Search Results (63,200)

Glioblastoma (GBM) is characterized by hypoxia-driven metabolic adaptation and profound therapeutic resistance. Ferroptosis, an iron-dependent lipid peroxidation-related cell death process, has emerged as a potential vulnerability; however, its relationship with hypoxia signaling remains incompletely defined. In this study, we performed integrative transcriptomic and single-cell RNA sequencing analyses to investigate the relationship between hypoxia signaling and ferroptosis-related gene signatures in GBM. Intersection analysis of hypoxia-associated differentially expressed genes and curated ferroptosis-related gene sets identified 29 core candidate genes. FerroScore stratification revealed that tumors with higher ferroptosis-related transcriptional signatures were significantly associated with poor overall survival. Among these genes, HILPDA emerged as a hypoxia-associated gene consistently linked to ferroptosis-related gene expression patterns and immune-related transcriptional programs. HILPDA expression showed significant correlations with iron-ROS axis components, including HMOX1, NOX4, and STEAP3, and was associated with immune microenvironment changes characterized by T cell depletion and inflammatory infiltration. Single-cell RNA-seq analysis further supported the cellular-level association between HILPDA expression and hypoxia-related transcriptional states. Structural equation modeling suggested that the relationship between HILPDA expression and ferroptosis-related gene signatures may be mediated through hypoxia-related pathways. Collectively, these findings indicate a transcriptomic association between hypoxia signaling and ferroptosis-related gene signatures in GBM and identify HILPDA as a candidate gene associated with this axis. Full article

Background: Bone metastasis is a major determinant of morbidity and therapeutic failure in advanced prostate cancer (PCa); however, the transcriptional programs and tumor microenvironmental alterations driving metastatic progression remain incompletely understood. This study aimed to systematically characterize transcriptomic differences between non-metastatic and bone-metastatic PCa and to identify key microenvironmental signaling pathways involved in tumor survival and chemoresistance. Methods: Bulk RNA sequencing was performed on 49 non-metastatic and 28 bone-metastatic PCa specimens. Differential expression analysis was integrated with weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis, and immune/stromal deconvolution. Key findings were validated using in vitro functional assays, including Transwell co-culture models, small interfering RNA (siRNA)-mediated gene silencing, cell viability, apoptosis, and docetaxel resistance analyses. Results: Transcriptomic profiling identified 574 differentially expressed genes. Bone-metastatic tumors were enriched in ribosome-related and translational pathways, whereas non-metastatic tumors displayed immune-associated signatures, including natural killer (NK) cell-mediated cytotoxicity and cytokine signaling. WGCNA revealed immune-related gene modules preferentially enriched in non-metastatic disease. Immune deconvolution demonstrated significantly higher infiltration of NK cells and endothelial cells in non-metastatic tumors. Chemokine-receptor analysis highlighted upregulation of the CXCL10-CXCR3 axis in non-metastatic PCa. In vitro, PCa cells expressed CXCR3, while endothelial cells markedly increased CXCL10 expression upon co-culture. Functional assays showed that endothelial-derived CXCL10 promoted PCa cell survival, suppressed apoptosis, and conferred resistance to docetaxel via CXCR3-dependent signaling; these effects were reversed by CXCL10 or CXCR3 knockdown. Conclusions: These findings uncover a context-dependent endothelial-immune chemokine network distinguishing non-metastatic from bone-metastatic PCa and identify the CXCL10-CXCR3 axis as a critical mediator of tumor survival and chemoresistance, suggesting a potential therapeutic vulnerability in advanced prostate cancer. Full article

The once-extensive coastal forested wetlands (CFWs) of the Mississippi River Delta (MRD) are declining under the combined pressures of pervasive hydrologic change, unregulated harvesting, relative water level rise (due to the combination of geological subsidence and sea-level rise—SLR), and climate change. We synthesize here over 50 years of research conducted in the MRD to examine the history of the CFWs and their management, their ecosystem functions and services, and the nature, extent, and severity of ongoing changes. Seedling recruitment failure and increasing salinity levels are the most immediate threats to forest persistence, necessitating management that restores hydrologic function and sediment and nutrient supply to allow seedling survival and minimizes saltwater intrusion. Collectively, the evidence indicates that managed inflows can bolster accretion and sustain forest function, and long-term resilience requires hydrologic restoration at landscape scales coupled with site-level actions that secure recruitment and address local degradation trajectories. These include freshwater and sediment introduction, protection from herbivory, and, in some cases, planting. Our research findings have important implications for worldwide CFWs, and tidal freshwater ecosystems in general, which occur mainly in tropical deltas. Full article

