Search Results (74,900)

The overexpression of hypoxia-inducible factor-1α (HIF-1α) suppresses STING signaling and modulates lipid metabolism in tumor cells, leading to abnormal lipid droplet (LD) accumulation. Herein, we constructed a manganese dioxide (MnO₂)-based nanomotor (HMIP@A). HMIP@A depletes intracellular hydrogen peroxide (H₂O₂) and glutathione (GSH) to generate oxygen (O₂), reactive oxygen species (ROS), and manganese (Mn²⁺). A dual strategy of “oxygen supplementation” and “small-molecule inhibition” synergistically downregulates HIF-1α, thereby suppressing LD biogenesis. This process sensitizes tumor cells to ROS, leading to severe DNA damage. Released Mn²⁺ and damaged DNA synergistically activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In vitro, HMIP@A markedly increases ROS production, lipid peroxidation (LPO), and DNA damage, thereby inducing tumor cell death, immunogenic cell death (ICD), and dendritic cell (DC) maturation. Furthermore, HMIP@A exhibits excellent penetration in tumor spheroids. Overall, this study provides a theoretical basis for the design of nanomedicines through a strategy integrating metabolic intervention, oxidative damage sensitization, and immune activation. Full article

Dynamic knowledge representation in curved manifolds conventionally relies on integer-order Markovian sequence encoders, intrinsically yielding exponential memory decay. This paradigm fails to model the anomalous diffusion and heavy-tailed historical dependencies inherent in complex evolutionary networks and dense physical environments. This manuscript proposes the Fractional–Temporal Lorentz Graph Convolutional Network (FTL-GCN), formalizing temporal evolution as a continuous fractional geometric flow explicitly defined on the tangent bundle of the Lorentz manifold. Analytical derivations demonstrate that the discrete Grünwald–Letnikov memory kernel establishes a non-exponential, power-law lower bound for historical state retention, preventing topological manifold collapse over extended temporal horizons. Empirical evaluations demonstrate that FTL-GCN achieves competitive forecasting accuracy against the latest 2025–2026 state-of-the-art discrete models within specific temporal windows, while uniquely mitigating predictive degradation by up to 52% in long-horizon dependency stress tests and maintaining sub-millisecond latency for physical control. The architecture is subsequently deployed within an in silico biophysical simulation for autonomous micro–nano robotic navigation in the Tumor Microenvironment (TME). By establishing a physical-mathematical structural analogy—mapping the empirical fractional viscoelasticity of the extracellular matrix to the cognitive network’s fractional derivative order—FTL-GCN sustains continuous-space navigation policies in dense anomalous environments where standard integer-order models experience mechanical slip. Full article

Skin aging is driven by both intrinsic and extrinsic factors, including ultraviolet (UV) radiation and environmental stressors. Tumor necrosis factor-alpha (TNF-α) is a key pro-aging cytokine that promotes reactive oxygen species (ROS) production, leading to collagen degradation and inflammatory responses in skin cells. In this study, we investigated the protective effects of Prunus persica flower extract and its major constituents (1–4) against TNF-α–induced oxidative and inflammatory responses in human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs). In HDFs, the extract and isolated compounds significantly suppressed TNF-α–induced ROS generation and matrix metalloproteinase-1 (MMP-1) secretion while enhancing collagen synthesis. Notably, mandelamide (4) markedly reduced MMP-1 secretion (from 7.53 ± 0.28 to 2.97 ± 0.12, p < 0.001) and restored collagen levels (from 3.3 ± 0.03 to 19.1 ± 0.58, p < 0.001). In HEKs, mandelamide attenuated the production of inflammatory mediators under TNF-α stimulation and further suppressed MMP expression while restoring the mRNA expression of hyaluronan synthase genes under TNF-α/ interferon-γ (IFN-γ) co-stimulation. Importantly, mandelamide exhibited selective activity under inflammatory conditions without affecting basal cellular states. Collectively, these findings demonstrate that mandelamide is a key bioactive constituent of Prunus persica (P. persica) flowers and exerts protective effects against inflammation-associated skin aging through the modulation of oxidative stress and extracellular matrix homeostasis. Full article

