Search Results (451)

Melanoma is an aggressive skin cancer that continues to present major therapeutic difficulties. Although targeted drugs and immune checkpoint inhibitors have improved outcomes, resistance and treatment-related toxicity limit long-term benefit. In recent years, nanotechnology has been explored as a way to improve how drugs are delivered and to achieve greater tumor selectivity. Among available nanocarriers, liposomes have attracted particular interest. Built from lipid bilayers, they can carry both hydrophilic and hydrophobic molecules, and they are generally well tolerated. Importantly, their surface can be modified with polymers or targeting ligands to direct the carrier more selectively to melanoma cells. Experimental models show that liposomal drug formulations can increase concentrations in tumor tissue while limiting distribution to healthy organs. They have also been used successfully to combine different types of agents, chemotherapies, immunomodulators, and nucleic acids, within a single delivery system. These findings suggest genuine potential to address several of the shortcomings of conventional treatments. Although translation to the clinic is slowed by challenges such as formulation stability and large-scale production, liposomes represent an important step toward safer and more effective melanoma therapy within the broader field of oncologic nanotechnology. Full article

Background: Radspherin^® is a novel α-emitting radiopharmaceutical administered intraperitoneally following complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for peritoneal metastases. It delivers short-range radiation aimed at eliminating residual microscopic disease. This qualitative study explored how participants with colorectal cancer experienced participating in an early-phase clinical trial involving CRS-HIPEC followed by Radspherin^®. Materials and Methods: Semi-structured interviews were conducted with ten participants enrolled in a phase 1/2a trial involving CRS-HIPEC and intraperitoneal Radspherin^®. The analysis was guided by a phenomenological and interpretive approach using reflexive thematic analysis. Results: Participants expressed a strong sense of motivation and hope tied specifically to receiving Radspherin^®, which they perceived as an opportunity to improve their prognosis. Many also viewed participation as a contribution to future cancer research. None attributed complications or side effects to Radspherin^®. Clear and supportive verbal communication from healthcare professionals was highly valued, while the written information was described as overwhelming. Despite fears of recurrence, most participants remained optimistic about regaining a meaningful life. While experiences with Radspherin^® were largely positive, participants also described pain, fatigue, and prolonged recovery related to CRS-HIPEC, including ongoing functional and psychosocial challenges. Conclusions: Participants associated Radspherin^® with hope and a therapeutic benefit but did not link it to their adverse events. Their willingness to participate in experimental treatment was shaped by trust in clinicians, clear communication, and a desire for extended survival. However, the burden of CRS-HIPEC-related side effects underscores the importance of tailored follow-up and support. Full article

The rising global burden of colorectal cancer (CRC) has now positioned it as the third most common cancer worldwide. Chemotherapy regimens are known to disrupt the composition of the gut microbiota and lead to long-term health consequences for cancer patients. However, the alteration of gut microbiota by specific chemotherapeutic agents has been insufficiently explored until now. The purpose of this study was to assess changes in the gut microbiota following treatment with VERU-111 as a chemotherapy agent for the treatment of CRC. We thus performed a metagenomic study using 16S rRNA gene amplicon sequencing of fecal samples from different experimental groups in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine model of CRC. To predict the functional potential of microbial communities, we used the resulting 16S rRNA gene sequencing data to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We found that the administration of VERU-111 led to a restructured microbial community that was characterized by increased alpha and beta diversity. Compared to the mice treated with DSS alone, VERU-111 treatment significantly increased the relative abundance of several bacterial species, including Verrucomicrobiota species, Muribaculum intestinale, Alistipes finegoldii, Turicibacter, and the well-known gut-protective bacterial species Akkermansia muciniphila. The relative abundance of Ruminococcus, which is negatively correlated with immune checkpoint blockade therapy, was diminished following VERU-111 administration. Overall, this metagenomic study suggests that the microbial shift after administration of VERU-111 is associated with suppression of several metabolic and cancer-related pathways that might, at least in part, facilitate the suppression of CRC. These favorable shifts in gut microbiota suggest a novel therapeutic dimension of using VERU-111 to treat CRC and emphasize the need for further mechanistic exploration. Full article