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly aggressive pediatric central nervous system (CNS) malignancies. AT/RT of the lateral ventricle is an exceptionally rare subgroup, with only 11 reported cases. SMARCB1 inactivation is the primary molecular feature of AT/RT. Current consensus is to classify AT/RT based on methylation and molecular profiles into the following subgroups: AT/RT-TYR, AT/RT-SHH, AT/RT-MYC, and a potentially distinct SMARCA4-deficient subtype. AT/RT-MYC exhibits high levels of CD8⁺ tumor-infiltrating lymphocytes, indicating immunogenic potential. Case presentation: We report three pediatric cases presenting with intracranial hypertension and seizures. Diagnosis was confirmed via histopathology and molecular profiling. Interventions included gross total resection, chemotherapy, radiotherapy, and combined immune checkpoint inhibitors (pembrolizumab and ipilimumab). Outcomes varied from rapid progression to 3-year recurrence-free survival. A cohort of 14 pediatric patients with lateral ventricle AT/RT, comprising 3 institutional cases and 11 cases identified from the PubMed database, was evaluated through a narrative synthesis. Conclusions: These advancements highlight the crucial role of molecular subtyping in tailoring personalized treatments, including epigenetic modifiers and immune-based regimens. However, clinical validation is essential to establish standardized protocols. Integrating genomic, epigenetic, and immune microenvironment profiling may enhance risk assessment and treatment precision, ultimately improving survival and quality of life in pediatric patients. Full article

Colorectal cancer (CRC), characterized by epidermal growth factor receptor (EGFR) overexpression, is often associated with poor prognosis and limited therapeutic response to conventional chemotherapy. In this study, we developed EGFR-targeted extracellular vesicles (EGFR-tEVs) by transiently engineering donor cells to display the GE11 peptide, aiming to enhance the precision of doxorubicin (Dox) delivery. The physicochemical properties of EGFR-tEVs were characterized using TEM, NTA, and Western blot. In vitro, EGFR-tEV-Dox exhibited increased cellular uptake in EGFR-overexpressing HCT-116 cells, leading to the activation of the p53-Bax-cleaved PARP1 apoptotic pathway. Notably, while Dox treatment induced p53 in normal colon fibroblasts (CCD18-Co), it did not trigger significant Bax activation or PARP1 cleavage, suggesting a preference for survival-related signaling in non-malignant cells. In a xenograft mouse model, EGFR-tEVs + Dox administration resulted in a 33.1% reduction in tumor volume and an 82.8% decrease in Ki-67 expression compared to the control group. These results indicate that transient receptor-mediated targeting enhances functional drug delivery to malignant tissues while minimizing pro-apoptotic induction in normal cells. Our findings suggest that EGFR-tEVs + Dox represents a balanced therapeutic strategy that improves antitumor efficacy with a favorable safety profile for EGFR-positive colorectal cancer. Full article

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which B-cell dysregulation plays a central pathogenic role beyond autoantibody production. Advances in B-cell biology have led to the development of targeted therapies, including inhibition of the B-cell activating factor (BAFF) pathway. Belimumab, a monoclonal antibody that neutralizes soluble BAFF, modulates B-cell survival signals upstream, promoting progressive immunologic remodeling rather than rapid depletion. This review integrates current knowledge on BAFF-dependent B-cell biology with mechanistic, pharmacokinetic, and clinical data to provide a comprehensive framework for understanding belimumab’s effects in SLE and lupus nephritis (LN). Belimumab preferentially reduces transitional and naïve B cells, while memory B cells show a relative transient increase followed by a gradual return to baseline levels, reflecting redistribution rather than expansion, and long-lived plasma cells are largely unaffected. These effects result in progressive remodeling of B-cell compartment dynamics and contribute to broader modulation of adaptive immune amplification pathways. Pharmacokinetic data support a threshold-based model of BAFF neutralization, with exposure influenced by disease-related factors such as proteinuria in LN. Clinical response is primarily determined by baseline disease biology, with greater benefit observed in patients with serologically active disease and less established organ involvement. Across clinical trials and real-world studies, belimumab reduces disease activity and flares, enables glucocorticoid tapering, and slows organ damage accrual. In LN, it improves renal outcomes and reduces the risk of kidney-related events. Collectively, these findings support belimumab as a disease-modifying therapy in SLE. Further research is needed to refine patient selection and optimize treatment sequencing and combination strategies. Full article

