Search Results (630)

Osteoporosis (OP) and osteosarcoma (OS) are biologically distinct skeletal disorders that share dysregulated bone remodeling, inflammatory signaling, and microenvironmental interactions. This study performed an integrative transcriptomic analysis to identify shared osteoimmune regulatory programs in circulating monocytes from postmenopausal women with OP and OS tumors from Central Mexican cohorts. Two independent RNA-seq cohorts were analyzed separately and then integrated: circulating monocytes from postmenopausal women with OP and controls (7 OP and 7 controls), and donor-matched OS tissues (7 tumors and 7 healthy bone samples). Differential expression, module-based filtering, pathway enrichment, cross-cohort functional integration, directional concordance, and targeted interaction network analyses were performed. The OP cohort showed 169 differentially expressed genes, whereas the OS cohort showed 2135 genes. Module-based filtering retained 82 genes in OP and 278 in OS, with only six genes directly shared. However, pathway-level integration identified convergent signals involving PI3K-Akt, HIF-1 signaling, lipid and atherosclerosis, phagosome, endoplasmic reticulum protein processing, focal adhesion, proteoglycans in cancer, and cancer-related pathways. Directional analysis of 27 shared pathway-associated genes revealed predominantly discordant regulation, with CTNNB1 emerging as a central network node. These findings suggest that OP and OS converge through specific osteoimmune pathways rather than through a uniform shared gene program. Full article

Objectives: Transient Receptor Potential Ankyrin 1 (TRPA1) has emerged as a stress-responsive ion channel involved in calcium homeostasis, redox signaling, migration, and cancer cell survival; however, the therapeutic relevance of TRPA1 activation versus inhibition remains poorly understood. In this study, we comparatively investigated the anticancer potential of the TRPA1 agonist ASP7663 and the TRPA1 antagonist HC030031 across a broad panel of human cancer cell lines. Methods: Antiproliferative and cytotoxic effects were evaluated using MTT and LDH assays, while apoptotic signaling, DNA fragmentation, mitochondrial membrane potential, migration inhibition, DNA/BSA interactions, topoisomerase I inhibition, and molecular docking analyses were comprehensively assessed. Results: ASP7663 exhibited markedly lower GI₅₀ values than HC030031 in most cancer models and demonstrated favorable tumor selectivity relative to normal cells. Mechanistically, ASP7663 induced robust apoptotic activation characterized by significant upregulation of Caspase-3, Caspase-8, and Caspase-9, together with enhanced DNA fragmentation and pronounced nuclear condensation. Rhodamine-123 staining further revealed substantial mitochondrial membrane depolarization, indicating activation of intrinsic apoptotic pathways. In addition, ASP7663 produced selective membrane damage in malignant cells, stronger inhibition of migration in osteosarcoma and chondrosarcoma models, enhanced CT-DNA/BSA binding affinity, partial topoisomerase I inhibition, and superior docking interactions with apoptosis-related targets, including Caspase-3, Caspase-8, Caspase-9, Bax, and Bcl-2. Conclusions: Collectively, these findings suggest that ASP7663 is a promising multi-target candidate for anticancer therapy and support further investigation of TRPA1-associated pathways as potential therapeutic targets in cancer. Full article

This study aimed to develop a low-cost, computer-controlled, extremely low-frequency 50 Hz electromagnetic field (ELF-EMF) generator and to investigate the effects of EMF exposure at intensities of 0.1, 1, 5, and 10 mT (millitesla) on human osteosarcoma (U2OS) and healthy bronchial epithelial (BEAS-2B) cell lines. First, a computer-controlled ELF-EMF generator was successfully designed and developed for in vitro exposure studies. Subsequently, the cells were exposed to 50 Hz EMFs at flux densities ranging from 0.1 to 10 mT, and cell viability was assessed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay 24 h after exposure. A significant decrease in cell viability was observed in U2OS cells exposed to 5 and 10 mT EMFs (p < 0.05), whereas no significant difference was detected at 0.1 and 1 mT exposures (p > 0.05). In BEAS-2B cells, a significant decrease in cell viability was observed only following exposure to 10 mT EMFs (p < 0.05), with no significant differences at 0.1, 1, or 5 mT exposures. These findings suggest that 50 Hz EMFs may affect cellular processes and inhibit the proliferation of U2OS cancer cells more than that of BEAS-2B cells. EMFs with specific frequencies and intensities may represent a novel approach for controlling the growth of U2OS cancer cells. Full article

