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Search Results (248)

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23 pages, 3957 KB  
Article
Pathogen-Specific Actinium-225 and Lutetium-177 Labeled Antibodies for Treatment of Biofilm-Associated Implant Infections: Initial In Vivo Proof-of-Concept
by F. Ruben H. A. Nurmohamed, Kevin J. H. Allen, Mackenzie E. Malo, Connor Frank, J. Fred F. Hooning van Duvenbode, Berend van der Wildt, Alex J. Poot, Marnix G. E. H. Lam, Jos A. G. van Strijp, Peter G. J. Nikkels, H. Charles Vogely, Harrie Weinans, Ekaterina Dadachova and Bart C. H. van der Wal
Antibiotics 2025, 14(12), 1283; https://doi.org/10.3390/antibiotics14121283 - 18 Dec 2025
Viewed by 383
Abstract
Background: the primary challenge with implant infections is the formation of biofilm, which harbors dormant bacteria that reduce the effectiveness of antibiotics and amplify antibiotic resistance, exacerbating the global antimicrobial resistance crisis. A potential novel treatment strategy is radioimmunotherapy, which uses antibodies linked [...] Read more.
Background: the primary challenge with implant infections is the formation of biofilm, which harbors dormant bacteria that reduce the effectiveness of antibiotics and amplify antibiotic resistance, exacerbating the global antimicrobial resistance crisis. A potential novel treatment strategy is radioimmunotherapy, which uses antibodies linked to radioisotopes to deliver targeted radiation to the bacteria and biofilm. We describe the first in vivo use of targeted radiation therapy, employing Actinium-225 (α-radiation) and Lutetium-177 (β-radiation) labeled antibodies to treat a Staphylococcus aureus biofilm-associated intramedullary implant infection. Untargeted radiation in the form of unbound radionuclide treatment was also evaluated. Methods: to assess therapeutic efficacy, bacterial counts were performed on implant and surrounding bone after seven days of follow-up. Biodistribution was evaluated using SPECT/CT and ex vivo gamma counting. Results: radioimmunotherapy using an antibody against wall teichoic acid which was labeled with Actinium-225 and Lutetium-177 achieved bacterial reductions between 45% and 93% on the implant and surrounding bone. Surprisingly, a similar antimicrobial effect was observed with unbound Actinium-225 treatment reducing the bacterial load by 80% on the implant and 98% in the surrounding bone. Indications of maximum tolerated dose (MTD) with Lutetium-177 labeled antibodies were observed through hepatic and renal function evaluations. Conclusions: These results should be interpreted in the context of the study’s constraints, particularly the limited animal sample size. Nonetheless, the results suggest that in vivo applied radiation may help reduce a biofilm-associated infection at the implant site as well as in the surrounding bone. These findings encourage further investigation into the use of targeted and non-targeted radiation, potentially combined with antibiotics, to develop effective strategies for eradicating biofilm-associated implant infections. Full article
(This article belongs to the Special Issue Challenges of Antibiotic Resistance: Biofilms and Anti-Biofilm Agents)
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15 pages, 670 KB  
Article
Diet Acceptance and Utilization Responses to Increasing Doses of Thymol in Beef Steers Consuming Forage
by Emma P. Fukuda, Jordan P. Suter, Russell W. Jessup and Merritt L. Drewery
Animals 2025, 15(24), 3637; https://doi.org/10.3390/ani15243637 - 17 Dec 2025
Viewed by 276
Abstract
Thymol is an antimicrobial terpene with potential as a feed additive for cattle; however, in vivo data describing the response of forage-fed beef cattle to the increasing provision of thymol is limited. As thymol may affect palatability and exert antimicrobial effects on rumen [...] Read more.
Thymol is an antimicrobial terpene with potential as a feed additive for cattle; however, in vivo data describing the response of forage-fed beef cattle to the increasing provision of thymol is limited. As thymol may affect palatability and exert antimicrobial effects on rumen microbes, defining its effects in vivo is critical to inform adoption. Accordingly, the objectives of this study were to evaluate cattle acceptance of thymol and characterize the effects of increasing thymol doses on diet utilization and ruminal fermentation, with the overarching goal of identifying a maximum tolerable dose for beef cattle. Two 4 × 4 Latin Square experiments were conducted using beef steers consuming forage and providing thymol dosed on alfalfa. Experiment 1 assessed acceptance of thymol at increasing concentrations (0, 110, 220, and 330 mg/kg intake), and experiment 2 assessed diet utilization and fermentation in response to one of four thymol doses: 0, 120, 240, and 480 mg/kg intake. For experiment 1, thymol dose did not affect treatment or forage intake (p ≥ 0.17). For experiment 2, thymol did not linearly or quadratically affect (p ≥ 0.28) forage organic matter (OM) intake or OM digestibility. There were also no linear or quadratic effects (p ≥ 0.09) on ruminal ammonia-N, volatile fatty acids, or pH. These data indicate that thymol can be provided to beef cattle at up to 330 mg/kg intake and 480 mg/kg intake without negatively impacting acceptance and diet utilization, respectively. Full article
(This article belongs to the Special Issue Feed Additives in Animal Nutrition)
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20 pages, 592 KB  
Article
First-in-Human Phase I Clinical Trial of SLC-391, a Novel and Selective AXL Inhibitor, in Patients with Advanced Solid Tumours
by Zaihui Zhang, Donna Morrison, Liang Lu, Madhu Singh, Jun Yan, Natasha Leighl, Scott A. Laurie and Sebastien Hotte
Pharmaceuticals 2025, 18(12), 1898; https://doi.org/10.3390/ph18121898 - 17 Dec 2025
Viewed by 465
Abstract
Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated [...] Read more.
Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of SLC-391 in patients with advanced solid tumours. Methods: Using a 3 + 3 design, SLC-391 was administered orally, either once daily (from 25 mg up to 175 mg QD) or twice daily (from 75 mg to 200 mg BID) in 21-day cycles. Results: Following single and repeated dosing, SLC-391 was generally well tolerated by subjects. The maximum tolerated dose (MTD) was not reached in this study. A total of 34/35 subjects experienced at least one TEAE. Three (8.6%) subjects experienced Grade 3 TRAEs that were considered related to SLC-391. Eight SAEs were reported in five (14.3%) subjects (seven Grade 3 SAEs and one Grade 2 SAE), in 150 mg QD (3/6, 50%), 175 mg QD (1/2, 50%), and 110 mg BID (1/3, 33.3%) cohorts. Four SAEs in three (8.6%) subjects led to dose interruption, drug withdrawal, or study discontinuation. Three DLTs were reported in two subjects: one subject experienced Grade 3 hematochezia (SUSAR/DLT) at 175 mg QD, and another subject experienced Grade 3 thrombocytopenia associated with Grade 1 hematuria at 200 mg BID. The median Tmax was 2.0 h. Plasma concentrations following multiple doses generally increased with higher doses and appeared to reach steady state by Day 21 and were generally dose-proportional. Twelve (12) out of 35 subjects with solid tumours achieved stable disease according to RECIST or mRECIST (mesothelioma), with durations of stable disease lasting up to 318 days on SLC-391 monotherapy. The clinical benefit rate was 34.3%. Conclusions: This first study of SLC-391 in adult subjects with advanced solid tumours demonstrated that a total daily dose of 300 mg (150 mg BID) of SLC-391 monotherapy was generally well tolerated, with no DLTs or SAEs observed at this dose. The drug’s promising safety profile, along with stable disease reported for several subjects with advanced solid tumours, provides a strong rationale for the phase 1b/2a clinical investigation of SLC-391 in combination with pembrolizumab in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) (NCT05860296). Full article
(This article belongs to the Section Medicinal Chemistry)
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13 pages, 2091 KB  
Article
Assessing Perfluorooctane Sulfonate (PFOS) Toxicity and Carcinogenicity Through Zebrafish (Danio rerio) Xenograft Assays
by Tessa Block, Joan Renee DeMaio, Lela Skopec, Margaret Ayers and Eric Glasgow
Toxics 2025, 13(12), 1077; https://doi.org/10.3390/toxics13121077 - 14 Dec 2025
Viewed by 720
Abstract
Persistent environmental pollutants such as per- and poly-fluoroalkyl substances (PFAS) have been associated with a wide range of toxic effects, including cancer. There are over 12,000 PFAS compounds, which may act as carcinogens individually or in combinations. Therefore, efficient in vivo new approach [...] Read more.
Persistent environmental pollutants such as per- and poly-fluoroalkyl substances (PFAS) have been associated with a wide range of toxic effects, including cancer. There are over 12,000 PFAS compounds, which may act as carcinogens individually or in combinations. Therefore, efficient in vivo new approach models of carcinogenicity are needed for evaluating environmental contaminant compounds and chemical mixtures. Here, we use the larval zebrafish xenograft assay to identify tumor growth activity of perfluorooctane sulfonate (PFOS), a known carcinogenic PFAS. Dose–response curves for PFOS exposure were used to identify the Maximum Tolerated Concentration (MTC) and Lethal Concentration causing 50% death (LC50) under xenograft conditions. Zebrafish xenografts were established by injecting fluorescently labeled kidney cancer cells into the embryonic body cavity near the developing kidney, followed by treatment with PFOS at a concentration of 5%, 10%, and 20% of the MTC. When treated with PFOS, zebrafish xenografts using renal cell carcinoma (ACHN) cells and clear renal cell carcinoma (Caki-1) cells show dose-dependent changes in tumor area. This study is the first to directly show cancer-promoting activity of a PFAS, using a rapid in vivo zebrafish xenograft assay, and demonstrates the utility of this model for validation of predicted cancer-promoting properties of environmental contaminants. Full article
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24 pages, 13793 KB  
Article
Reinforcement Learning-Driven Evolutionary Stackelberg Game Model for Adaptive Breast Cancer Therapy
by Fatemeh Tavakoli, Davud Mohammadpur, Javad Salimi Sartakhti and Mohammad Hossein Manshaei
Math. Comput. Appl. 2025, 30(6), 134; https://doi.org/10.3390/mca30060134 - 5 Dec 2025
Cited by 1 | Viewed by 562
Abstract
In this paper, we present an integrative framework based on Evolutionary Stackelberg Game Theory to model the strategic interaction between a physician, acting as a rational leader, and a heterogeneous population of treatment-sensitive and treatment-resistant breast cancer cells. The model incorporates ecological competition, [...] Read more.