This systematic review examines the emerging interplay between ferroptosis and disulfidptosis, two distinct forms of regulated cell death (RCD) centered on the SLC7A11 (also known as xCT)-mediated metabolic paradox. Traditionally recognized as a potent anti-ferroptotic factor, SLC7A11 imports cystine for glutathione synthesis to neutralize iron-dependent lipid peroxidation. However, the discovery of disulfidptosis identifies SLC7A11 as a metabolic liability, representing a paradigm shift in our understanding of cellular antioxidant defense. This discovery reveals a transformative vulnerability in SLC7A11-overexpressing cells, shifting the focus from conventional survival mechanisms to the consequences of catastrophic structural collapse. Beyond metabolic exhaustion, this review highlights the role of metal dyshomeostasis as a primary driver, spanning from iron-catalyzed ferroptosis to copper-mediated metabolic interference. This conceptual framework redefines the SLC7A11 axis as a targetable “double-edged sword” in therapy-resistant malignancies. Clinical synthesis of multi-omic gene signatures, such as the disulfidptosis- and ferroptosis-related gene prognostic score (DRGPS) and the ferroptosis- and disulfidptosis-related gene (FDRG) scores, demonstrates their robust value in prognostic stratification and in predicting immunotherapy response across malignancies, including lung adenocarcinoma and hepatocellular carcinoma. Furthermore, we evaluate the capacity of disulfidptosis to prime immunogenic cell death (ICD) and remodel the immunosuppressive tumor microenvironment to bypass chemoresistance. By integrating mechanistic insights with clinical data, this review provides a comprehensive framework for targeting the SLC7A11 axis as a transformative therapeutic vulnerability in precision oncology. Full article

Background/Objectives: Pulsed Electric Field (PEF) therapy is a non-thermal ablation technique that induces immunogenic cell death through high-voltage, short-duration electrical pulses. This may enhance antitumor immunity by releasing intact tumor antigens and potentially generating abscopal effects. We report early outcomes in 32 patients with primary lung cancer or lung oligometastases treated with PEF at a community hospital, with a median (IQR) follow-up of 180.5 (158–207) days. Methods: This retrospective study collected demographics, cancer type, treatment response, and outcomes for patients undergoing PEF ablation. Tumor response was assessed using Sum of Longest Dimensions per RECIST 1.1 to classify progressive disease, stable disease, partial response, or complete response. Volumetric changes were additionally analyzed using RECIST 1.1 percentage thresholds applied to change in volume. Results: At initial 3-month follow-up, 26 of 32 patients demonstrated stable disease, partial response, or complete response, suggesting an 81.25% disease control rate/clinical benefit rate among this cohort. Among patients with Stage III–IV disease, 27.6% (8/29) showed radiographic evidence of a possible abscopal response. At 6 months, 24 of 32 patients remained alive and evaluable, with 62.5% (20/32) maintaining stable disease, partial response, or complete response. Conclusions: Despite patients having progressive disease on systemic therapy before PEF, early outcomes post-ablation suggest favorable local control and potential immunologic benefit. Patients with early-stage disease not receiving systemic therapy also showed excellent local response. Patients tolerated therapy very well. Clinical benefit was observed in 81.25% of patients at 3 months and 62.5% at 6 months, with radiographic evidence of possible abscopal responses in 27.6% of advanced-stage patients, supporting further exploration of the immunogenic potential of PEF demonstrated in preclinical and emerging clinical studies. Full article