Background: The survival benefit of primary tumor resection (PTR) in patients with synchronous metastatic primary malignant bone neoplasms (PMBNs) remains controversial. We aimed to evaluate the association between PTR and survival outcomes using a large population-based cohort with rigorous confounding control. Methods: Patients diagnosed with synchronous metastatic PMBNs (osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma) between 2004 and 2022 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were stratified by receipt of PTR. Propensity score matching (PSM; 1:1 nearest-neighbor, caliper = 0.03) was applied to balance baseline covariates. Kaplan–Meier analysis with log-rank testing and multivariable Cox proportional hazards regression stratified by matched pairs were used to assess overall survival (OS) and cancer-specific survival (CSS). Subgroup analyses were performed across four histological subtypes. Results: A total of 1046 patients were included (resection: n = 658, 62.9%; no resection: n = 388, 37.1%). After PSM, 488 patients (244 per group) were retained. In the matched cohort, PTR was independently associated with significantly improved Overall survival (OS) (HR = 0.34, 95% CI: 0.21–0.54, p < 0.001) and cancer-specific survival (CSS) (HR = 0.35, 95% CI: 0.22–0.55, p < 0.001). Subgroup analyses demonstrated significant survival benefit in osteosarcoma and chondrosarcoma (both p < 0.001), but not in Ewing sarcoma or chordoma. Conclusions: PTR is associated with a significant survival benefit in selected patients with synchronous metastatic PMBNs, particularly those with osteosarcoma and chondrosarcoma. These findings support individualized, multidisciplinary decision-making regarding surgical intervention in this population. Full article

Characterized by its highly aggressive behavior and propensity for metastasis, osteosarcoma remains a formidable clinical challenge with restricted treatment modalities. Cancer stem-like cells (CSCs) are widely recognized as central orchestrators of oncogenic progression and therapeutic intractability; however, the precise epigenetic regulations governing these processes are yet to be fully elucidated. Here, we investigated the role of the long non-coding RNA DANCR in regulating osteosarcoma stemness. DANCR expression was significantly upregulated in human osteosarcoma tissues and positively correlated with the stemness markers CD133, SOX2, and CD90. Functional assays demonstrated that DANCR overexpression enhanced stem-like properties, including an enriched CD133+/CD44+ cellular fraction and enhanced spheroid-forming capacity, concurrently accelerating in vitro cellular proliferation, migration, and invasive potential. In a xenograft mouse model, DANCR upregulation promoted in vivo tumor growth and lung metastasis. Mechanistically, dual-luciferase reporter assays and RNA immunoprecipitation (RIP) revealed that DANCR acts as a competing endogenous RNA (ceRNA) by sponging miR-145-5p, thereby facilitating the de-repression of CD133 and contributing to Akt/mTOR signaling activation. In addition, DANCR/miR-145-5p modulation was associated with changes in autophagy-associated markers. Collectively, these findings identify the DANCR/miR-145-5p/CD133 axis as a regulator of osteosarcoma stemness and progression, providing new insights into tumor biology and highlighting a potential molecular target for therapeutic investigation. Full article