Background: Oral mucositis (OM) is a significant complication after allogeneic stem cell transplantation. Objectives: This prospective, observational cohort study assessed the effectiveness of a polyvinylpyrrolidone-zinc gluconate and taurine (PVP-ZG-TAU) oral gel in managing OM. The primary objective was to determine whether the gel reduced the incidence and grade of OM and accelerated its resolution. Methods: The study enrolled 82 patients; 39 received the PVP-ZG-TAU gel, and 43 represented a historical control group. To prevent oral mucositis, both groups maintained good oral hygiene. In the experimental group, patients received three sprays of PVP-ZG-TAU gel, three times a day, from the start of conditioning chemotherapy until day +15 after allo-SCT. Results: In the PVP-ZG-TAU group, 79.1% patients experienced grade 1–2 OM and 20.9% experienced grade 3–4 OM. In the control group, 74.4% had grade 1–2 OM, and 25.6% had grade 3–4 OM (p = ns). Resolution occurred significantly faster in the PVP-ZG-TAU group, with an 84% resolution rate per 100 person-weeks, compared with 62% in the control group. Cox regression analysis revealed that treatment was associated with a 68% greater likelihood of earlier resolution (adjusted hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.03–2.74; p = 0.036). Conclusions: These findings suggest that PVP-ZG-TAU can reduce OM duration and serve as a supportive intervention for allo-SCT patients. Full article

Objective: Identifying biomarkers that predict metastatic potential or guide treatment selection is critical for improving breast cancer (BC) management. Previously, we established the Mitotic Network Activity Index (MNAI) as a prognostic marker in BC. Here, we bioinformatically and experimentally evaluated MNAI as a biomarker for metastasis risk and therapeutic response. Methods: We used Kaplan–Meier and Cox proportional hazard regression analyses to assess the association between MNAI and distant metastasis-free survival (DMFS) across 14 published BC datasets. A total of 16 publicly available clinical trial datasets, including the I-SPY trials, were used to evaluate the predictive value of MNAI for treatment response. Additionally, wound-healing and transmembrane assays were conducted to determine the effects of PLK1, CHEK1, and BUB1 inhibition on BC cell migration and invasion. Results: High MNAI levels were strongly associated with shorter DMFS. Multivariate analysis further confirmed MNAI as an independent risk factor for DMFS, beyond estrogen receptor status and PAM50-based molecular subtypes. Functionally, pharmacologic disruption of the mitotic network using PLK1, CHEK1, or BUB1 inhibitors significantly reduced cell migration and invasion in MDA-MB-231 and BT-549 BC cell lines. Moreover, BC cells with high MNAI increased sensitivity to microtubule-targeting agents such as docetaxel, paclitaxel, and ixabepilone but increased resistance to tamoxifen, AKT1/2 inhibitors, and mTOR inhibitors. Consistent with these findings, analysis of 16 clinical trial cohorts revealed that patients with high MNAI achieved higher pathological complete response rates to taxane-containing and ixabepilone-based therapies. Conclusions: Our findings demonstrate the MNAI as a clinically actionable biomarker that can refine risk stratification and guide the selection of targeted or chemotherapy regimens, advancing precision medicine in BC management. Full article

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

Intestinal health is essential for maintaining systemic physiological balance through nutrient absorption, immune regulation, and host–microbiota interactions. Atractylodes macrocephala (Baizhu), a traditional medicinal plant long used for gastrointestinal dysfunction, has attracted growing interest because its polysaccharides (AMPs) show promises in intestinal disorders. In this review, we summarize preclinical studies on AMPs identified through searches of PubMed, Web of Science, ScienceDirect, Google Scholar and the China National Knowledge Infrastructure (CNKI), focusing on their extraction, purification, structural features and gut-related activities. Experimental evidence suggests that AMPs are metabolized by gut microbiota into short-chain fatty acids and other bioactive metabolites that regulate mucosal immunity, enhance epithelial barrier function and modulate host metabolic pathways. AMPs have been shown to promote the growth of beneficial taxa, restore dysbiotic communities, up-regulate tight junction proteins, suppress intestinal inflammation and modulate gut–brain axis signaling involved in intestinal motility and visceral sensitivity. These actions underlie their protective effects reported in models of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colorectal cancer, chemotherapy-induced mucosal injury, and metabolic-associated systemic inflammation. Overall, current data support AMPs as microbiota-modulating, immunomodulatory, epithelial-protective and neuro-regulatory agents with potential as functional food-derived interventions for intestinal health. In this review, we also highlight key limitations and priorities for future research on structure–function relationships and clinical translation. Full article

