Search Results (832)

Date palm (Phoenix dactylifera L.) is a vital crop cultivated primarily in developing regions, playing a strategic role in global food security through its significant contribution to nutrition, economy, and livelihoods. Global and regional production trends revealed increasing demand and expanded cultivation areas, underpinning the fruit’s importance in national food security policies and economic frameworks. The date fruit’s rich nutritional profile, encompassing carbohydrates, dietary fiber, minerals, and bioactive compounds, supports its status as a functional food with health benefits. Postharvest technologies and quality preservation strategies, including temperature-controlled storage, advanced drying, edible coatings, and emerging AI-driven monitoring systems, are critical to reducing losses and maintaining quality across diverse cultivars and maturity stages. Processing techniques such as drying, irradiation, and cold plasma distinctly influence sugar composition, texture, polyphenol retention, and sensory acceptance, with cultivar- and stage-specific responses guiding optimization efforts. The cold chain and innovative packaging solutions, including vacuum and modified atmosphere packaging, along with biopolymer-based edible coatings, enhance storage efficiency and microbial safety, though economic and practical constraints remain, especially for smallholders. Microbial contamination, a major challenge in date fruit storage and export, is addressed through integrated preservation approaches combining thermal, non-thermal, and biopreservative treatment. However, gaps in microbial safety data, mycotoxin evaluation, and regulatory harmonization hinder broader application. Date fruit derivatives such as flesh, syrup, seeds, press cake, pomace, and vinegar offer versatile functional roles across food systems. They improve nutritional value, sensory qualities, and shelf life in bakery, dairy, meat, and beverage products while supporting sustainable waste valorization. Emerging secondary derivatives like powders and extracts further expand the potential for clean-label, health-promoting applications. This comprehensive review underscores the need for multidisciplinary research and development to advance sustainable production, postharvest management, and value-added utilization of date palm fruits, fostering enhanced food security, economic benefits, and consumer health worldwide. Full article

By 2030, the world’s population is projected to reach 8.5 billion, posing significant challenges for food production. Traditional agriculture, which requires large amounts of water, soil, and energy, can contribute to the depletion of natural resources and environmental degradation. In this context, organic hydroponic systems emerge as a sustainable alternative, allowing for more efficient, controlled, and resilient production in the face of climate change. In this research, the physical development of romaine lettuce and the physicochemical parameters of the crop water are evaluated as a function of the number of daily recirculations. The crop variables are measured with the help of an intelligent control system, which allows the real-time monitoring of the process variables. The methodological approach is mixed: quantitative, for the recording of physicochemical variables, and qualitative, for the physical analysis of the crop throughout the process, With the experiments conducted it was found that the treatment with four daily recirculations promoted the most significant physiological growth of the plants. Despite having a pH of approximately five and dissolved oxygen of 6 mg/L, this treatment maintained adequate levels of TDS (2050 ppm) and hardness (1000 ppm), favoring the development of the crop. The treatments with less recirculation presented lower growth values. These results suggest that increased recirculation can optimize yields in floating-root hydroponic systems, addressing global food challenges from an environmentally responsible perspective. Full article

Background: Dentistry is undergoing a digital transformation driven by emerging technologies such as Artificial Intelligence (AI), Internet of Things (IoT), Digital Twins (DTs), and Large Language Models (LLMs). These advancements offer new paradigms in clinical diagnostics, patient monitoring, treatment planning, and medical education. However, integrating these technologies also raises critical questions around security, privacy, ethics, and trust. Objective: This review aims to provide a structured synthesis of the recent literature exploring AI, IoT, DTs, and LLMs in dentistry, with a specific focus on their application domains and the associated ethical, privacy, and security concerns. Methods: A comprehensive literature search was conducted across PubMed, IEEE Xplore, and SpringerLink using a custom Boolean query string targeting publications from 2020 to 2025. Articles were screened based on defined inclusion and exclusion criteria. In total, 146 peer-reviewed articles and 18 technology platforms were selected. Each article was critically evaluated and categorized by technology domain, application type, evaluation metrics, and ethical considerations. Results: AI-based diagnostic systems and LLM-driven patient support tools were the most prominent technologies, primarily applied in image analysis, decision-making, and health communication. While numerous studies reported high performance, significant methodological gaps exist in evaluation design, sample size, and real-world validation. Ethical and privacy concerns were mentioned frequently, but were substantively addressed in only a few works. Notably, IoT and Digital Twin implementations remained largely conceptual or in pilot stages, highlighting a technology gap in dental deployment. Conclusions: The review identifies significant potential for converged intelligent dental systems but also reveals gaps in integration, security, ethical frameworks, and clinical validation. Future work must prioritize cross-disciplinary development, transparency, and regulatory alignment to realize responsible and patient-centered digital transformation in dentistry. Full article