In this paper, we present an integrative framework based on Evolutionary Stackelberg Game Theory to model the strategic interaction between a physician, acting as a rational leader, and a heterogeneous population of treatment-sensitive and treatment-resistant breast cancer cells. The model incorporates ecological competition, evolutionary adaptation, and spatial heterogeneity, enabling prediction of tumor progression under clinically relevant treatment protocols. Using tumor volume data obtained from breast cancer-bearing mice treated with Capecitabine and Gemcitabine, we estimated treatment and subject-specific parameters via the GEKKO optimization package in Python. Benchmarking against classical tumor growth models (Exponential, Logistic, and Gompertz) showed that while classical models capture monotonic growth, they fail to reproduce complex, non-monotonic behaviors such as treatment-induced regression, rebound, and phenotypic switching. The game-theoretic approach achieved superior alignment with experimental data across Maximum Tolerated Dose, Dose-Modulation Adaptive Therapy, and Intermittent Adaptive Therapy protocols. To enhance adaptability, we integrated reinforcement learning (RL) for both single-agent and combination chemotherapy. The RL agent learned dosing policies that maximized tumor regression while minimizing cumulative drug exposure and resistance, with combination therapy exploiting dose diversification to improve control without exceeding total dose budgets. Incorporating reaction diffusion equations allowed the model to capture spatial dispersal of sensitive (cooperative) and resistant (defector) phenotypes, revealing that spatially aware adaptive strategies more effectively suppress resistant clones than non-spatial approaches. These results demonstrate that evolutionarily informed, spatially explicit, and computationally optimized strategies can outperform conventional fixed-dose regimens in reducing resistance, lowering toxicity, and improving efficacy. This framework offers a biologically interpretable tool for guiding evolution-aware, patient-tailored cancer therapies toward improved long-term outcomes. Full article
(This article belongs to the Special Issue Feature Papers in Mathematical and Computational Applications 2025)
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24 pages, 3857 KB  
Article
Soil Ca2SiO4 Supplying Increases Drought Tolerance of Young Arabica Coffee Plants
by Miroslava Rakocevic and Rafael Vasconcelos Ribeiro
Plants 2025, 14(23), 3666; https://doi.org/10.3390/plants14233666 - 2 Dec 2025
Viewed by 500
Abstract
Silicon (Si) may benefit the growth and physiology of various cultivated species, especially under stress conditions. Here, we hypothesized that soil Si supplying as Ca2SiO4 would increase the drought tolerance and water use efficiency of young Coffea arabica L. (Arabica [...] Read more.
Silicon (Si) may benefit the growth and physiology of various cultivated species, especially under stress conditions. Here, we hypothesized that soil Si supplying as Ca2SiO4 would increase the drought tolerance and water use efficiency of young Coffea arabica L. (Arabica coffee) plants, by maintaining shoot water status and photosynthesis under low water availability. To test such a hypothesis, morphological and physiological (leaf water potential, leaf gas exchange, photochemical activity, chlorophyll content) traits of coffee plants were evaluated under varying soil Ca2SiO4 applications (0, 3000, 6000 kg ha−1) and water availability. The chemical composition of plant tissues was evaluated under well-watered conditions after six months of Ca2SiO4 application, with fertilized plants showing higher concentrations of Ca (leaves and roots) and B (all plant organs) as compared to plants not supplied with Ca2SiO4 (control treatment). As there were no changes in Si concentration in plant organs under Ca2SiO4 application, our data indicate that the coffee species is a Si non-accumulator, or at least the cultivar ‘Catuaí Vermelho’ evaluated herein. Additionally, the photosynthetic capacity of coffee plants increased with 6000 kg Ca2SiO4 ha−1 compared to the control under well-watered conditions, as given by increases in gross and net photosynthesis under light saturation, light saturation point, maximum RuBisCO carboxylation rate, maximum electron transport-dependent RuBP regeneration, and maximum rate of triose phosphate use. Such photosynthetic improvements underlined high leaf CO2 assimilation, transpiration, carboxylation efficiency, and chlorophyll content in plants grown under Si supplying and well-watered conditions. The negative impact of water deficit on leaf gas exchange was alleviated by Ca2SiO4 application, but the instantaneous water use efficiency was maintained as similar in both water regimes, as expected for Si non-accumulator species. Morphologically, coffee stem diameter was increased under Ca2SiO4 application, regardless of water regime. In conclusion, our data revealed that high Ca2SiO4 doses benefit coffee performance and also suggest that the use of steel slag—an industrial byproduct rich in Ca2SiO4—can be considered as a sustainable practice for residue recycling in agriculture while improving C. arabica growth and physiology under varying water availability. Full article
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29 pages, 941 KB  
Review
Nanoparticles Used for the Delivery of RNAi-Based Therapeutics
by Tianrui Ren, Liang Ma, Ping Fu and Chuyue Zhang
Pharmaceutics 2025, 17(11), 1502; https://doi.org/10.3390/pharmaceutics17111502 - 20 Nov 2025
Cited by 1 | Viewed by 1880
Abstract
RNA interference (RNAi) offers programmable, sequence-specific silencing via small interfering RNA (siRNA) and microRNA (miRNA), but clinical translation hinges on overcoming instability, immunogenicity, and inefficient endosomal escape. This review synthesizes advances in non-viral nanocarriers—liposomes, polymeric nanoparticles, and extracellular vesicles (EVs)—that stabilize nucleic acids, [...] Read more.
