshape the TME, which enhances tumor growth, invasion, metastasis, and chemoresistance. Understanding of CAF biology and its crosstalk with tumor-infiltrating immune cells is crucial not only to gain insight in tumorigenesis but to optimize the potential of novel targeted immunotherapies for cancers. The complex relationships between CAFs and tumor-infiltrating immune cells remain unclear and need further study. Herein, in this narrative review we have focused on updates of CAF biology and its interactions with tumor-infiltrating immune cells in generating immunosuppressive TME and resistance to cell death. Full article
(This article belongs to the Section Tumor Microenvironment)
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16 pages, 5172 KiB  
Article
LAMP1 as a Target for PET Imaging in Adenocarcinoma Xenograft Models
by Bahar Ataeinia, Arvin Haj-Mirzaian, Lital Ben-Naim, Shadi A. Esfahani, Asier Marcos Vidal, Umar Mahmood and Pedram Heidari
Pharmaceuticals 2025, 18(8), 1122; https://doi.org/10.3390/ph18081122 - 27 Jul 2025
Viewed by 460
Abstract
Background: Lysosomal-associated membrane protein 1 (LAMP1), typically localized to the lysosomal membrane, is increasingly implicated as a marker of cancer aggressiveness and metastasis when expressed on the cell surface. This study aimed to develop a LAMP1-targeted antibody-based PET tracer and assess its efficacy [...] Read more.
Background: Lysosomal-associated membrane protein 1 (LAMP1), typically localized to the lysosomal membrane, is increasingly implicated as a marker of cancer aggressiveness and metastasis when expressed on the cell surface. This study aimed to develop a LAMP1-targeted antibody-based PET tracer and assess its efficacy in mouse models of human breast and colon adenocarcinoma. Methods: To determine the source of LAMP1 expression, we utilized human single-cell RNA sequencing and spatial transcriptomics, complemented by in-house flow cytometry on xenografted mouse models. Tissue microarrays of multiple epithelial cancers and normal tissue were stained for LAMP-1, and staining was quantified. An anti-LAMP1 monoclonal antibody was conjugated with desferrioxamine (DFO) and labeled with zirconium-89 (89Zr). Human triple-negative breast cancer (MDA-MB-231) and colon cancer (Caco-2) cell lines were implanted in nude mice. PET/CT imaging was conducted at 24, 72, and 168 h post-intravenous injection of 89Zr-DFO-anti-LAMP1 and 89Zr-DFO-IgG (negative control), followed by organ-specific biodistribution analyses at the final imaging time point. Results: Integrated single-cell and spatial RNA sequencing demonstrated that LAMP1 expression was localized to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in addition to the cancer cells. Tissue microarray showed significantly higher staining for LAMP-1 in tumor tissue compared to normal tissue (3986 ± 2635 vs. 1299 ± 1291, p < 0.001). Additionally, xenograft models showed a significantly higher contribution of cancer cells than the immune cells to cell surface LAMP1 expression. In vivo, PET imaging with 89Zr-DFO-anti-LAMP1 PET/CT revealed detectable tumor uptake as early as 24 h post-injection. The 89Zr-DFO-anti-LAMP1 tracer demonstrated significantly higher uptake than the control 89Zr-DFO-IgG in both models across all time points (MDA-MB-231 SUVmax at 168 h: 12.9 ± 5.7 vs. 4.4 ± 2.4, p = 0.003; Caco-2 SUVmax at 168 h: 8.53 ± 3.03 vs. 3.38 ± 1.25, p < 0.01). Conclusions: Imaging of cell surface LAMP-1 in breast and colon adenocarcinoma is feasible by immuno-PET. LAMP-1 imaging can be expanded to adenocarcinomas of other origins, such as prostate and pancreas. Full article
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34 pages, 32238 KiB  
Article
ACLC-Detection: A Network for Remote Sensing Image Detection Based on Attention Mechanism and Lightweight Convolution
by Shaodong Liu, Faming Shao, Chenshan Yang, Juying Dai, Jinhong Xue, Qing Liu and Tao Zhang
Remote Sens. 2025, 17(15), 2572; https://doi.org/10.3390/rs17152572 - 24 Jul 2025
Viewed by 248
Abstract
Detecting small objects using remote sensing technology has consistently posed challenges. To address this issue, a novel detection framework named ACLC-Detection has been introduced. Building upon the Yolov11 architecture, this detector integrates an attention mechanism with lightweight convolution to enhance performance. Specifically, the [...] Read more.