Biomaterials modified by antibacterial substances, including nanoparticles, open new opportunities for the effective treatment of infected wounds. Unfortunately, most publications focused only on experiments in vitro, with limited understanding of their potential for the clinic. This study evaluates the effectiveness in vivo of electrospun chitosan/polylactic acid (Ch/PLA) membranes enriched with silver nanoparticles (AgNPs) for purulent wound treatment. The composite biomaterial integrates chitosan’s biocompatibility and antimicrobial activity with PLA’s structural integrity, while AgNPs enhance antibacterial efficacy against major wound pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia aureus. A full-thickness purulent wound model was established in a rat model, and the animals were divided into three treatment groups: (i) Ch/PLA, (ii) Ch/PLA-AgNPs, and (iii) PLA-chlorhexidine (control). Wound healing was monitored over 21 days through macroscopic evaluation, histology, immunohistochemistry, and microbiological analysis. The Ch/PLA-AgNPs membranes significantly reduced bacterial colonization within 4–6 days, promoted granulation tissue formation, and accelerated epithelialization compared to the non-modified Ch/PLA scaffold. By day 15, complete wound closure was observed in the Ch/PLA-AgNPs group, comparable to PLA-chlorhexidine-treated wounds. Immunohistochemical analysis revealed a controlled inflammatory response with a balanced macrophage M1/M2 transition, supporting efficient tissue regeneration. Furthermore, systemic toxicity assessments indicated no significant adverse effects on internal organs. These findings demonstrate that electrospun Ch/PLA-AgNPs membranes effectively accelerate purulent wound healing by combining antimicrobial protection with biocompatible tissue support. This innovative approach presents a promising alternative to conventional wound dressings and paves the way for clinical applications in managing infected wounds. Full article

Purpose: This study evaluates the combined prognostic value of the apparent diffusion coefficient (ADC) from multiparametric MRI (mpMRI) and prostate-specific antigen (PSA) levels at 6 months post-radiotherapy (RT) in assessing treatment response in prostate cancer patients treated with RT and androgen deprivation therapy (ADT). Materials and Methods: All prostate cancer patients classified as unfavorable intermediate-risk, high-risk, or very high-risk, according to NCCN criteria, who received ADT and RT between 2008 and 2019 and underwent mpMRI and PSA testing 6 months after RT were included. Patients were stratified into three profiles based on threshold PSA (≤ vs. >0.1 ng/mL) levels and ADC (≤ vs. >1.24 × 10⁻³ mm²/s) values: Profile A: low PSA and high ADC; Profile B: either high PSA/high ADC or low ADC/low PSA; Profile C: high PSA and low ADC. Ten-year progression-free survival (PFS) and metastasis-free survival (MFS) were analyzed using Kaplan–Meier curves and multivariate Cox regression. Results: Ninety-eight consecutive patients were retrospectively analyzed, of which 73 (74.5%) were high-risk. After a mean follow-up of 95.3 months, 19 (19.39%) patients progressed. Ten-year PFS, MFS, and overall survival were 75.6%, 87%, and 89.5% respectively. Progression events were 9.1% (Profile A), 29.4% (Profile B), and 44.4% (Profile C). Eight-year PFS was 89.2% (profile A), 70.9% (profile B) HR: 3.021 (CI 95%: 1.031–8.849; p = 0.044) and 44.4% (profile C) HR: 6.145 (CI 95%: 1.645–22.955; p = 0.007). Multivariate analysis confirmed a higher risk of progression in patients from profile B with HR: 3.958 (CI 95%: 1.18–13.191; p = 0.025) and profile C with HR: 41.945 (CI 95%: 5.000–351.761; p < 0.001) compared to patients from profile A. Metastasis events were 5.5% (Profile A), 8.8% (Profile B), and 33.3% (Profile C). Eight-year MFS was 100% (profile A), 89.6% (profile B) HR: 1.373 (CI 95%: 0.277–6.811; p = 0.689), and 74.1% (profile C) HR: 5.566 (CI 95%: 1.119–27.692; p = 0.047). Conclusions: The integration of PSA response and ADC measures at 6 months post-RT provides an effective combined prognostic factor to identify patients at higher risk of relapse, supporting closer monitoring and potential treatment intensification. Full article