Background: Dual mobility (DM) total hip arthroplasty (THA) was introduced to reduce postoperative instability, one of the most frequent causes of revision after hip replacement. Its use has progressively expanded beyond revision surgery to selected high-risk primary cases; however, comparative data integrating both clinical and radiographic outcomes from real-world tertiary centers remain limited. Methods: A retrospective comparative study was conducted including 78 patients who underwent THA with a DM acetabular component between January 2019 and December 2024, and 78 matched controls who received conventional fixed-bearing THA during the same period. Matching criteria were age, sex, and procedure type (primary versus revision). Clinical outcomes were assessed using the Harris Hip Score (HHS) and visual analogue scale (VAS) for pain. Radiographic evaluation focused on component positioning, radiolucent lines, and signs of loosening. Complications and revision rates were compared between groups. Results: The mean age was 71 ± 9 years, and 62% of patients were female. Mean follow-up was 38 months. HHS improved from 54 ± 10 preoperatively to 89 ± 8 postoperatively in the DM group (p < 0.001), with similar final functional outcomes in the conventional THA group (90 ± 9, p = 0.48), and comparable improvement between groups (p = 0.62). Radiographic parameters demonstrated stable fixation and appropriate component positioning in both groups, with no significant intergroup differences. The dislocation rate was numerically lower in the DM group (1.3% vs. 5.1%), although this difference did not reach statistical significance (p = 0.37). No cases of intraprosthetic dislocation occurred. Overall implant survival free from revision at five years was 96.5% for DM and 94.7% for conventional THA (p = 0.47). Conclusions: DM THA achieved excellent clinical and radiographic outcomes, with a numerically lower dislocation rate than conventional THA. Mid-term implant survivorship was comparable between groups, supporting DM as a reliable option for improving stability in appropriately selected patients. Full article

Background/Objectives: Nivolumab plus ipilimumab (IO–IO) provides durable clinical benefit in metastatic renal cell carcinoma (mRCC), yet long-term real-world data focusing on progression-free and treatment-free (PF–TF) survival remain limited. This study aimed to evaluate the long-term outcomes of IO–IO with a particular focus on the frequency and clinical characteristics of PF–TF. Methods: We retrospectively analyzed 63 patients with mRCC treated with first-line IO–IO across eight institutions with a minimum potential follow-up of five years. Progression-free survival (PFS), PFS2, and overall survival (OS) were assessed. PF–TF was defined as absence of disease progression and any cancer-directed therapy at the five-year landmark. Clinical and treatment-related factors were compared between patients with and without PF–TF. Results: The median PFS, PFS2, and OS were 7.5 (95% confidence interval [CI], 5.1–13.3), 26.2 (95% CI, 13.6–46.6), and 47.4 months (95% CI, 29.3–not reached), respectively. At 5 years, 11 patients (17%) achieved PF–TF. Baseline characteristics, IMDC risk classification, and peripheral blood biomarkers were not predictive of PF–TF. PF–TF was associated with the absence of bone metastases, presence of lymph node metastases, and occurrence of immune-related adverse events (irAEs), as well as the delayed onset of irAEs. No PF–TF patients required corticosteroid pulse therapy, and durable PF–TF was observed even after early treatment discontinuation due to adverse events. Conclusions: IO–IO demonstrated sustained long-term efficacy in real-world practice, with a subset achieving durable PF–TF. These findings highlight IO–IO as a strategy capable of providing long-term disease control with reduced treatment burden in selected patients with mRCC. Full article