RNA interference (RNAi) offers programmable, sequence-specific silencing via small interfering RNA (siRNA) and microRNA (miRNA), but clinical translation hinges on overcoming instability, immunogenicity, and inefficient endosomal escape. This review synthesizes advances in non-viral nanocarriers—liposomes, polymeric nanoparticles, and extracellular vesicles (EVs)—that stabilize nucleic acids, tune biodistribution, and enable organ- and cell-selective delivery. We highlight design levers that now define the field: ligand-guided targeting, stimuli-responsive release, biomimicry and endogenous carriers, and rational co-delivery with small molecules. Across major disease areas—cancer and cardiovascular, respiratory, and urological disorders—these platforms achieve tissue-selective uptake (e.g., macrophages, endothelium, and myocardium), traverse physiological barriers (including the blood–brain barrier and fibrotic stroma), and remodel hostile microenvironments or immune programs to enhance efficacy while maintaining favorable safety profiles. Early clinical studies reflect this diversity, spanning targeted nanoparticles, local drug depots, exosome and cellular carriers, and inhaled formulations, e.g., and converge on core phase-I endpoints (safety, maximum tolerated dose, pharmacokinetics/pharmacodynamics, and early activity). Looking ahead, priorities include good manufacturing practice scale, consistent manufacture—especially for EVs; more efficient loading and cargo control; improved endosomal escape and biodistribution; and rigorous, long-term safety evaluation with standardized, head-to-head benchmarking. Emerging directions such as in vivo EVs biogenesis, theragnostic integration, and data-driven formulation discovery are poised to accelerate translation. Collectively, nanoparticle-enabled RNAi has matured into a versatile, clinically relevant toolkit for precise gene silencing, positioning the field to deliver next-generation therapies across diverse indications. Full article
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12 pages, 1230 KB  
Article
Relative Efficacy of Alirocumab, Evolocumab, Inclisiran, and Bempedoic Acid on Lipids in Patients with Cardiovascular Disease or Familial Hypercholesterolaemia
by Sophia Khattak, Antonio Ochoa-Ferraro, Nazish Khan, Sudhakar George, Sohail Q. Khan, Jonathan N. Townend, Charlotte Dawson and Mark R. Thomas
J. Clin. Med. 2025, 14(22), 7946; https://doi.org/10.3390/jcm14227946 - 10 Nov 2025
Viewed by 2504
Abstract
Background: Lowering lipid levels after an acute coronary syndrome is critical for preventing recurrent adverse cardiovascular events. Multiple medications are now available, but there is limited evidence comparing how frequently they lead to the achievement of guideline-recommended lipid targets. Methods and Results: This [...] Read more.