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality despite major advances in diagnostics and therapies. The prognosis remains poor, mostly due to late-stage presentation and molecular heterogeneity. Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. The development of EGFR tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in patients with EGFR mutations. Variant allele frequency (VAF) is a quantitative genomic measure representing the proportion of sequencing reads harboring a given mutation. In NSCLC tissue, the EGFR mutation VAF reflects tumor clonality and intratumoral heterogeneity, and accumulating evidence suggests an association between EGFR VAF and response to EGFR-targeted TKIs. Methods: To address the limited synthesis of data on the relevance of EGFR mutation VAF in NSCLC, we conducted a narrative review of the literature using PubMed/MEDLINE and Embase databases and current clinical guidelines, synthesizing available evidence on EGFR VAF, including its biological, molecular, and therapeutic implications in EGFR-mutated disease. The review was structured in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) checklist. Results: EGFR VAF and on-treatment VAF dynamics are consistently associated with treatment response, progression-free survival, and overall survival in osimertinib-treated NSCLC. Baseline VAF enables risk stratification, early clearance kinetics predict durable benefit, and longitudinal VAF monitoring facilitates early detection of resistance. Importantly, the prognostic implications of VAF differ fundamentally between tissue-based and plasma-based measurements: high tissue VAF reflects clonal homogeneity and predicts favorable TKI response, whereas high plasma VAF indicates elevated tumor burden and is associated with inferior outcomes. In the second-line setting, the T790M/activating mutation ratio serves as a surrogate for resistance clonality and independently predicts osimertinib efficacy. Conclusions: EGFR VAF represents a promising dynamic molecular biomarker for treatment monitoring and precision decision-making in EGFR-mutated NSCLC. Full article

Over the past 200 years (1820–2020), global life expectancy has nearly tripled, increasing from 26 to 72.91 years, due to factors such as poverty reduction and public health initiatives. Today, society faces different challenges than it did centuries ago. In patient care and healthcare system priorities, the goal is to develop smart, feasible, long-lasting, cost-effective, readily available, adverse-reaction-free, adaptable, and personalized solutions that minimize patient discomfort, reduce caregiver effort, and decrease hospitalization duration and costs. In this context, biomaterials serve as versatile tools capable of performing a wide range of diagnostic, therapeutic, and theragnostic functions. Thanks to their biocompatibility, biodegradability, surface chemistry, and responsiveness, biomaterials are currently addressing issues such as patient compliance (through controlled drug-delivery systems and smart wound dressings), long transplant waiting lists, transplant rejection, non-adaptable prosthetics (artificial organs), oncology treatment efficacy (nano-formulations for theragnostics and multiple tumor targeting), and inconsistent in vitro drug-testing models (organs-on-a-chip). In this review, we focus on biomaterials’ smartness, then explore databases for efficient product design, and finally highlight their applications in the biomedical field, especially in drug delivery, tissue engineering, and regenerative medicine. Full article

Background: Growth hormone deficiency (GHD) is one of the most common endocrine sequelae in survivors of pediatric medulloblastoma, largely resulting from hypothalamic–pituitary irradiation. Concerns regarding the oncologic safety of growth hormone (GH) replacement have historically limited its use. This study aimed to evaluate growth response to GH therapy and its potential association with tumor relapse in medulloblastoma survivors treated between 2000 and 2023. Methods: We conducted a retrospective single-center cohort study including 74 patients diagnosed with medulloblastoma before 18 years of age. GHD was confirmed by stimulation testing according to standard criteria. Auxological, endocrine, and oncologic data were collected longitudinally. Growth outcomes were compared among patients without GHD (n = 38), patients with untreated GHD (n = 13), and patients with GHD receiving GH treatment (n = 23). Relapse rates were assessed following GH initiation and compared with those of untreated patients. Results: GHD was diagnosed in 48.7% of patients. Baseline height SDS did not differ among groups. Patients with untreated GHD experienced a significant decline in height SDS (−1.93 ± 0.78), whereas GH-treated patients showed a significant increase (+0.39 ± 0.06; p < 0.0001). Final height SDS was significantly lower in untreated GHD patients (−2.45 ± 0.36) compared with GH-treated patients (−1.71 ± 0.68) and patients without GHD (−0.68 ± 0.24; p < 0.0001). No evidence of an increased risk of tumor relapse was observed in association with GH therapy during follow-up. Conclusions: GH replacement significantly improves growth outcomes in medulloblastoma survivors with confirmed GHD without apparent increase in relapse risk when initiated after stable remission. The early identification and multidisciplinary management of GHD are essential components of long-term survivorship care. Full article