Triple-negative breast cancer (TNBC) is known for being aggressive and potentially resistant to chemotherapy. This means that new ways to improve cancer treatments are a priority. So, the anticancer effect of binary combinations of fucoidan (FuLt) and the chemotherapeutic agents doxorubicin, paclitaxel, and 5-fluorouracil was evaluated. The Chou-Talalay combination index method was used to do this. This method allows the assessment of interactions between products by determining synergism, additive effect and antagonism with combination index <1, =1 and >1, respectively. Synergistic indices (SIs) were selected and applied to 4T1 homotypic spheroids. Oxidative stress caused by SIs was determined after 72 h by measuring the production of ROS and NO in both homotypic and heterotypic spheroids. Three SIs with an inhibitory effect of at least ≥ 0.50 and a dose reduction index > 1 were selected. Considering the experimental and simulated SI, twelve, nineteen, and seven SIs were found for FuLt with doxorubicin, paclitaxel, and 5-fluorouracil, respectively. The highest levels of ROS and NO occurred at 12 and 72 h, respectively, in homotypic and heterotypic spheroids, indicating an immunomodulatory effect in heterotypic spheroids. These results suggest that the synergistic combination of FuLt with chemotherapeutic agents improves drug efficacy and modulates redox dynamics in 4T1 spheroids. Furthermore, FuLt alone exhibits cytotoxic properties. Full article

Background: Multidrug resistance (MDR) remains a major obstacle in cancer chemotherapy, and overexpression of ABCB1 plays a critical role in the pathogenesis of MDR. Despite decades of research, significant clinical progress in the development of ABCB1 inhibitors has yet to be achieved. The small-molecule H89 is originally identified as an inhibitor of protein kinase A (PKA), but it also exhibits various functions unrelated to the PKA. This study investigates H89 as a novel ABCB1-inhibitor to reverse MDR in colorectal cancer (CRC). Methods: Cytotoxicity assays were performed on ABCB1-overexpressing MDR cell line HCT-8/V and parental CRC cell line HCT-8. Drug accumulation was quantified via flow cytometry, and cell cycle effects were analyzed using propidium iodide staining. The ATPase activity of ABCB1 was detected using an ATPase activity assay kit. Molecular docking utilized the ABCB1 crystal structure. Results: Both 3 μM and 10 μM H89 significantly reverses resistance to two ABCB1 substrate drugs (doxorubicin and vincristine) in HCT-8/V cells in a dose-dependent manner, with no such effect observed inHCT-8 cells. The combination of H89 and doxorubicin or vincristine resulted in a significant increase in the proportion ofHCT-8/Vcells in the sub-G1 and G2/M phases. Further mechanistic studies reveal that H89 exerts its effect by inhibiting the drug efflux function of ABCB1, thereby increasing the intracellular accumulation of the substrate drugs and reversing multidrug resistance. Furthermore, H89 did not alter the expression of ABCB1. H89 effectively inhibited the ATPase activity of ABCB1. Molecular docking simulations revealed the binding mode of H89 with ABCB1. Conclusions: The combination of H89 with ABCB1 substrate drugs significantly reverses multidrug resistance in colorectal cancer. These findings provide a strong theoretical and experimental foundation for the development of novel MDR-reversing agents targeting ABCB1. Full article

SENP1 (sentrin-specific protease 1) mediates sumoylation, a reversible post-translational modification that attaches the SUMO (small ubiquitin-like modifier) protein to target proteins. These modified proteins are essential in many key cellular processes, including cell cycle regulation, DNA repair, and apoptosis. Disruptions in the balance between sumoylated and desumoylated proteins can lead to various pathological conditions, such as cancer. Experimental data suggest that certain natural compounds, including momordin Ic (Mc), hinokiflavone (HNK), triptolide (TPL), ursolic acid (UA), streptonigrin (SN), vialinin A (VA), thelephantin G (TG), and others, effectively inhibit SENP1 activity, thereby influencing the levels of sumoylated proteins and cellular processes. This article reviews existing knowledge on the structure and function of natural SENP1 inhibitors, particularly their potential application in cancer therapy, including their capacity to overcome resistance to conventional chemotherapies. Some of the natural SENP1 inhibitors tested so far interact directly with the enzyme’s active site. The current understanding of how this interaction occurs is also discussed. Full article