Cigarette smoke (CS) is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). Investigating the impact of CS on human airway epithelium is important for understanding COPD development and combating its effects. While some studies show that long exposure to CS activates inflammasome formation in airway epithelium, leading to cytokines’ maturation and release, its acute effect on inflammation regulation requires further elucidation. Due to the importance of acute cellular responses in modulating cell survival and controlling inflammatory outcomes, we examined the effect of acute cigarette smoke extract exposure on human bronchial epithelial cells. Due to the high reactive oxygen species content in CS, we hypothesize that acute CS exposure activates the integrated stress response (ISR) pathway leading to stress granules (SG) formation to facilitate oxidative stress resolution and promote cell survival. Immunostaining, fluorescence confocal imaging, quantitative analyses, and immunoblotting were performed to test our hypothesis. We report here that acute exposure to CS extract triggers canonical SG formation by activating the ISR pathway via the PERK/eIF2α arm in a reactive oxygen species-dependent manner. SG formation is abolished upon inhibiting PERK or eIF2α function, or by scavenging oxidants prior to smoke exposure. Characterizing SG formation in terms of measuring SG size and abundance and the sequestration of the SG marker G3BP1 reveals that SG formation is maximal at 15% CS extract exposure for 2 h and undergoes gradual disassembly at longer exposure times. This is closely dependent on cytoplasmic p-eIF2α levels. These results demonstrate that acute exposure to CS activates the protective ISR pathway to potentially reduce the detrimental effects of CS and promote stress resolution and cell survival. Full article

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article

Classical Hodgkin lymphoma (cHL) is a paradigmatic example of a malignancy in which the tumor microenvironment (TME) plays a dominant role in disease biology. Malignant Hodgkin and Reed–Sternberg (HRS) cells typically constitute only a small minority of the tumor mass (approximately 1–5%). HRS cells are embedded within a complex, highly structured immune and stromal milieu that drives survival, immune evasion, and therapy response. Over the past decade, transcriptomic approaches, particularly single-cell RNA sequencing, have reshaped our understanding of cellular heterogeneity within cHL. However, these approaches lack spatial context, a limitation that is especially relevant in cHL, where cell–cell interactions and physical proximity are central to immune evasion and tumor support. Recent advances in spatial transcriptomics now enable genome-scale, spatially resolved interrogation of gene expression in situ. In this review, we summarize spatially resolved studies of the cHL microenvironment, discuss what they reveal about HRS-centered cellular niches and immune evasion, and highlight how these findings may inform risk stratification, biomarker discovery and microenvironment-directed therapies. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoi-somerase 1 (TOP1)-DNA complexes. We have previously developed a TDP1 inhibitor, compound OL9-116, which is capable of enhancing the action of the anticancer drug topotecan (TPC), a TOP1 poison, in vitro and in vivo. In this study, the inhibition mode of OL9-116 (uncompetitive) was investigated. We have shown that N-terminal domain of TDP1, which is important for the cell function of TDP1 but is not involved in catalysis directly, reduced the inhibitory potency of OL9-116 probably by influencing the conformation of the enzyme. OL9-116 did not reduce cell viability and did not affect mitochondrial membrane potential. OL9-116 enhanced the cytotoxic/antiproliferative effect of TPC on the panel of tumor cells. This effect was not observed on nontumor cells or TDP1-deficient cells. OL9-116 and TPC had different effects on TDP1 and TOP1 gene expression detected by PCR depending on the cell type and the presence of functional TDP1. The direct relation between the effects of the compounds on the gene expression and cell survival was not found. The obtained data indicated a synergistic effect of OL9-116 and TPC, which appeared to be mediated by TDP1 inhibition rather than by an effect on TDP1 gene expression. Full article