Objective: To evaluate patient perceptions regarding ultrasound-guided embryo transfer, visualisation of embryos prior to transfer, and continuity of care with the same physician during in vitro fertilisation (IVF) treatments. Setting: Between January and September 2023, this study was conducted at the IVF MOMO’ FertiLIFE centre in Bisceglie, Italy. Design: Descriptive and observational study based on an anonymous survey administered to IVF patients at the time of embryo transfer. The goal was to assess the subjective emotional and psychological response to selected procedural elements of the embryo transfer process. Participants: Out of 284 distributed questionnaires, 200 were included in the final analysis. Inclusion required fully completed responses. Questionnaires with incomplete, unclear answers or patient refusal were excluded. The study group was compared with the general IVF patient population treated at the centre over the past 5 years to ensure representativeness. Methods: Patients completed a structured questionnaire using a five-point Likert scale. Statistical analysis included descriptive statistics, Spearman’s rank correlation, Friedman test, and exploratory factor analysis. Ethical approval was obtained (CELFer no. 07/2021), and all participants provided written informed consent. Results: The majority of patients reported a heightened sense of calm and reassurance during ultrasound-guided embryo transfer. Viewing embryos on a monitor before transfer was also positively perceived. A strong preference emerged for continuity of care with the same physician throughout the IVF process. While this study did not assess objective stress levels or clinical outcomes, the findings highlight the psychological comfort associated with these patient-centred practices. Limitations: This single-centre study is based on self-reported data and lacks objective assessments of psychological well-being. Therefore, results reflect personal perceptions rather than measurable clinical outcomes. Broader, multicentre research using validated psychological tools is needed to confirm and expand these findings. Furthermore, the questionnaire used in this study was developed internally and not validated externally with standardised psychometric instruments. Conclusions: This study provides insight into IVF patients’ subjective experiences, emphasising the perceived emotional benefits of specific procedural and relational aspects of care. These findings support the integration of patient-centred strategies—such as visual engagement and physician continuity—into routine IVF practice to enhance overall patient well-being. Full article

Tuberculosis remains a serious infectious disease that causes over 1.3 million deaths annually. Following the COVID-19 pandemic, the global incidence of tuberculosis has increased to 10.8 million cases. Pregnant women represent a particularly vulnerable population requiring tailored approaches to the prevention, diagnosis, and treatment of tuberculosis. SARS-CoV-2 infection may have impacted existing clinical protocols. Implementing updated methods of tuberculosis prevention, diagnosis, and treatment in pregnant women could help reduce adverse maternal and fetal outcomes. The aim of this review was to explore potential modifications in tuberculosis management among pregnant women in the post-COVID-19 era, including co-infection with SARS-CoV-2. Methods: A review was conducted, incorporating a systematic literature search across major international databases, including Medline, PubMed, Web of Science, Scopus, and Google Scholar. The search covered publications released between December 2019 and September 2024 and used targeted keywords such as “COVID-19” OR “SARS-CoV-2”, “tuberculosis” OR “TB” OR “latent tuberculosis infection” OR “pulmonary tuberculosis”, and “pregnancy” OR “pregnant women”. Results: Pregnant women living with HIV are at increased risk of developing tuberculosis, which can negatively affect both maternal and perinatal outcomes. Screening for tuberculosis is recommended for all HIV-positive pregnant women, even in the absence of clinical symptoms. Notably, immunological testing before and during pregnancy facilitates the timely and safe detection of tuberculosis infection, enabling preventive and therapeutic interventions during any stage of gestation and the early postpartum period, for the benefit of both mother and child. Drug–drug interactions play a significant role in tuberculosis management, both among anti-tuberculosis agents and with medications for comorbid conditions. Current knowledge of the pharmacokinetics and pharmacodynamics of antituberculosis agents, coupled with therapeutic drug monitoring, supports the development of individualized and effective treatment regimens, which are particularly critical for pregnant patients. Recommendations for managing tuberculosis in pregnant women after COVID-19 infection include measuring D-dimer levels, performing echocardiography, and consulting cardiologists to prevent treatment-related complications. Conclusions: Pregnant women represent a distinct subgroup of tuberculosis patients requiring individualized management. Changes observed in tuberculosis progression and treatment responses in pregnant women before and after SARS-CoV-2 infection should inform therapeutic choices, especially in cases of drug-resistant tuberculosis treated with bedaquiline. COVID-19 has been associated with increased cardiovascular risk, which may heighten the likelihood of adverse drug reactions in this population, especially given the limited therapeutic options. Further research is required to assess the long-term outcomes of latent tuberculosis infection in pregnant women and to evaluate the safety and efficacy of novel regimens for drug-resistant TB during pregnancy. Full article