Background/Objectives: The NETest is a blood-based, machine learning-enhanced multigene transcript assay designed to detect and monitor neuroendocrine tumors (NETs). This study evaluated the accuracy of the recently validated NETest2.0^® (2025) to (1) detect the presence of disease and (2) assess its utility as a clinically meaningful tool for monitoring NET status across diverse patient cohorts, including post-surgical surveillance, observation (“watch-and-wait”), and treatment settings. Methods: This registry study (NCT02270567) evaluated two objectives. For Objective 1, 1290 samples from 886 patients, of which 404 had paired follow-up samples, were analyzed for concordance between NETest2.0^® and imaging-detectable disease. For Objective 2, paired blood samples (n = 404; median interval 7 months [IQR 4–13.8]) from NET patients across specialized centers were assessed. NETest2.0^® scores were correlated with clinically adjudicated disease status using imaging as the comparator. Cohorts included post-surgical residual disease detection (n = 71), post-surgical recurrence monitoring (n = 44), observation (n = 72), and treatment monitoring (n = 217; somatostatin analogs, PRRT, and other therapies). Analyses were performed by cohort and in aggregate. Results: For Objective 1, NETest2.0^® (cut-off ≥ 50) demonstrated an AUC of 0.96, sensitivity of 91.9%, specificity of 94.9%, PPV of 98.4%, NPV of 77.1%, and overall accuracy of 92.5%. Performance was consistent across tumor grades and sites. For Objective 2, 286 patients (70.8%) were stable, and 118 (29.2%) had progression or recurrence. NETest2.0^® score changes correlated significantly with outcomes: scores decreased in stable patients (median −14.6%) and increased in progressive disease (median + 15.4%; p < 0.0001). Any increase (>0%) in score was associated with progression. Diagnostic performance for detecting progression reached a sensitivity of 78.0%, specificity of 98.3%, PPV of 91.1%, NPV of 90.2%, and accuracy of 83.9%. Conclusions: NETest2.0^® accurately detects disease and provides a clinically actionable tool for monitoring NETs. Its high specificity and predictive performance support risk-adapted surveillance, potentially reducing unnecessary imaging while identifying early progression across diverse clinical settings. Full article

Cryptorchidism is the most prevalent congenital anomaly of the male genitourinary tract, with an incidence of approximately 1 to 9 percent in full-term male infants, decreasing with age due to spontaneous descent. It encompasses testes that fail to descend into the scrotum, which may be intra-abdominal, inguinal, or ectopic, and can be associated with syndromic, genetic, or environmental factors. The descent process occurs in two phases: intra-abdominal, driven by gubernacular development and androgen-independent mechanisms, and inguinoscrotal, regulated by hormonal and mechanical factors including androgens and the gubernaculum. Clinically, cryptorchidism manifests as absent or hypoplastic scrotal testes, often with inguinal fullness. Palpation and physical examination are primary diagnostic tools, with imaging such as ultrasound or MRI reserved for specific cases. Surgical exploration remains the definitive diagnostic modality, especially for nonpalpable testes. Early referral, ideally before 12 months of age, is essential for timely orchidopexy, which aims to position the testes within the scrotum to reduce risks of torsion, trauma, subfertility, and malignancy. Hormonal therapy shows limited efficacy and is generally not recommended as a primary treatment modality. Long-term outcomes indicate that early orchidopexy improves spermatogenic potential and fertility. Men with a history of cryptorchidism exhibit elevated risks of subfertility and testicular germ cell tumors, with the risk being higher if surgical correction is delayed or if testes remain intra-abdominal. The increased malignancy risk persists even after orchidopexy, underscoring the importance of vigilant surveillance. Management strategies emphasize a multidisciplinary approach, combining surgical intervention with ongoing monitoring, to optimize functional and oncological outcomes. Early diagnosis, appropriate surgical treatment, and patient education are critical components in minimizing long-term complications associated with cryptorchidism. Full article