This study evaluated the potential of pomegranate (Punica granatum) juice byproducts (PJB) as a functional dietary additive for juvenile red seabream (Pagrus major). Four experimental diets were formulated to contain various levels of PJB (0, 2.5, 5.0, and 10.0 g/kg) and fed to fish with an initial body weight of 7.0 ± 0.01 g for 8 weeks. Growth performance, feed utilization, digestive enzyme activity, whole-body composition, plasma biochemical parameters, antioxidant responses, immune parameters, and resistance to Edwardsiella tarda infection were evaluated. Fish fed the diet containing 2.5 g/kg PJB exhibited significantly higher final body weight, weight gain, and specific growth rate compared with the control group and those with higher PJB doses, whereas feed intake, feed efficiency, and protein efficiency ratio were not significantly affected by dietary treatment. Intestinal trypsin and lipase activities were significantly elevated in the PJB2.5 group, whereas amylase activity remained unchanged. Whole-body proximate composition and plasma biochemical parameters, including aspartate aminotransferase, alanine aminotransferase, total cholesterol, glucose, and total protein, were not significantly influenced by dietary PJB supplementation. Dietary inclusion of PJB at 2.5 g/kg also significantly enhanced plasma antioxidant enzyme activities, as evidenced by increased superoxide dismutase and glutathione levels, while catalase activity was elevated in fish fed the PJB2.5 and PJB5 diets. Innate immune responses were also stimulated, with significantly higher serum lysozyme activity and interleukin-1 levels observed in fish fed the PJB2.5 diet. Following experimental challenge with E. tarda, fish fed diets containing 2.5 and 5.0 g/kg PJB exhibited significantly higher cumulative survival than the control group. In conclusion, dietary supplementation with PJB at 2.5 g/kg improved growth performance, digestive capacity, antioxidant status, innate immune responses, and disease resistance in juvenile P. major without adverse physiological effects. Full article

Background/Objectives: Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy with a highly variable clinical behavior. While early-stage disease is often indolent, progression to dermal invasion and lymph node metastasis is associated with a poor prognosis. Reliable biomarkers that reflect tumor aggressiveness and predict clinical outcomes are lacking. The stimulator of interferon genes (STING) pathway plays a central role in innate immune signaling and antitumor immunity; however, its clinical significance in EMPD remains unclear. Methods: We retrospectively analyzed STING expression using immunohistochemistry in formalin-fixed, paraffin-embedded tumor specimens obtained from 63 patients with EMPD. Associations between STING expression and clinicopathological features were evaluated. Overall survival was analyzed using Kaplan–Meier methods, and prognostic factors were assessed using univariate and multivariate Cox proportional hazards regression analyses. Results: STING expression was positive in 26 (41%) and negative in 37 (59%) patients. Loss of STING expression was significantly associated with dermal invasion and lymph node swelling. Kaplan–Meier analysis demonstrated a significantly poorer overall survival in patients with STING negativity than in those with STING positivity. In univariate analysis, lymph node swelling, dermal invasion, and STING expression were significantly associated with survival. Multivariate Cox regression analysis identified lymph node swelling as an independent adverse prognostic factor, whereas STING expression was an independent favorable prognostic factor. Loss of STING expression is closely associated with aggressive clinicopathological features and independently predicts poor prognosis in EMPD. Conclusions: STING expression may serve as a useful prognostic biomarker and provides insight into the immunobiology of EMPD. Full article

Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully understood. Methods: The four publicly available CRC microarray datasets—GSE41258, GSE44076, GSE81558, and GSE117606—along with TCGA-COAD and TCGA-READ datasets and their associated clinical data were obtained. MDK expression was measured at both the mRNA and protein levels using quantitative real-time PCR (qRT-PCR) and Western blotting. To investigate its oncogenic functions, a comprehensive set of assays was performed: transwell and wound healing assays for invasion and migration; CCK-8 and colony formation assays for proliferation; and tail vein/spleen injection models combined with xenograft models to study metastasis and tumor growth in vivo. To uncover underlying mechanisms, Western blotting was used to examine the involvement of epithelial–mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Results: MDK is significantly overexpressed in CRC tissues and cells compared to normal tissues and cells. Notably, patients with high MDK levels show poorer overall survival (OS). Overexpression of MDK increases CRC invasion, migration, proliferation, and metastasis both in vivo and in vitro, while its knockdown reverses these effects. Mechanistically, MDK activates the PI3K/AKT pathway, leading to increased AP2A1 expression and promotion of EMT in CRC. Conclusions: MDK promotes invasion, migration, proliferation, metastasis, and EMT in CRC cells through the PI3K/AKT pathway by inducing AP2A1 expression, which could serve as a diagnostic marker. The PI3K inhibitor LY294002 significantly reduces AP2A1 levels and inhibits MDK-induced malignant behaviors. Targeting MDK-related signaling pathways may offer new strategies for CRC treatment. Full article