Background: Despite improvements in medical therapy, heart failure with reduced ejection fraction (HFrEF) is a major burden on the healthcare system and remains a leading cause of death with a 5-year mortality rate of more than 60%. Novel therapeutic agents such as angiotensin-receptor-neprilysin-inhibitors (ARNIs) lead to significant improvement in clinical outcomes. Optimal therapy monitoring under these novel drugs is crucial for improving the outcome. In this trial, the diagnostic potential of four novel cardiovascular biomarkers—GDF-15, sST2, H-FABP, and suPAR—was evaluated during follow-up in patients with HFrEF. Methods: In this prospective cohort pilot study, 70 patients with HFrEF with ischemic (n = 34) and non-ischemic (n = 36) origin were included. All included patients were on a stable treatment regimen and in a non-decompensated state. The clinical parameters NYHA class, LVEF, MPI/Tei index and ESC Score 2 and the laboratory parameters sST2 (remodeling, inflammation), GDF-15 (remodeling, inflammation), H-FABP (subclinical ischemia and ischemia), suPAR (remodeling, inflammation) and NT-proBNP were assessed before ARNI therapy initiation and at 3 to 6 months at follow-up. Before starting ARNI therapy with sacubitril/valsartan patients had stable and well-established heart failure therapy. Results: There was a sufficient response to therapy with significant improvement in ejection fraction from 29.9% to 38.5% (p < 0.001) and a significant decrease in NT-proBNP from 1402 pg/mL to 572.0 pg/mL (p = 0.003). Interestingly, along with that, a significant increase in sST2 levels from 9602 pg/mL to 12,001 pg/mL (p = 0.039) but no significant change in H-FABP (p = 0.397), GDF-15 (p = 0.382) or suPAR (p = 0.328) were observed. Furthermore, the baseline sST2 level correlated with the risk of cardiovascular events calculated with the ESC Score 2 and the GDF15 level at follow-up correlated with the right ventricular global function, assessed with the MPI/Tei index and this correlation persisted after correction for confounders (r = 0.323, p = 0.039; r = 0.504, p = 0.011). Conclusions: The novel biomarker sST2 but not H-FABP, GDF-15 and suPAR was significantly affected by medical therapy with ARNIs. Monitoring sST2 might offer new opportunities for therapy guidance and disease management. However, these results are hypothesis generating and should be interpreted with caution, given the pilot nature of this study. Full article

Urban water, defined as water not used for agriculture or to support natural ecosystems, is increasingly impacted by anthropogenic pollution. Among the key concerns are emerging contaminants (ECs), a diverse group of largely unregulated chemical compounds that pose growing threats to both water and the life it supports. This review critically examines the challenges associated with the presence of ECs in urban water through two complementary approaches that together offer both scientific and policy-oriented insights. The first approach focuses on evaluating the difficulties in classifying, characterizing, detecting, monitoring, enforcing policies, and assessing the risks of ECs. The second approach focuses on assessing whether current efforts in research, public awareness, regulation, treatment, recycling, and international collaboration align with the United Nations Sustainable Development Goals (SDGs), particularly SDG 6 (clean water and sanitation), SDG 11 (sustainable cities and communities), and SDG 12 (responsible consumption and production). Current efforts to address the challenges posed by ECs and to achieve SDG targets remain insufficient, particularly in the areas of treatment and recycling. Globally, only 56% of household wastewater is treated safely, and industrial wastewater treatment in low-income countries remains severely lacking, with coverage under 30%. Globally, the effective management of ECs is hindered by outdated and inadequate treatment infrastructure, low recycling rates, and the technical complexity of handling multi-contaminant waste streams. In developing regions, these challenges are compounded by weak regulatory enforcement and limited public awareness. To effectively address ECs in urban water and fully meet the SDG targets, more integrated and globally coordinated efforts are necessary. Full article