Reliable osteosarcoma tissue characterization combines radiographic evidence of bone-level structural change with histopathological assessment of cellular morphology. In rare cancers, however, patient-matched multimodal datasets are rarely available because radiology and pathology follow separate clinical workflows and cohort sizes are small. This study examines whether decision-level fusion can integrate radiographs and histopathology images originating from independent, unpaired patient cohorts, and reports the results as a methodological proof of concept rather than as a clinically validated diagnostic system. Two EfficientNet-B0 encoders were trained separately using osteosarcoma-positive radiographs from the Kaggle Bone Tumor Classification dataset (180 images) and H&E-stained histopathology tiles from the TCIA Osteosarcoma Tumor Assessment collection (1144 tiles from four patients). Histopathology tiles carry three labels: non-tumor, viable tumor, and necrotic tumor. Because radiographs do not provide tissue-viability labels and cannot directly distinguish viable from necrotic tumor, the radiographic branch was used as a weak radiograph-derived probability prior mapped into the shared three-class decision space during fusion. Fusion operates only on modality-specific probability vectors; no case-level or patient-level pairing is assumed or required. The adaptive gating network estimates a per-sample radiograph-prior weight, α, from the concatenated vector, [Pr, Ph], where Pr denotes the radiograph-derived probability prior, Ph denotes the histopathology probability vector, and 1 − α denotes the histopathology weight. To limit leakage in the small histopathology cohort, the four patients were assigned to fixed training (P001 and P002), calibration (P003), and test (P004) partitions with strict patient-level separation. On the single held-out test patient (171 tiles), adaptive gating fusion classified 166 of 171 tiles correctly (97.08% accuracy, macro-F1 of 0.97, and macro-AUC of 0.99), compared with 161 of 171 tiles (94.15%) for fixed-α fusion at α = 0.25. McNemar’s test for this comparison gave χ² = 3.20, p = 0.074, so the improvement was numerically higher but not statistically significant at the 0.05 level. Simpler classifiers on the same three-dimensional fused vector reached comparable accuracy (95.91–96.49%), and none differed significantly from adaptive gating. These results indicate that confidence-aware decision-level fusion is feasible under unpaired, data-constrained conditions, and that its present value lies in interpretable per-sample modality weighting rather than in a demonstrated accuracy advantage. The single-patient histopathology test set precludes any claim of clinical generalizability; validation on larger, multi-institutional, patient-level cohorts remains necessary. Full article

Background: Metastasis and poor chemotherapy response have stagnated therapeutic progress in osteosarcoma (OS) for the past three decades. Defining the transition from localized to metastatic OS before overt dissemination is fundamental for improving survival. However, effective early diagnostic tools remain scarce, largely due to limited exploitation of the metastasis-associated tumor microenvironment’s own record of prior environmental and stress exposures encoded in cell-intrinsic transcriptional states. Here, we employed a supervised machine learning framework with iterative resampling and multi-stage model selection to identify molecular markers associated with metastasis in osteosarcoma and to develop a computational signature, Auto-RS. Methods: Transcriptomic and clinical data from 139 OS patients with ≥5 years of follow-up were analyzed. A LASSO–Cox framework was applied to derive a gene expression-based risk score, Auto-RS, from which a nomogram integrating age and sex was generated for individualized prognosis. Model interpretability was assessed across six independent single-cell OS patient datasets, and drug sensitivity predictions were inferred by integrating Auto-RS with the Precily algorithm to uncover actionable therapeutic vulnerabilities. Results: Auto-RS, constructed from the expression of four autophagy genes (BNIP3, MYC, PEA15, and SAR1A), served as an independent prognostic factor for overall survival (HR = 1.091; 95% CI, 1.047–1.136; p < 0.001). Time-dependent ROC analysis showed that Auto-RS was the most accurate single predictor (AUC = 0.88), exceeding metastasis (0.83), sex (0.45), and age (0.39). A basic prognostic model (BpM) incorporating metastasis status yielded a C-index of 0.741 (95% CI, 0.679–0.803). The addition of Auto-RS (CpM) improved discrimination (C-index = 0.788; 95% CI, 0.731–0.845), whereas a model without metastasis information (ApM) retained predictive ability (C-index = 0.709; 95% CI, 0.640–0.778). Single-cell analysis confirmed that Auto-RS features aligned with known metastatic trajectories, reflecting the transition from proliferative to invasive tumor states and highlighting coordinated programs among cancer-associated fibroblasts and immune cells. Drug sensitivity integration through Precily identified gemcitabine and cytarabine as FDA-approved agents predicted in silico to show greater sensitivity in the high-risk subgroup. Conclusions: We identified autophagy-mediated transcriptional ‘stress fingerprints’ that are tightly associated with OS metastasis. The Auto-RS signature, composed of BNIP3, MYC, PEA15, and SAR1A, enables early therapeutic stratification of patients independent of overt metastatic status. Moreover, Auto-RS delineates key molecular underpinnings of OS metastasis at single-cell resolution. As a practical laboratory tool, Auto-RS may represent a step toward improved risk stratification, where advances in metastasis prediction and therapeutic guidance converge to improve outcomes in OS. Full article