Robust brain tumor classification from magnetic resonance imaging (MRI) remains challenging due to complex structural heterogeneity and subtle inter-class variability. Beyond predictive accuracy, conventional convolutional neural networks predominantly rely on texture-dominant features and fixed receptive fields, which may limit the extraction of clinically meaningful structural information. This study proposes a morphology-aware multi-scale deep representation learning framework that embeds morphological inductive bias directly within hierarchical feature extraction. The proposed architecture synergistically integrates trainable morphological operations with multi-scale convolutional feature learning inside a unified residual framework, supported by an in-block morphological refinement mechanism and a morphology-aware downsampling module. Unlike prior approaches that treat morphological operators as preprocessing or auxiliary branches, the proposed design incorporates differentiable dilation and erosion into the core feature hierarchy to guide structure-aware representation formation. The model was evaluated using five-fold cross-validation and an independent test set, achieving an overall test accuracy of 99.31% with consistently high macro-averaged precision, recall, F1-score, and AUC values. Grad-CAM analysis further demonstrates that the learned representations emphasize clinically relevant tumor regions, supporting interpretable structural knowledge extraction. Ablation studies confirm that performance improvements arise from the synergistic integration of multi-scale learning and morphology-aware refinement. Overall, embedding structural inductive bias within multi-scale deep representation learning enhances robustness, stability, and interpretable knowledge extraction for brain tumor MRI analysis. Full article

Wilms tumor (WT), the most common kidney neoplasm in children, is closely associated with hereditary factors. This study included 134 WT patients (62 males, median age of 7 years, age at diagnosis of 24.9 months) with unilateral (n = 90, 67%) or bilateral WT (n = 44, 33%). Genetic testing was performed using targeted sequencing of 415 genes and multiplex ligation–dependent probe amplification (MLPA). Twenty-five mutations in eight genes were found in 17% (n = 23) of patients: WT1 (n = 10), TRIM28 (n = 4), REST (n = 3), CHEK2 (n = 3), BRCA2 (n = 2), NF1 (n = 1), RAD50 (n = 1), and CDC73 (n = 1). Large deletions of the 11p13 region were revealed in 6% (n = 5) of patients. The 11p15 locus methylation was studied in blood, tumor, and healthy kidney tissue of nine patients suspected of Beckwith–Wiedemann syndrome (BWS) using methylation-sensitive MLPA (MS–MLPA). BWS was diagnosed in 3% (n = 4) of cases (one patient had mosaic disease). Thus, genetic and epigenetic aberrations were identified in 32 WT patients (24%). These patients had a higher frequency of bilateral WT and a higher rate of abnormalities compared to patients without aberrations (56% vs. 25%, p = 0.002; and 86% vs. 25%, p < 0.0001, respectively). The detection of WT hereditary predisposing factors is crucial for treatment strategies and long-term patient surveillance. Full article

Dpep is a cell-penetrating peptide that targets transcription factors ATF5, CEBPB and CEBPD to selectively suppress growth and survival of diverse tumor cell types in vitro and in vivo. Due to these actions and its apparent safety, the peptide has potential as a cancer therapeutic. How Dpep might be combined with other anti-cancer agents to achieve synergistic efficacy and to overcome possible peptide resistance has not been assessed in depth. Based on prior work indicating that Dpep promotes apoptotic cancer cell death and up-regulates multiple pro-apoptotic and tumor suppressor genes, we studied combinations of Dpep with ABT-263, a pro-apoptotic BCL2 family inhibitor, and decitabine, a hypomethylating drug. Combining Dpep with each agent alone or together synergistically suppressed the growth of a range of solid and liquid tumor cell types. Moreover, the combinations synergistically inhibited the growth of cells lines that were selected either in vivo or in vitro for Dpep resistance. Finally, we tested the combination of Dpep with ABT-263 in a mouse melanoma xenograft model. The combination more effectively inhibited tumor growth than either agent alone and, in contrast to vehicle or ABT-263, produced a 40% durable survival rate. Taken together, these observations highlight potential drug partners for the therapeutic development of Dpep. Full article