Medullary thyroid carcinoma (MTC) is a rare (~2–5% of all thyroid cancers) neuroendocrine thyroid malignancy originating from parafollicular C-cells of the thyroid gland with variable biological behavior and potential for early metastasis. Diagnosis, staging, and surveillance are heavily reliant on circulating biomarkers. We aimed to provide a comprehensive overview of circulating biomarkers in the management of MTC and propose an integrated, evidence-based algorithm to guide clinical decision-making using both established and emerging biomarkers. This is a narrative review on the evolving landscape of biomarker-driven management in MTC with emphasis on analytical advancements, clinical applications, and the prognostic implications of individual and combined biomarkers. Calcitonin remains the cornerstone biomarker for MTC, and new generation immunoassays have addressed several pre-analytical and analytical challenges such as pre-analytical degradation, inter-assay variability, and biological confounders. Procalcitonin (ProCT) has emerged as a stable and less interference-prone alternative or adjunct to calcitonin, which is particularly useful in cases with indeterminate calcitonin levels. Carcinoembryonic antigen (CEA) remains a useful complementary biomarker often correlating with aggressive behavior, advanced disease, and distant metastases. Kinetic evaluation (doubling times) of calcitonin and CEA offers independent prognostic information values and those < 6 months are associated with poor survival, whereas those > 2 years suggest favorable outcomes. Newer biomarkers such as pro-gastrin-releasing peptide (ProGRP) and carbohydrate antigen 19-9 (CA19-9) show potential in monitoring advanced disease and response to therapy. Their role is still under investigation but appears promising, particularly when used in conjunction with calcitonin and CEA. Our work advances a comprehensive and clinically pragmatic framework for the management of MTC by integrating established and emerging biomarkers with evidence-based algorithms, offering greater diagnostic precision, more reliable prognostic stratification, and improved personalization of follow-up and treatment strategies. Full article

Background/Objectives: Chronic hepatitis C virus (HCV) infection is associated with a wide spectrum of extrahepatic manifestations, involving the immune, dermatologic, endocrine, vascular, and neuropsychiatric systems. Among these, mixed cryoglobulinemic vasculitis (CryoVas) remains one of the most clinically relevant complications. This work aims to provide a structured overview of HCV-related extrahepatic conditions and to analyze the clinical and virological outcomes of direct-acting antivirals (DAAs) in CryoVas patients. Methods: We first categorized and reviewed extrahepatic manifestations of HCV across five major domains: immune, inflammatory/metabolic/vascular, dermatological, thyroid, and neuropsychiatric. Subsequently, we conducted a comparative analysis of five clinical studies evaluating the impact of DAA therapy in patients with CryoVas. Data on demographics, clinical symptoms, treatment regimens, sustained virological response, and clinical response were extracted and summarized. Results: HCV was found to be associated with numerous extrahepatic conditions, including mixed cryoglobulinemia, non-Hodgkin lymphoma, autoimmune thyroiditis, insulin resistance, and neurocognitive symptoms. In the CryoVas subgroup analysis, virological response rates were uniformly high (88.9–100%), but clinical remission varied significantly. Complete response ranged from 39% to 90%, highlighting a discrepancy between viral eradication and extrahepatic symptom resolution. These findings underscore the need for individualized follow-up and further investigation into persistent immunological dysfunction post-sustained virological response (SVR). However, clinical outcomes were more variable: complete response (CR) varied between 39% and 90%, partial response (PR) ranged from 4% to 42%, and no response (NR) was reported in 0% to 40% of cases. Although significant improvement in key manifestations such as purpura, arthralgia, and neuropathy was frequently observed, a subset of patients continued to exhibit residual or refractory symptoms despite achieving SVR. Conclusions: HCV infection exerts multisystemic effects that extend beyond liver pathology. While DAAs offer near-universal virological clearance, the heterogeneous clinical response in CryoVas underscores the need for closer monitoring of extrahepatic outcomes. Future research should assess whether combining DAAs with immunomodulatory strategies can improve symptom control and long-term outcomes in patients with severe or refractory CryoVas. Full article