Osteosarcoma (OS) is the most common primary bone cancer in adolescents and young adults. Despite tremendous preclinical and clinical efforts to advance therapy for OS, the standard of care, consisting of surgical resection and pre- and postoperative chemotherapy, has remained unchanged for over 40 years. Growing molecular understanding of OS highlights tumor heterogeneity as a major obstacle to therapeutic advances. In this narrative review, we comprehensively discuss current evidence of OS heterogeneity and strategies to overcome the barrier. Evidence shows that OS heterogeneity is multifactorial: it retains complex and dynamic somatic genomics, including genomic instability, alterations in tumor suppressors, and amplification/overexpression of oncogenes such as MYC. The tumor is associated with various germline vulnerabilities. OS’s tumor microenvironment has intense cellular and spatial diversity, which significantly shapes its heterogeneity. The effects of lineage plasticity, as well as epigenetic and metabolomic mechanisms, on OS heterogeneity are under study. To overcome this extreme heterogeneity, the therapeutic strategies for OS must be comprehensive and diversified. While surgical resection remains a mainstay of treatment, efforts to identify actionable biomarkers that guide risk stratification and therapy are ongoing. Diverse preclinical models offer insights into OS biology and novel therapeutics. To enhance combinational therapy for OS, various agents, including multi-targeted receptor tyrosine kinase inhibitors, immunotherapies, and epigenetic and metabolic modifiers, are being investigated. Distinctive efforts are continuing to establish maintenance therapy for OS. In summary, elucidating the complex drivers of OS heterogeneity, together with the development of multifaceted strategies to address them, is critical to accelerating therapeutic progress in OS. Full article

Radiotherapy is one of the most effective methods of cancer treatment. New, more effective, and safer radiotherapy methods can be developed thanks to selective radioprotectors. In our study, we investigated the antioxidant and radiomodulatory activity of sodium aminodihydrophthalazinedione (the drug Tameron^®) on human mesenchymal stem cells (MSCs) and human osteosarcoma cells of the MNNG/Hos line in vitro. We have shown that sodium aminodihydrophthalazinedione effectively scavenged radiation-induced hydrogen peroxide in aqueous solution in a concentration-dependent manner after X-ray irradiation. We also showed that sodium aminodihydrophthalazinedione (0.25 mM and above) effectively protects human MSCs from the damaging effects of X-rays, reducing the level of intracellular ROS and the number of apoptotic cells after irradiation, enhancing the restoration of double-stranded DNA breaks and clonogenic activity. Meanwhile, the effect of sodium aminodihydrophthalazinedione on human osteosarcoma MNNG/Hos cells was different: it increased the number of apoptotic cells and reduced the rate of repair of double-stranded DNA breaks. Transcriptomic studies on both cell culture types using nanopore sequencing technology after X-ray irradiation and sodium aminodihydrophthalazinedione pretreatment revealed a significant level of modulation of key genes responsible for DNA repair, antioxidant activity, and genome stability. Our data show that sodium aminodihydrophthalazinedione may be a promising therapeutic agent for modulating the cellular effects of radiation exposure. Full article

Background: Osteosarcoma remains a biologically complex and clinically challenging malignancy, with survival gains plateauing despite decades of multimodal therapy incorporating surgery and cytotoxic chemotherapy. Unlike cancers in which mutation-centric precision oncology has yielded transformative advances, osteosarcoma is characterized by profound structural variation, copy number alteration dominance, and dynamic clonal evolution, limiting the effectiveness of single-target approaches. These realities motivate alternative strategy-level frameworks that better align treatment selection with evolving disease behavior. Methods: This narrative educational review synthesizes contemporary evidence from osteosarcoma biology, radiobiology, and translational oncology to propose a state-based framework for integrating radiotherapy—particularly stereotactic body radiotherapy (SBRT/SABR) and spatially fractionated radiotherapy (SFRT)—into osteosarcoma management and clinical trial design. Rather than relying solely on static anatomic stage, this framework emphasizes clinically actionable, time-varying state variables, including disease burden patterns (localized, oligometastatic, polymetastatic), tempo of progression, prior systemic response, and feasibility of complete local control. Results: Within this context, radiotherapy is presented not only as a local control modality but also as a hypothesis-generating biologic intervention, capable of perturbing tumor vasculature, inflammatory signaling, innate DNA-sensing pathways, and immune/myeloid programs in a dose-, fractionation-, and spatial-distribution-dependent manner. The review critically examines both the potential opportunities (e.g., local eradication, immune modulation) and limitations (e.g., rarity of abscopal responses, risk of unintended systemic signaling) of radiobiotherapy combinations, emphasizing the need for cautious interpretation and prospective validation. Conclusions: Finally, the article outlines practical implications for state-stratified, biomarker-embedded clinical trials, highlighting endpoints beyond conventional response criteria, including circulating tumor DNA dynamics, immune and myeloid signatures, and long-term patterns of disease progression. Overall, this review frames radiobiotherapy as an educational and investigational paradigm intended to support rational hypothesis generation, multidisciplinary decision-making, and learning-oriented trial designs in osteosarcoma, rather than as definitive clinical guidance. Full article