Background: Lowering lipid levels after an acute coronary syndrome is critical for preventing recurrent adverse cardiovascular events. Multiple medications are now available, but there is limited evidence comparing how frequently they lead to the achievement of guideline-recommended lipid targets. Methods and Results: This observational study evaluated the impact of novel lipid-lowering therapies (alirocumab, evolocumab, inclisiran, and bempedoic acid) in patients with a history of atherosclerotic cardiovascular disease or familial hypercholesterolaemia treated with maximum-tolerated doses of high-intensity statin therapy with or without ezetimibe. Our primary assessment was the achievement of LDL-C below 1.4 mmol/L as per the European Society of Cardiology guidelines. The study comprised of 256 patients. Reduction in LDL-C was greatest with alirocumab and evolocumab, achieving a reduction of 62% (95% confidence interval [CI], 51 to 93; p < 0.001) and 58% (95% CI, 47 to 88; p < 0.001) after 12 months, respectively. This was followed by inclisiran with a reduction of 47% (95% CI, 37 to 78; p < 0.001) and bempedoic acid with a reduction of 36% (95% CI, 22 to 69; p < 0.001). Patients treated with alirocumab and evolocumab started from a higher baseline LDL-C than inclisiran, due to the higher LDL threshold required for initiation of alirocumab and evolocumab in the UK. Despite this, inclisiran, evolocumab, and alirocumab were all associated with similar proportions of patients achieving LDL targets: 35%, 42%, and 37% of patients achieved a guideline-recommended LDL-C target of <1.4 mmol/L. Patients with a baseline LDL-C > 4 mmol/L were more likely to reach the ESC target when treated with alirocumab or evolocumab compared to inclisiran, with results of 33.3% vs. 24.1% (p = 0.016) and 35.7% vs. 24.1% (p = 0.05). Conclusions: Alirocumab and evolocumab were associated with the greatest reductions in LDL-C, followed by inclisiran and bempedoic acid. Overall, alirocumab, evolocumab, and inclisiran led to approximately 40% of patients reaching ESC targets for LDL-C. In patients with a baseline LDL-C > 4 mmol/L, significantly more patients achieved LDL-C targets when treated with alirocumab or evolocumab compared to inclisiran. Strength and limitations: This was the first study to comprehensively compare the efficacy of novel lipid-lowering therapies in achieving guideline-recommended LDL targets within a high-risk cardiovascular population. The sample size was relatively small, especially for patients treated with bempedoic acid. Full article
(This article belongs to the Section Vascular Medicine)
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41 pages, 4538 KB  
Article
Polyprenylated Acylphloroglucinols from Hypericum rochelii and Hypericum olympicum—Cytotoxic Effects on Non-Tumorigenic Cell Lines and Antibacterial Potential
by Yana Ilieva, Maya M. Zaharieva, Lyudmila Dimitrova, Mila D. Kaleva, Teodor Marinov, Lili I. Dobreva, Tanya Chan Kim, Zlatina Kokanova-Nedialkova, Iliyan Trayanov, Sofia Titorenkova, Stanislava S. Boyadzhieva, Svetla Danova, Paraskev Nedialkov and Hristo Najdenski
Pharmaceuticals 2025, 18(10), 1591; https://doi.org/10.3390/ph18101591 - 21 Oct 2025
Viewed by 780
Abstract
Objectives: Research on the antimicrobial effect of Hypericum plant constituents is very rarely accompanied by studies of the cytotoxic effect on cell lines. In the current study, besides microbiological tests, an investigation of the cytotoxicity of Hypericum active ingredients on five non-tumorigenic [...] Read more.
Objectives: Research on the antimicrobial effect of Hypericum plant constituents is very rarely accompanied by studies of the cytotoxic effect on cell lines. In the current study, besides microbiological tests, an investigation of the cytotoxicity of Hypericum active ingredients on five non-tumorigenic cell lines, as well as research into the effect on other factors of host homeostasis, was performed. Methods: The main methods applied included an MTT assay, the broth microdilution method (BMD), real-time PCR, live cell imaging with Hoechst dye, Western blot, an enzyme-linked immunosorbent assay (ELISA), and skin irritation test on rabbits. Results: The mean inhibitory concentrations (IC50) of six selected agents—previously phytochemically characterized extracts and compounds—ranged from 0.63 to 48 µg/mL. Due to their strong antimicrobial effect and favorable cytotoxic profile, the extract RochC from Hypericum rochelii and the compound olympiforin B from Hypericum olympicum were selected for subsequent studies at their previously determined minimum inhibitory concentrations (MICs) against Staphylococcus aureus—0.625 and 1 µg/mL, respectively. These doses were lower than their IC50 values and the maximum tolerated concentrations (MTCs), according to ISO 10993-5, Annex C, for fibroblast cells, including a human gingival line. The MIC values of RochC and Olympiforin B against the cariogenic Streptococcus mutans were 6 and 3 µg/mL, respectively, values lower than the IC50 values of the gingival cells. Olympiforin B inhibited the gene expression of the staphylococcal biofilm-related genes icaA and icaD, while RochC induced icaA and had a versatile effect on icaD. The MIC values for lactobacilli strains were higher than for S. aureus. The phytoconstituents did not cause cytopathic effects or apoptosis in CCL-1 fibroblasts at 2 × MIC. However, the agents at 1 × MIC significantly induced Atg5 and Atg7, proteins related to autophagy. Cytochrome P450 was not induced in liver cells, with the exception of a dose of 2 × MIC of RochC. The agents did not irritate rabbit skin in vivo at a dose of even 10 × MIC. Conclusions: The extract and compound have potential for further pharmacological development. Full article
(This article belongs to the Section Medicinal Chemistry)
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15 pages, 603 KB  
Article
The Effectiveness of SBRT for Solitary or Synchronous Multiple Pulmonary Nodules Suspicious of Early-Stage Lung Cancer Without Pathological Confirmation
by Emese Csiki, Dóra Bölcskei, Márton Barabás, Kristóf Gál, Johanna Mikáczó, Szidónia Miklós, Krisztina Trási, Dóra Solymosi, Judit Papp, Mihály Simon and Árpád Kovács
Biomedicines 2025, 13(10), 2534; https://doi.org/10.3390/biomedicines13102534 - 17 Oct 2025
Viewed by 1294
Abstract
Background: Stereotactic body radiotherapy (SBRT) is an established curative modality for patients with early-stage non-small cell lung cancer (NSCLC) who are not candidates for surgery. In circumstances where neither surgical resection nor tissue sampling can be performed, SBRT may still be administered [...] Read more.