Detecting small objects using remote sensing technology has consistently posed challenges. To address this issue, a novel detection framework named ACLC-Detection has been introduced. Building upon the Yolov11 architecture, this detector integrates an attention mechanism with lightweight convolution to enhance performance. Specifically, the deep and shallow convolutional layers of the backbone network are both introduced to depthwise separable convolution. Moreover, the designed lightweight convolutional excitation module (CEM) is used to obtain the contextual information of targets and reduce the loss of information for small targets. In addition, the C3k2 module in the neck fusion network part, where C3k = True, is replaced by the Convolutional Attention Module with Ghost Module (CAF-GM). This not only reduces the model complexity but also acquires more effective information. The Simple Attention module (SimAM) used in it not only suppresses redundant information but also has zero impact on the growth of model parameters. Finally, the Inner-Complete Intersection over Union (Inner-CIOU) loss function is employed, which enables better localization and detection of small targets. Extensive experiments conducted on the DOTA and VisDrone2019 datasets have demonstrated the advantages of the proposed enhanced model in dealing with small objects in aerial imagery. Full article
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27 pages, 1103 KiB  
Review
Tumor Microenvironmental Dynamics in Shaping Resistance to Therapeutic Interventions in Melanoma: A Narrative Review
by Laci M. Turner, Hanna Terhaar, Victoria Jiminez, Bailey J. Anderson, Emily Grant and Nabiha Yusuf
Pharmaceuticals 2025, 18(8), 1082; https://doi.org/10.3390/ph18081082 - 22 Jul 2025
Viewed by 400
Abstract
Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, [...] Read more.
Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article
(This article belongs to the Special Issue Combating Drug Resistance in Cancer)
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19 pages, 1797 KiB  
Systematic Review
Identifying Factors Influencing Local Acceptance of Renewable Energy Projects: A Systematic Review
by Hazirah H. Zaharuddin, Vani N. Alviani, Mazlina A. Majid, Hiromi Kubota and Noriyoshi Tsuchiya
Sustainability 2025, 17(14), 6623; https://doi.org/10.3390/su17146623 - 20 Jul 2025
Viewed by 398
Abstract
Renewable energy projects are critical for sustainable development, yet their success often hinges on local community acceptance. This study refines the Community Acceptance Framework to classify and better understand the social and behavioral factors that shape community responses to renewable energy projects. To [...] Read more.
Renewable energy projects are critical for sustainable development, yet their success often hinges on local community acceptance. This study refines the Community Acceptance Framework to classify and better understand the social and behavioral factors that shape community responses to renewable energy projects. To support the reclassification, we draw selectively on three psychological concepts to refine definition and streamline categories. Based on a systematic review of 212 studies, we identified 29 influencing factors and categorized them into a seven-dimensional framework: social, economic, environmental, political, process, project details, and temporal. The findings reveal that financial capital, which reflects economic gains, emerges as the most frequently cited factor influencing local acceptance. However, when viewed dimensionally, the social dimension encompassing factors such as social capital, cognitive response, and cultural capital accounts for the largest share of influencing factors. Additionally, the often-overlooked political and temporal dimensions highlight the importance of governance quality and timely community engagement. While the framework offers a more robust and context-sensitive tool for analyzing acceptance dynamics, empirical validation is needed to assess its practical applicability. Nevertheless, the refined CAF can guide policymakers, researchers, and practitioners in designing renewable energy initiatives that are both technically sound, economically viable, and socially inclusive. Full article
(This article belongs to the Section Psychology of Sustainability and Sustainable Development)
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18 pages, 9009 KiB  
Article
Cancer-Associated Fibroblasts Establish Spatially Distinct Prognostic Niches in Subcutaneous Colorectal Cancer Mouse Model
by Zhixian Lin, Jinmeng Wang, Yixin Ma, Yanan Zhu, Yuhan Li, Zhengtao Xiao and Wei Zhao
Cancers 2025, 17(14), 2402; https://doi.org/10.3390/cancers17142402 - 19 Jul 2025
Viewed by 467
Abstract
Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within [...] Read more.
Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within MC38 subcutaneous tumors in a syngeneic mouse model. Results: We identified two spatially distinct tumor zones, partitioned by cancer-associated fibroblasts (CAFs), that differ markedly in cellular composition, oncogenic signaling, immune infiltration, and metabolic states. One zone exhibited features of TGF-β-driven extracellular matrix remodeling, immune exclusion, and hyperproliferative metabolism, while the other was enriched for immunosuppressive macrophages, metabolic reprogramming via PPAR and AMPK pathways, and high-risk cell populations. Spatially resolved cell–cell communication networks further revealed zone-specific ligand–receptor interactions—such as ANGPTL4–SDC2 and PROS1–AXL—that underpin stromal remodeling and immune evasion and are associated with patient prognosis. Conclusions: Collectively, our study uncovers how region-specific cellular ecosystems and intercellular crosstalk establish prognostically divergent niches within subcutaneous CRC tumors, offering insights into spatially guided therapeutic strategies. Full article
(This article belongs to the Section Tumor Microenvironment)
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19 pages, 2501 KiB  
Article
Genes Encoding Multiple Modulators of the Immune Response Are Methylated in the Prostate Tumor Microenvironment of African Americans
by Vinay Kumar, Tara Sinta Kartika Jennings, Lucas Ueta, James Nguyen, Liankun Song, Michael McClelland, Weiping Chu, Michael Lilly, Michael Ittmann, Patricia Castro, Arash Rezazadeh Kalebasty, Dan Mercola, Omid Yazdanpanah, Xiaolin Zi and Farah Rahmatpanah
Cancers 2025, 17(14), 2399; https://doi.org/10.3390/cancers17142399 - 19 Jul 2025
Viewed by 416
Abstract
Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma [...] Read more.
Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC). Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs, p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001). Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men. Full article
(This article belongs to the Section Tumor Microenvironment)
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31 pages, 2698 KiB  
Review
Tumor Microenvironment in Melanoma—Characteristic and Clinical Implications
by Hubert Sikorski, Michał Aleksander Żmijewski and Anna Piotrowska
Int. J. Mol. Sci. 2025, 26(14), 6778; https://doi.org/10.3390/ijms26146778 - 15 Jul 2025
Viewed by 794
Abstract
Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines [...] Read more.
Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies for Melanoma)
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20 pages, 3793 KiB  
Article
Chemoresistance Evolution in Ovarian Cancer Delineated by Single-Cell RNA Sequencing
by Yuanmei Wang, Zongfu Tang, Haoyu Li, Run Zhou, Hao Wu, Xiaoping Cen, Yi Zhang, Wei Dong and Huanming Yang
Int. J. Mol. Sci. 2025, 26(14), 6760; https://doi.org/10.3390/ijms26146760 - 15 Jul 2025
Viewed by 362
Abstract
High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy characterized by intraperitoneal spread and chemotherapy resistance. Chemotherapies have demonstrated limited effectiveness in HGSOC, underscoring the urgent need to evaluate how the tumor microenvironment (TME) was reshaped by chemotherapy in different sites of [...] Read more.