Recent studies indicate that ferroptosis shows unique advantages in oncotherapy, particularly in reversing multidrug resistance (MDR). Despite current therapeutic advancements, the treatment of high-incidence malignancies with dismal prognoses continues to face challenges, including limited clinical efficacy, significant side effects, and drug resistance. In recent years, Chinese herbal medicine (CHM) has gained increasing attention in anti-tumor therapy. CHM bioactive components are highly effective in inducing tumor cell ferroptosis, inhibiting tumor proliferation and migration, and reversing drug resistance. Additionally, some components can protect normal cells and improve the tumor microenvironment. This review systematically summarizes the regulatory roles of various CHM bioactive components in ferroptosis across common human cancers. We further analyze the underlying molecular mechanisms, focusing on the modulation of key regulatory targets (e.g., GPX4, SLC7A11, and Nrf2) and critical signaling cascades (e.g., PI3K/AKT/mTOR and p53). Furthermore, the differential effects of bioactive compounds from CHM on common tumors were evaluated, alongside their potential in combination therapy. This review provides a theoretical foundation for the development of novel anticancer drugs targeting ferroptosis regulation and offers new perspectives for the clinical application of CHM in oncology. Full article

Cancer and multidrug-resistant microbial infections remain major global health challenges, underscoring the need for multifunctional, biocompatible, and environmentally sustainable therapeutic platforms. Herein, selenium–hyaluronic acid nanoconjugates (Se/HA NPs) were synthesized through an eco-friendly ascorbic acid-mediated reduction approach to improve the bio-functional stability and therapeutic performance of selenium-based nanomaterials. The formation of Se/HA NPs was confirmed by transmission electron microscopy (TEM), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), and Fourier-transform infrared spectroscopy (FTIR). FTIR analysis supported the involvement of ascorbic acid- and hyaluronic acid-associated functional groups in nanoparticle formation and stabilization. TEM revealed well-dispersed, predominantly spherical nanoparticles with diameters ranging from 29.72 to 80.38 nm, while XRD confirmed their crystalline nature with an average crystallite size of 31.2 nm. Biologically, Se/HA NPs exhibited strong antibacterial activity against Enterococcus faecalis (21 mm), Staphylococcus aureus (24 mm), Escherichia coli (25 mm), and Klebsiella pneumoniae (27 mm), outperforming hyaluronic acid alone and showing activity comparable to standard antibiotics, with a minimum inhibitory concentration (MIC) of 15.62 µg/mL. Notably, Se/HA NPs showed pronounced antifungal activity against Candida albicans, with an inhibition zone of 34 mm and an MIC of 7.8 µg/mL. In MG-63 osteosarcoma cells, Se/HA NPs demonstrated potent cytotoxicity, with a half-maximal inhibitory concentration (IC₅₀) of 8.36 µg/mL compared with 746.37 µg/mL for hyaluronic acid. Moreover, Se/HA NPs enhanced wound closure to 73.41% and showed strong anti-inflammatory activity, with an IC₅₀ of 5.37 µg/mL, demonstrating multifunctional bioactivity. Full article