Background: Stereotactic body radiotherapy (SBRT) is an established curative modality for patients with early-stage non-small cell lung cancer (NSCLC) who are not candidates for surgery. In circumstances where neither surgical resection nor tissue sampling can be performed, SBRT may still be administered empirically, with accumulating evidence indicating excellent efficacy and safety. Objective: This single-institution retrospective study aimed to evaluate the clinical outcomes of SBRT for presumed malignant lung lesions, focusing on local control, survival, and treatment-related toxicity, and to compare these findings with published results in histologically confirmed NSCLC. Methods: Between 2018 and 2024, 80 cases with 85 pulmonary lesions received SBRT at the Department of Oncoradiology, University of Debrecen. All patients underwent comprehensive staging with chest CT and PET-CT, and treatment decisions were made by a multidisciplinary tumor board. Eligibility required the absence of other primary malignancies within 5 years. Treatment planning was based on 4D-CT imaging with internal target volume delineation across multiple respiratory phases. SBRT was delivered on linear accelerators in 4–8 fractions, to a total dose of 48–60 Gy, using volumetric-modulated arc therapy and daily image guidance with 4D cone-beam CT. Results: Most patients presented with solitary lesions, while several had synchronous or metachronous multiple lesions (maximum 3 lesions). The median age was 70.1 years, with 60% ECOG performance status 1. Median follow-up was 21 months. One- and two-year local control rates were 89.8% and 94.3%, respectively, with a 51.4% complete response rate at two years. Mean overall survival was 49.6 months. No grade ≥ 3 toxicities were observed. Conclusions: Empirical SBRT is a safe, well-tolerated, and highly effective treatment option in elderly, inoperable patients with presumed malignant lung lesions. Its favorable efficacy supports its broader use as a curative alternative when histological confirmation is not feasible. Full article
(This article belongs to the Special Issue Advances in Lung Cancer: From Bench to Bedside)
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29 pages, 959 KB  
Review
Metronomic Chemotherapy in Dogs and Cats: Mechanisms, Indications, and Clinical Perspectives
by Rafael Costa Bitencourt, Giovanna Gabrielle Cruvinel, Verônica Maria Teixeira de Castro Terrabuio, Laís Calazans Menescal Linhares, Guilherme Andraus Bispo, Letícia Abrahão Anai, Márcia Ferreira da Rosa Sobreira, Annelise Carla Camplesi, Andrigo Barboza De Nardi and Aureo Evangelista Santana
Cancers 2025, 17(20), 3318; https://doi.org/10.3390/cancers17203318 - 14 Oct 2025
Viewed by 4106
Abstract
Metronomic chemotherapy (MC) represents an emerging strategy in veterinary oncology which involves the continuous or regularly scheduled administration of low-dose chemotherapeutic agents. Unlike conventional protocols known as maximum tolerated dose chemotherapy (MTDC), MC aims to inhibit tumor angiogenesis, stimulate antitumor immune responses, and [...] Read more.
Metronomic chemotherapy (MC) represents an emerging strategy in veterinary oncology which involves the continuous or regularly scheduled administration of low-dose chemotherapeutic agents. Unlike conventional protocols known as maximum tolerated dose chemotherapy (MTDC), MC aims to inhibit tumor angiogenesis, stimulate antitumor immune responses, and delay or prevent the emergence of drug resistance. This review is structured into three key sections: the mechanisms of action of MC; its clinical indications in dogs and cats, particularly for advanced or treatment-resistant cancers; and reported outcomes regarding efficacy, safety, and tolerability. Additionally, we explore the growing interest in combining MC with other therapies, as well as the challenges and future directions for optimizing its use. Current evidence suggests that MC is a promising and well-tolerated option for managing various malignancies—such as carcinomas, sarcomas, and hemangiosarcomas—especially in patients who are not candidates for MTDC. Full article
(This article belongs to the Special Issue Metronomic Chemotherapy in Cancer Treatment)
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18 pages, 1132 KB  
Article
Characterization of Lactiplantibacillus paraplantarum HK-1 and GABA Synthesis Under Simulated Gastrointestinal Conditions
by Susana Castro-Seriche, Joaquin Alvarez-Norambuena, Paulina Lincoñir-Campos, Cristian Gutiérrez-Zamorano, Alvaro Ruiz-Garrido, Bruno Jerez-Angulo, Apolinaria García-Cancino and Alonso Jerez-Morales
Foods 2025, 14(19), 3345; https://doi.org/10.3390/foods14193345 - 26 Sep 2025
Cited by 1 | Viewed by 959
Abstract
Gamma-aminobutyric acid (GABA) is a bioactive amino acid with anti-inflammatory and neurotransmitter properties, yet limited information exists regarding its production by Lactiplantibacillus paraplantarum. We evaluated factors that influence GABA synthesis by L. paraplantarum HK-1 and assessed its production in vitro and under [...] Read more.