High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy characterized by intraperitoneal spread and chemotherapy resistance. Chemotherapies have demonstrated limited effectiveness in HGSOC, underscoring the urgent need to evaluate how the tumor microenvironment (TME) was reshaped by chemotherapy in different sites of tumor foci. In this study, we performed single-cell transcriptomic analysis to explore the TME in samples obtained from various sites of tumor foci, with or without the history of Neoadjuvant chemotherapy (NACT). We discovered that chemotherapy reshaped the tumor immune microenvironment, evident through the reduction in human leukocyte antigen (HLA) diversity and the increase in PDCD1/CD274 in CD8_ANXA1, LAMP3+ dendritic cell (DC_LAMP3), and EREG+ monocytes (mono_EREG). Moreover, cancer.cell.2, cancer-associated C3+ fibroblasts (CAF_C3), and Fibrocyte_CD34, which are prone to accumulate in the metastatic site and post-NACT group, harbored poor clinical outcome, reflected in the immune exclusion and tumor progression signaling. Cell–cell communication identified a stronger interaction between cancer.cell.2 and CAF_C3, as well as Fibrocyte_CD34, in post-NACT samples, indicating that chemotherapy reshapes pre-existing cell clusters in a site-dependent manner. Our findings suggest that chemotherapy and sites of foci were critical for the transcriptional reprogramming of pre-existed cell clusters. Our study offers a single-cell phenotype data substrate from which to develop a personalized combination of chemotherapy and immunotherapy. Full article
(This article belongs to the Section Molecular Oncology)
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14 pages, 5269 KiB  
Article
The Role of Copigmentation in Colour Attributes and Their Evolution in Model Wine: A Thermodynamic and Colorimetric Study
by Arianna Ricci, Cristian Galaz-Torres, Giuseppina Paola Parpinello, Miriana Demola, Marco Spiga and Andrea Versari
Foods 2025, 14(14), 2467; https://doi.org/10.3390/foods14142467 - 14 Jul 2025
Viewed by 307
Abstract
The colour evolution of malvidin-3-O-glucoside (Mv-3-O-glc) elicited by caffeic acid (CAF), (+)-catechin (CA), or syringic acid (SI) was spectrophotometrically monitored in model wine solution, modulating the malvidin-to-polyphenol molar ratio (1:1 to 1:20) and the pH (2.8–3.8). The spectral features [...] Read more.
The colour evolution of malvidin-3-O-glucoside (Mv-3-O-glc) elicited by caffeic acid (CAF), (+)-catechin (CA), or syringic acid (SI) was spectrophotometrically monitored in model wine solution, modulating the malvidin-to-polyphenol molar ratio (1:1 to 1:20) and the pH (2.8–3.8). The spectral features provided the thermodynamic parameters Gibbs free energy (ΔG0) and equilibrium constant (Keq), showing that the copigmentation extent is maximized at pH 3.6 and a higher molar ratio (1:20), and that copigments have different efficiency. In a long-term evolution (12 months), transient complexes evolved into different colour characteristics. Spectrophotometry and colorimetry (chroma C*, hue H*, and lightness L*) revealed the formation of stable pigments with peculiar orange-reddish colour when CAF was present; however, in the case of CA, an accentuated yellow tone was observed. SI showed minimum impact in the long-term evolution of Mv-3-O-glc. This study expands knowledge on oenological copigmentation, further exploring its potential implication in the colour of aged red wines. Full article
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15 pages, 2126 KiB  
Review
Prognostic Value of the Immunohistochemical Detection of Cellular Components of the Tumor Microenvironment in Oral Squamous Cell Carcinoma: A Systematic Review
by Hannah Gil de Farias Morais, Caroline Fernandes da Costa, Maurília Raquel de Souto Medeiros, Bárbara de Assis Araújo, Everton Freitas de Morais, Ricardo D. Coletta and Roseana de Almeida Freitas
Curr. Issues Mol. Biol. 2025, 47(7), 544; https://doi.org/10.3390/cimb47070544 - 12 Jul 2025
Viewed by 660
Abstract
This study aims to investigate the prognostic impact of cellular components of the tumor microenvironment (TME), analyzed through immunohistochemistry, in oral squamous cell carcinoma (OSCC). This review was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). [...] Read more.