Purpose: Survivors of childhood lower extremity and pelvic osteosarcoma have a high burden of functional, strength, and range of motion (ROM) impairment. However, longitudinal trajectories of these outcomes have not been well studied. Methods: This longitudinal study included patients enrolled on an institutional therapeutic protocol with lower extremity or pelvic osteosarcoma. Functional assessments (functional mobility assessment, FMA) were performed at diagnosis, prior to surgery, 10–12 weeks post-surgery, end of therapy, and 6, 18, and 48 months post-therapy. Generalized mixed models were used to evaluate differences in FMA scores, strength, and ROM across time points. Results: The study included 35 patients (mean age 13.1 ± 3.4 years) with osteosarcoma of the lower extremity (n = 34) and pelvis (n = 1). The majority underwent a limb salvage procedure (74.3%). FMA scores were lowest at the pre-therapy time point (least squared (LS) mean 27.2, standard error (SE) 2.2) and highest at the 48-month follow-up time point (LS mean 48.4, SE 2.4, p-trend < 0.01). A large proportion of participants had scores indicating functional impairment throughout the study period including 80% of participants at the 48-month follow-up. Strength and ROM scores demonstrated similar trends in improvement over time; however, they remained below normative scores at long-term follow-up. Conclusions: A high burden of impairment in function, strength, and ROM persists among survivors of childhood lower extremity and pelvic osteosarcoma from diagnosis through long-term follow-up. Implications for Cancer Survivors: A lifelong focus on mitigating impairments in function, strength, and ROM is needed among survivors of childhood pelvic and lower extremity osteosarcoma. Full article

MicroRNA (miRNA) regulation plays a pivotal role in intracellular gene expression. Analysis of miRNA profiles can provide critical insights into disease states. As cancer-associated molecules reported in previous studies, miRNAs may serve as candidate classificatory features for exploratory cancer classification. This research analyzed serum miRNA data from patients with 13 solid cancer types and individuals without cancer. The study comprised two distinct analyses: first, stratifying the dataset into cancer and non-cancer groups to identify miRNAs differentially represented in cancer patients; and second, subdividing the cancer patient data into 13 predefined solid-cancer types to identify candidate miRNA features that discriminate among these cancer types. We employed seven feature-ranking algorithms to evaluate miRNA contributions in both analyses and generate feature lists. Each list was examined using an incremental feature selection method to extract essential miRNAs and build good-performing classification models. Several candidate miRNAs were identified for distinguishing pan-cancer samples from non-cancer ones: miR-4783-3p has been linked to associated with the regulation of endocrine cell differentiation, and miR-663a has been reported in hepatocellular carcinoma and thyroid carcinoma. The analysis also highlighted miRNAs that differentiate solid cancer types, including miR-629-3p, reported to be upregulated in lung and breast cancer, and miR-6087, reported to be downregulated in osteosarcoma and bladder cancer. Full article

Background: The long-term kidney outcomes in paediatric osteosarcoma survivors treated with nephrotoxic chemotherapeutic agents are not well-described. Methods: We conducted a multi-centre retrospective cohort study and recruited paediatric osteosarcoma survivors who survived beyond 5 years from cancer diagnosis over a 20-year period. Chronic kidney disease (CKD) was defined as evidence of kidney impairment, chronic tubulopathy, and proteinuria upon last follow-up. Results: We included 89 patients (57% males) with a mean follow-up period of 14.9 years. A total of 42 subjects (47.2%) developed CKD, 28 of whom had CKD stage 1 with either chronic tubulopathy or proteinuria; 14 patients had CKD stage 2 (eGFR < 90 mL/min/1.73 m²), while two had CKD stage 3 (eGFR < 60 mL/min/1.73 m²). Chronic tubular dysfunction was reported in 34 patients (38%), with hypomagnesemia being the most common manifestation. Proteinuria and hypertension were infrequently observed, in 3% and 8% of cases, respectively. We found that a history of severe AKI and aminoglycoside exposure during the treatment course were significant risk factors for CKD, but the dose-dependent relationships between the development of CKD and cisplatin, ifosfamide, and methotrexate could not be demonstrated. Conclusions: CKD is prevalent among paediatric osteosarcoma survivors. Caution is needed when using multiple nephrotoxic agents at the same time, as this could increase the risk of CKD in the long run. Multi-disciplinary regular surveillance should be performed to identify and manage CKD early, including kidney function, electrolyte, and proteinuria monitoring. Full article