Gamma-aminobutyric acid (GABA) is a bioactive amino acid with anti-inflammatory and neurotransmitter properties, yet limited information exists regarding its production by Lactiplantibacillus paraplantarum. We evaluated factors that influence GABA synthesis by L. paraplantarum HK-1 and assessed its production in vitro and under simulated gastrointestinal conditions. GABA production was analyzed using HPLC with pre-column derivatization, gene expression was assessed through RT-qPCR, and probiotic characteristics were evaluated using standard microbiological methods. L. paraplantarum HK-1 demonstrated dose-dependent GABA production with monosodium glutamate (MSG) supplementation, achieving maximum levels at 500 mM MSG (161.1 µg/mL), which was significantly higher than those in other treatments (p < 0.01). A strong positive correlation was observed between MSG concentration and GABA production (r = 0.908, p = 0.002). Gene expression analysis revealed a 61.6-fold higher gadB expression at 500 mM MSG compared to 250 mM, though statistical significance with GABA production was not achieved (r = 0.741, p = 0.259). The strain exhibited appropriate probiotic characteristics including γ-hemolytic activity, bile salt tolerance, and acid resistance. Under simulated gastrointestinal conditions, maximum GABA production occurred in the distal colon (148.3 ± 19.0 µg/mL with probiotic vs. 7.2 ± 6.2 µg/mL control), with overall production significantly higher in probiotic-treated groups (p < 0.001). Overall, L. paraplantarum HK-1 produced GABA throughout gastrointestinal phases and showed traits consistent with probiotic use. These results position HK-1 as a promising GABA-producing candidate for functional food applications, pending in vivo validation. Full article
(This article belongs to the Section Food Microbiology)
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38 pages, 2445 KB  
Article
Optimal Control and Tumour Elimination by Maximisation of Patient Life Expectancy
by Byron D. E. Tzamarias, Annabelle Ballesta and Nigel John Burroughs
Mathematics 2025, 13(19), 3080; https://doi.org/10.3390/math13193080 - 25 Sep 2025
Viewed by 555
Abstract
We propose a life-expectancy pay-off function (LEP) for determining optimal cancer treatment within a control theory framework. The LEP averages life expectancy over all future outcomes, outcomes that are determined by key events during therapy such as tumour elimination (cure) and patient death [...] Read more.
We propose a life-expectancy pay-off function (LEP) for determining optimal cancer treatment within a control theory framework. The LEP averages life expectancy over all future outcomes, outcomes that are determined by key events during therapy such as tumour elimination (cure) and patient death (including treatment related mortality). We analyse this optimisation problem for tumours treated with chemotherapy using tumour growth models based on ordinary differential equations. To incorporate tumour elimination we draw on branching processes to compute the probability distribution of tumour population extinction. To demonstrate the approach, we apply the LEP framework to simplified one-compartment models of tumour growth that include three possible outcomes: cure, relapse, or death during treatment. Using Pontryagin’s maximum principle (PMP) we show that the best treatment strategies fall into three categories: (i) continuous treatment at the maximum tolerated dose (MTD), (ii) no treatment, or (iii) treat-and-stop therapy, where the drug is given at the MTD and then halted before the treatment (time) horizon. Optimal treatment strategies are independent of the time horizon unless the time horizon is too short to accommodate the most effective (treat-and-stop) therapy. For sufficiently long horizons, the optimal solution is either no treatment (when treatment yields no benefit) or treat-and-stop. Patients, thus, split into an untreatable class and a treatable class, with patient demographics, tumour size, tumour response, and drug toxicity determining whether a patient benefits from treatment. The LEP is in principle parametrisable from data, requiring estimation of the rates of each event and the associated life expectancy under that event. This makes the approach suitable for personalising cancer therapy based on tumour characteristics and patient-specific risk profiles. Full article
(This article belongs to the Section E3: Mathematical Biology)
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11 pages, 466 KB  
Review
Hypo-Fractionated Stereotactic Radiosurgery for the Management of Brain Metastases
by Stylianos Pikis, Georgios Mantziaris, Kimball Sheehan, Darrah Sheehan and Jason P. Sheehan
Cancers 2025, 17(18), 3026; https://doi.org/10.3390/cancers17183026 - 16 Sep 2025
Viewed by 2728
Abstract
The increasing prevalence of brain metastases in cancer patients due to longer life expectancy and improvements in neuroimaging highlights the need for effective local treatments. Despite advancements in systemic targeted therapies, their low blood–brain barrier (BBB) penetrance limits their intracranial efficacy. Stereotactic radiosurgery [...] Read more.