Background: Gastric cancer (GC) remains a leading cause of cancer mortality. E3 ubiquitin ligases, as central regulators of protein stability and signaling within the ubiquitin–proteasome system, have been implicated in tumor progression, but their functional roles in GC are not well established. Methods: We integrated bioinformatics analysis of TCGA and GEO datasets, in vitro experiments (including cell proliferation, migration, and apoptosis assays), and computational modeling to identify key prognostic factors in GC. Results: We established two molecular subtypes (E3GC1/E3GC2) with distinct clinical outcomes and developed a 10-gene prognostic signature. The model showed moderate predictive accuracy (AUC: 0.61–0.71) and was validated externally. MMRN1 was upregulated in GC cells and its knockdown significantly inhibited malignant phenotypes. Critically, drug sensitivity analysis revealed high-risk patients were more sensitive to proteasome inhibitors (bortezomib), while low-risk patients responded better to taxane-based chemotherapy (docetaxel). Molecular docking predicted a high-confidence interaction between MMRN1 and NEDD4L, suggesting potential ubiquitination regulation. Conclusions: MMRN1 drives GC cell proliferation and migration in vitro and may be regulated by NEDD4L-mediated ubiquitination. Our study provides a foundation for E3 ligase-based patient stratification and personalized therapy selection in GC. While this study provides comprehensive multi-omics evidence supporting the role of MMRN1 in GC progression, its clinical translation is limited by the lack of in vivo validation and direct experimental evidence of NEDD4L-MMRN1 physical interaction. Further studies using animal models and clinical specimens are warranted to confirm these findings. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) being the most prevalent subtype. NSCLC is marked by a complex genetic makeup, involving numerous driver mutations and epigenetic changes that drive tumor growth and resistance to treatment. While several approaches, including chemotherapy and targeted therapy, have been used for lung cancer treatment, their overall responses remain dismal, indicating the need to explore alternative targets implicated in cancer growth. Among various candidates, peroxisome proliferator-activated receptor-gamma (PPARγ), which plays critical roles in regulating cellular functions related to tumorigenesis, has been explored as a promising target for NSCLC intervention. To that end, thiazolidinediones, including pioglitazone, that target PPARγ have shown promise in multiple cellular and preclinical models of NSCLC. Mechanistically, pioglitazone inhibits cancer growth and induces apoptosis via downregulating key signaling pathways, including mitogen-activated protein kinase (MAPK), which play critical roles in regulating cellular activities such as epithelial-to-mesenchymal transition (EMT), cellular bioenergetics, and glucose metabolism. This review highlights the recent updates on the mechanistic insights and the efficacy of PPARγ agonist-based approaches, with an emphasis on pioglitazone, for the treatment of NSCLC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring pioglitazone’s effect on metabolic pathways, chemical-carcinogen-induced tumorigenesis, the targeting of cell signaling pathways, and then its combination with other therapeutic agents. We also present clinical studies that support pioglitazone’s potential in chemoprevention and underscore its further exploration in large cohorts of NSCLC patients. Full article

Bone metastases from osteosarcoma occur in only 10% of patients, and related preclinical models are lacking. A patient diagnosed with pelvic osteosarcoma developed a metachronous scapular metastasis and was treated with multi-agent chemotherapy and surgery. Patient-derived tissue fragments (PDTFs) were obtained from leftover material after diagnosis and biobanking. PDTFs were grown on chick chorioallantoic membrane, establishing an in vivo-like predictive model. Additionally, we obtained a patient-derived cell culture, OS-MET-R-092, which has been maintained in vitro for nearly one year. OS-MET-R-092 cells were authenticated based on short tandem repeats and on their morphology when grown on commercial 3D scaffolds. Using U-2 OS and SaOS-2 as controls, we characterized growth, clonogenic potential, ability to form spheroids, migration, osteogenic differentiation, and expression of related genes. OS-MET-R-092 cells showed a low proliferation rate, impaired differentiation potential, and migratory abilities comparable to SaOS-2, while expressing higher levels of some MMPs and CD44. Functionally, OS-MET-R-092 cells demonstrated a resistant phenotype to doxorubicin, cisplatin, gemcitabine, and docetaxel, corroborated by higher expression of chemo-resistance-related genes. Collectively, OS-MET-R-092 represents a valuable tool for studying bone metastasis from osteosarcoma across various experimental settings and serves as the foundational building block for composite and translatable 3D models. Full article