Background and Objectives: Periodontitis is a chronic inflammatory disease that leads to progressive destruction of periodontal tissues and remains a significant global health burden. While conventional therapies such as scaling and root planning offer short-term improvements, they often fall short in maintaining long-term microbial control, underscoring the need for adjunctive strategies. This study evaluated the clinical and microbiological effects of a novel essential oil (EO)-based gel—SmartGel OV—formulated with Origanum vulgare. Materials and Methods: Thirty adults with periodontitis were enrolled in a 4-month observational study, during which SmartGel OV was applied daily via gingival massage. Clinical outcomes and bacterial profiles were assessed through probing measurements and real-time PCR analysis. Additionally, a pilot AI-based tool was explored as a supplemental method to monitor inflammation progression through intraoral images. Results: Significant reductions were observed in Fusobacterium nucleatum and Capnocytophaga spp., accompanied by improvements in clinical markers, including probing depth, bleeding on probing, and plaque index. The AI framework successfully identified visual inflammation changes and supported early detection of non-responsiveness. Conclusions: SmartGel OV demonstrates promise as a natural adjunctive treatment for periodontitis and AI monitoring was included as an exploratory secondary tool to assess feasibility for future remote tracking. Full article

The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase (TPMT) was initially the primary focus, the discovery of nudix hydrolase 15 (NUDT15) appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of NUDT15 pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of NUDT15 in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated NUDT15 variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that NUDT15 genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, NUDT15 pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines. Full article

Background/Objectives: The advent of tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), achieving survival rates near those of the general population. Despite this success, prolonged therapy presents challenges, including physical, emotional, and financial burdens. Treatment-free remission (TFR), defined as sustained deep molecular response (DMR) after discontinuing TKIs, has emerged as a viable clinical goal. This study evaluates real-world data from the Canary Islands Registry of CML (RCLMC) to explore outcomes, predictors, and the feasibility of TFR. Methods: This retrospective observational study included 393 patients diagnosed with CML-CP between 2007 and 2023. Molecular response was monitored according to international guidelines. Survival probabilities were estimated using the Kaplan–Meier method. Logistic regression analysis was performed to identify predictors of molecular relapses after TKI discontinuation. Results: Of the 383 patients who received TKI treatment, 58.3% achieved molecular response grade 2 (MR2) (BCR-ABL1 ≤ 1%), 95.05% achieved MR2, and 50.5% reached MR4 within the first year. Of the 107 patients attempting TFR, 73.2% maintained remission at 36 months. Relapses occurred in 24 patients, all regaining molecular response upon reintroduction of TKIs. No cases of disease progression were observed. Conclusions: Our findings support the feasibility and safety of TFR in a real-world clinical setting for well-selected patients, with outcomes consistent with international studies. The study underscores the importance of molecular monitoring and patient-specific strategies to optimize outcomes. Full article

Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly understood. The effects of PTX (30 and 60 mg/kg) and NCTD (0.75 and 3 mg/kg), administered alone or in combination, in a DBA/2J murine B16-F1 melanoma model via intraperitoneal and intratumoral (IT) routes were evaluated. Tumor growth was monitored, and molecular analyses included RNA sequencing and immunofluorescence quantification of PI3K, AKT1, mTOR, ERBB2, BRAF, and MITF protein levels, and molecular docking simulations were performed. In the final stage of the experiment, combination therapy significantly reduced tumor volume compared to monotherapies, with the relative tumor volume decreasing from 18.1 ± 1.2 (SD) in the IT Control group to 0.6 ± 0.1 (SD) in the IT combination-treated group (n = 6 per group; p < 0.001). RNA-seq revealed over 3000 differentially expressed genes in intratumoral treatments, with enrichment in pathways related to oxidative stress, immune response, and translation regulation (KEGG and Reactome analyses). Minimal transcript-level changes were observed for BRAF and PI3K/AKT/mTOR genes; however, immunofluorescence showed reduced total and phosphorylated levels of PI3K, AKT1, mTOR, BRAF, and ERBB2. MITF protein levels and pigmentation increased, especially in PTX-treated groups, indicating enhanced melanocytic differentiation. Docking analyses predicted direct binding of both drugs to PI3K, AKT1, mTOR, and BRAF, with affinities ranging from −5.7 to −7.4 kcal/mol. The combination of PTX and NCTD suppresses melanoma progression through dual mechanisms: inhibition of PI3K/AKT/mTOR signaling and promotion of tumor cell differentiation. Full article