The increasing prevalence of brain metastases in cancer patients due to longer life expectancy and improvements in neuroimaging highlights the need for effective local treatments. Despite advancements in systemic targeted therapies, their low blood–brain barrier (BBB) penetrance limits their intracranial efficacy. Stereotactic radiosurgery (SRS) has largely supplanted whole-brain radiation therapy (WBRT) for patients with up to 10 brain lesions due to superior neurocognitive outcomes and high local control. While single-fraction SRS provides low radiation toxicity with smaller lesions, high-volume metastases necessitate doses above tolerance limits to achieve comparable local control. As tumor volume increases, the number of tumor cells also increases, requiring higher doses of radiation than the maximum tolerated doses reported in the RTOG 9005 study to achieve tumor control. Hypo-fractionated SRS (HySRS) permits the delivery of high radiation doses over 2–5 fractions, thus mitigating the risk of radiation toxicity while maintaining high local control. This review presents the available evidence and ongoing clinical trials on HySRS for the management of brain metastases. Full article
(This article belongs to the Special Issue Radiosurgery for Brain Tumors)
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13 pages, 781 KB  
Article
Retrospective Evaluation of Omalizumab Treatment Efficacy in Patients with Bullous Pemphigoid
by Nazlı Caf, Zafer Türkoğlu, Göknur Özaydın Yavuz, İrem Doğan, Sümeyye Nur Aydın, İkram Kevser Atilla and Hafize Uzun
J. Clin. Med. 2025, 14(18), 6382; https://doi.org/10.3390/jcm14186382 - 10 Sep 2025
Viewed by 818
Abstract
Background/Objectives: Bullous pemphigoid (BP) is a manageable condition, and the primary goal of treatment is to control the disease while minimizing the use of corticosteroids due to their potential side effects with long-term use. The primary aim of this study was to [...] Read more.
Background/Objectives: Bullous pemphigoid (BP) is a manageable condition, and the primary goal of treatment is to control the disease while minimizing the use of corticosteroids due to their potential side effects with long-term use. The primary aim of this study was to assess the effectiveness of omalizumab (OMZ) treatment in bullous pemphigoid patients using both objective and subjective indicators, including bullous pemphigoid disease area index (BPDAI) score, peripheral eosinophil count, serum total IgE level, systemic corticosteroid dosage, and pruritus severity (VAS pruritus). The secondary aim was to explore potential predictors of treatment response, such as baseline BPDAI, age, gender, lesion distribution, serum total IgE, peripheral eosinophil count, maximum and minimum corticosteroid dose, and comorbidities, as well as to evaluate the time to clinical response and corticosteroid tapering. Methods: This retrospective analysis included 25 BP patients treated with OMZ as add-on therapy to systemic corticosteroids between January 2023 and December 2024 at Health Sciences University, Başakşehir Çam and Sakura Training and Research Hospital, Dermatology and Venerology Clinic. No other systemic immunosuppressants were permitted. All patients were already receiving systemic corticosteroids at enrolment. This retrospective analysis included 25 BP patients receiving omalizumab (300 mg/4 weeks) as an add-on to systemic corticosteroids, initiated primarily for steroid-refractory disease and/or persistent, sleep-disrupting pruritus. Baseline was defined immediately before the first OMZ dose; assessments were performed at baseline and week 12. Clinical (BPDAI, VAS pruritus) and laboratory (eosinophil count, total IgE levels) parameters were assessed at baseline and week 12. Results: OMZ treatment significantly reduced disease severity, as evidenced by a mean decrease in the BPDAI score of 105.0 ± 48.9 (95% CI 84.8–125.2) compared to baseline (p < 0.001). Peripheral eosinophil count also decreased by 0.6 ± 0.3 (95% CI 0.4–0.7) after treatment (p < 0.001). Total serum IgE levels declined significantly in 92% of patients (95% CI 244.5–2171.3) compared to pretreatment (p < 0.001), although two patients (8%) showed an increase (202.0 ± 258.8) after OMZ treatment. OMZ treatment led to a mean systemic corticosteroid dose reduction of 37.0 ± 14.1 mg (95% CI 31.1–42.8 mg), with a median corticosteroid tapering time of 4 weeks (3.0–4.0). Additionally, pruritus severity, measured by pruritus VAS, decreased by 6.2 ± 1.4 (95% CI 5.6–6.7) following treatment (p < 0.001). OMZ was well tolerated, with no serious adverse events. Conclusions: Within a 12-week observation window, we observed improvements in disease activity and pruritus alongside reduced corticosteroid exposure. Given the retrospective, uncontrolled add-on design, these findings do not establish causality but support further prospective controlled evaluation of omalizumab as a steroid-sparing option. Importantly, OMZ treatment significantly reduced the mean corticosteroid dose, pruritus VAS score, total IgE levels, and eosinophil count, indicating therapeutic activity and supporting its use as an effective steroid-sparing option in the management of bullous pemphigoid. Full article
(This article belongs to the Section Dermatology)
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