We report a unique pediatric acute myeloid leukemia (AML) case characterized by a CBFB::MYH11 fusion located on a supernumerary ring chromosome 16. Following diagnosis through comprehensive blood and bone marrow assays, the patient was enrolled in the Children’s Oncology Group (COG) study AAML1831 and randomized to the experimental treatment arm (Arm B). She received induction chemotherapy with CPX-351 (liposomal daunorubicin and cytarabine), gemtuzumab and ozogamicin (GO), and the cardioprotectant dexrazoxane and achieved complete remission (CR). The patient completed the treatment with sustained CR for 18 months. This case represents a rare cytogenetic phenomenon that is not well-documented in the current literature. Through a review of relevant publications, we contextualize this case within the spectrum of core binding factor AML (CBF-AML), highlighting diagnostic approaches, treatment strategies, and prognostic implications, particularly in cases involving atypical CBFB::MYH11 fusions. The durable remission observed in this patient, despite the unusual cytogenetic presentation, provides valuable insights into therapeutic management. This report underscores the cytogenetic and molecular heterogeneity of CBFB::MYH11 AML and emphasizes the importance of comprehensive genetic profiling using advanced techniques such as chromosomal microarray and next-generation sequencing. Full article

Background/Objectives: The purpose of this preclinical pilot study was to explore the potential of green tea extract (GTE) to mitigate and/or prevent oxaliplatin-induced allodynia and axonal damage in rats, when compared to duloxetine (DLX), an ASCO-recommended treatment for established neuropathic pain. Methods: Using a randomized, placebo-controlled experimental design, Sprague Dawley rats (N = 41) received 4 intraperitoneal oxaliplatin (2 mg/kg) injections every other day over 7 days. One week prior to the first oxaliplatin dose, animals began 1 of 4 interventions (saline; GTE 100 mg/kg; DLX 3 mg/kg; GTE 100 mg/kg + DLX 3 mg/kg). A naïve group (n = 6) that received no neurotoxic oxaliplatin or intervention was added to serve as a baseline measure for sNfL. Interventions were administered daily for 4 weeks. Mechanical sensitivity (allodynia) was measured 3 times per week using von Frey testing to determine paw withdrawal thresholds. Von Frey testing began one day prior to the start of interventions to establish baselines and continued through Day 35. Groups were compared to their respective baselines to calculate changes in paw withdrawal thresholds. To measure axonal damage, alterations in serum levels of neurofilament light (sNfL) protein were measured at Day 35 using ELISA. Group differences were identified using two-way analysis of variance (ANOVA). Pearson correlation coefficient was used for correlation analysis between paw withdrawal thresholds and sNfL levels at Day 35. Partial eta-squared and Hedges’ g were used to measure effect sizes. Statistical significance was assigned at P ≤ 0.05 with a 95% confidence interval. Results: Overall, the saline group showed significant reductions in mean paw withdrawal thresholds across experimental timepoints, denoting more severe allodynia caused by oxaliplatin. Conversely, intervention groups exhibited mean paw withdrawal thresholds that were significantly greater than the saline group, indicating less allodynia. The average level of sNfL was also significantly higher in the saline group (113.58 ± 43.84 pg/mL) compared to GTE100 (72.75 ± 26.85), DLX3 (59.93 ± 20.57), and DLX3 + GTE100 (77.04 ± 24.35) intervention groups, suggesting less oxaliplatin-induced axonal damage in these groups. The naïve group exhibited the lowest levels of sNfL (45.69 ± 14.64) when compared to the oxaliplatin-receiving groups (saline and intervention). There were large effect sizes between the saline group, naïve (g = 1.88), GTE100 (g = 1.123), DLX3 (g = 1.157), and DLX3 + GTE100 (g = 1.030) groups. There was also a moderate negative correlation [r(30) = −0.38, p = 0.04] between sNfL levels and paw withdrawal thresholds. Conclusions: The preliminary findings from this pilot study suggest that GTE may be an effective, nutraceutical intervention for mitigating OIPN-associated neuropathic pain, warranting further investigation as an intervention to mitigate chemotherapy-associated neurotoxicities like OIPN. Full article