Objectives: This study evaluates the epidemiological characteristics and survival, functional, and esthetic outcomes of pediatric patients diagnosed with head and neck sarcoma (PHNS) who underwent individualized surgical treatment for local disease control and/or for defect reconstruction. Methods: A cohort of 45 patients aged 0–18 years with histologically confirmed PHNS who underwent surgical resection and/or reconstructive procedures was analyzed. Extracted variables included demographic data, tumor histology and stage, surgical margin status, and systemic therapy modalities. Reconstructive strategies were assessed, considering technique, sequencing, and total duration of treatment. Survival analysis was performed, focusing on both overall survival (OS) and event-free survival (EFS). Results: Rhabdomyosarcoma constituted the predominant diagnosis (19/45), followed by Ewing sarcoma (7/45) and chondrosarcoma (5/45). The maxilla represented the most common primary site (18/45), whereas orbital origin was the least frequent (3/45). Complete surgical excision (R0) was achieved in 80.5% of resected cases. Margin status showed no statistically significant association with final outcome (p = 0.7786). In contrast, nodal metastasis, local recurrence, and distant dissemination were independently and collectively correlated with mortality. Survival analysis demonstrated a 3-year OS of 100% and an EFS of 79.8%, and a 5-year OS of 94.7% with an EFS of 70.7%. Conclusions: Implementation of an individualized surgical and reconstructive protocol was associated with effective local tumor control and favourable reconstructive outcomes. Oncologic prognosis was driven primarily by nodal involvement and recurrent or metastatic disease rather than margin status alone. Full article

Background: Macrophage migration inhibitory factor (MIF) is a critical modulator of the tumor immune microenvironment (TME). Its clinical significance in head and neck squamous cell carcinoma (HNSCC) remains controversial because of HPV-dependent tumor biology and the limitations of single-timepoint biomarker assessments. This preliminary study evaluates whether dynamic changes in circulating MIF (ΔMIF) in an HPV-stratified longitudinal cohort reflect disease severity and treatment response. Methods: Ninety-six serial serum samples were analyzed from 27 HNSCC patients (22 HPV-positive, 5 HPV-negative) from diagnosis through therapy and follow-up. Serum MIF and anti-HPV16 E7 IgG were quantified by ELISA, and ΔMIF was defined as the change in MIF concentration between consecutive visits. Results: Baseline MIF did not correlate with clinical stage in the total cohort (p = 0.63). However, 56% of HPV-positive patients exhibited a positive correlation between elevated MIF and advanced stage. Following chemoradiotherapy, the HPV-negative group showed a consistent and significant decline in MIF (mean ΔMIF = −1.23, p = 0.031), corresponding with no evidence of disease (NED). In contrast, the HPV-positive group showed heterogeneous trajectories (mean ΔMIF = +0.21, p = 0.94), with several patients demonstrating paradoxical declines in MIF during active disease or relapse, followed by recovery upon reaching NED. In select cases, MIF dynamics were closely synchronized with anti-E7 IgG levels. Conclusions: Serum MIF dynamics are strongly dependent on HPV status. While MIF serves as a reliable therapy-monitoring marker in HPV-negative HNSCC, it may play a complex and paradoxical immunomodulatory role in HPV-positive disease. These preliminary findings support the need for larger prospective, HPV-stratified trials. Full article