This study aims to investigate the prognostic impact of cellular components of the tumor microenvironment (TME), analyzed through immunohistochemistry, in oral squamous cell carcinoma (OSCC). This review was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Searches were performed in EMBASE, Medline/PubMed, Cochrane Collaboration Library, Web of Science, ScienceDirect, Scopus, and Google Scholar. After applying the study criteria, 59 articles were included, involving the analysis of cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. It was found that TME rich in α-SMA-positive CAFs, tumor-associated macrophages, and dendritic cells contribute to the invasion and progression of OSCC, resulting in a poorer prognosis. In contrast, the presence of high amounts of NK CD57+ cells, CD8+/CD45RO+ T cells, and PNAd+ endothelial cells are associated with anti-tumor immune responses in OSCC and improved survival rates. CD3+ and CD4+ T cells, Treg cells, B cells, and mast cells have shown little to no evidence of prognostic utility. Several stromal components of TME were found to have a strong impact on the aggressiveness of OSCC, reaffirming the potential use of these biomarkers as prognostic tools and therapeutic targets. Full article
(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment, 2nd Edition)
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Article
Establishment of Human Lung Cancer Organoids Using Small Biopsy and Surgical Tissues
by Mina Hwang, Junsu Choe, Yong Jae Shin, Bo-Gyeong Seo, Kyung-Mi Park, Sun Hye Shin, Byung Woo Jhun, Hongseok Yoo, Byeong-Ho Jeong, Kyeongman Jeon, Kyungjong Lee, Junghee Lee, Yeong Jeong Jeon, Jong Ho Cho, Seong Yong Park, Hong Kwan Kim and Sang-Won Um
Cancers 2025, 17(14), 2291; https://doi.org/10.3390/cancers17142291 - 10 Jul 2025
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Abstract
Background/Objectives: Lung cancer is a highly diverse disease, and reliable preclinical models that accurately reflect tumor characteristics are essential for studying lung cancer biology and testing new therapies. This study aimed to establish patient-derived tumor organoids (PDTOs) using small biopsy samples and surgical [...] Read more.
Background/Objectives: Lung cancer is a highly diverse disease, and reliable preclinical models that accurately reflect tumor characteristics are essential for studying lung cancer biology and testing new therapies. This study aimed to establish patient-derived tumor organoids (PDTOs) using small biopsy samples and surgical specimens to create a model system that preserves the genetic and histological features of the original tumors. Methods: PDTOs were generated from 163 lung cancer specimens, including 109 samples obtained using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or bronchoscopy, 52 surgical specimens, and 2 pleural fluid samples. The organoid establishment rate beyond passage three was assessed, and histological subtypes and genetic profiles were analyzed using immunohistochemical staining and targeted exome sequencing. Results: The overall PDTO establishment rate was 34.4% (56/163), and 44.6% (25/56) of these organoids retained the histological and genetic features of the parental tumors. Genetic analysis identified key mutations, including KRAS G12C, EGFR L858R, MET exon 14 skipping mutation, and ROS1 fusion. PDTOs successfully formed tumors in mice while maintaining the genetic characteristics of the original tumors. Co-culture of PDTOs with cancer-associated fibroblasts (CAFs) resulted in increased resistance to paclitaxel. In the co-culture model of PDTOs with immune cells, dose-dependent growth inhibition of PDTOs was observed in response to immune checkpoint inhibitors. Conclusions: PDTOs established from small biopsy and surgical specimens serve as a valuable model for studying lung cancer biology, tumor microenvironment interactions, and drug response. This model has the potential to improve personalized treatment strategies. Full article
(This article belongs to the Special Issue New Perspectives in the Treatment of Thoracic Cancers)
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