Search Results (3,782)

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, often diagnosed at advanced stages with poor survival outcomes. Homologous recombination (HR), a major DNA double-strand break (DSB) repair pathway, safeguards genomic stability via error-free repair. While HR deficiency has been well established as a driver of genomic instability and tumorigenesis in several cancer types, the role of HR in HNSCC remains relatively understudied. Methods: Here, we analyzed the expression patterns of key HR proteins in HNSCC and investigated their association with clinical parameters, DNA methylation, immune cell infiltration, and patient survival outcome. Results: Surprisingly, our results demonstrate that HR factors are consistently upregulated in HNSCC, in both HPV-positive and HPV-negative groups. Survival analysis identified many HR factors, including ATM, BRCA1, BRCA2, PALB2, LIG1, RPA1, and RPA2, as potential prognostic biomarkers for better overall survival. Interestingly, we observed a significant correlation between HR protein overexpression and immune cell infiltration in HNSCC, suggesting a potential immunomodulatory role of HR proteins. To experimentally validate this association in both HPV-positive and -negative cell lines, we showed that MRE11 and RAD51 overexpression in HNSCC cells led to increased phosphorylation of IRF3 and STAT1, indicating activation of the cGAS/STING-mediated innate immune signaling. Conclusion: Together, our findings provide a comprehensive overview of the HR pathway in HNSCC, highlighting the dual role of HR proteins in both genomic maintenance and immune regulation. The consistent upregulation of HR proteins, their association with disease progression, and potential immunogenic effects underscore their promise as diagnostic/prognostic biomarkers and therapeutic targets in HNSCC. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for reliable biomarkers and therapeutic targets. To address this need, we focused on UDP-glucose pyrophosphorylase 2 (UGP2). Although UGP2 has been implicated in tumorigenesis across multiple cancers, its precise role and clinical significance in CRC remain poorly understood. This study aimed to comprehensively characterize UGP2 in CRC through an integrated approach encompassing proteomic screening, bioinformatics analysis, and experimental validation. We identified UGP2 as a significantly downregulated tumor-suppressive factor in CRC. Specifically, UGP2 expression was significantly downregulated in CRC tissues compared with that in normal controls and exhibited strong correlations with aggressive clinicopathological features, including lymphatic invasion, perineural invasion, and colon polyp history, and patient age. It also demonstrated high diagnostic accuracy in CRC, with an area under the receiver operating characteristic curve (AUC) of 0.990. Reduced UGP2 levels were associated with poorer overall survival and disease-specific survival. Hypermethylation of the UGP2 promoter correlated with a favorable prognosis in patients with CRC. UGP2 expression positively correlated with immune cell infiltration within the tumor microenvironment. Functionally, UGP2 knockdown increased CRC cell proliferation and migration while suppressing apoptosis. Conversely, its overexpression yielded the opposite effects, confirming UGP2’s role in constraining malignant phenotypes. Collectively, these findings establish UGP2 as a key CRC tumor suppressor whose downregulation drives malignant progression and predicts adverse clinical outcomes, suggesting its potential as a dual-purpose diagnostic and prognostic biomarker. Full article

Background/Objectives: Neuroinflammation is a leading factor in secondary brain damage following a traumatic brain injury (TBI). Existing therapeutic approaches have limited efficacy against neuroinflammation. The bone marrow, the primary hematopoietic organ, is also a source of inflammatory cells. We propose that targeting the sympathetic regulation of inflammatory cell mobilization could reduce neuroinflammation after TBI. Methods: In ICR mice, we investigated the immune cell response in the blood, bone marrow, motor cortex, and the subventricular zone after TBI modeling and treatment with the sympatholytic agent reserpine. Results: TBI induced neutrophilia and lymphocytosis in the peripheral blood, activated hematopoiesis in the bone marrow, and triggered neuroinflammation and degenerative changes in the cerebral cortex (CC) and the subventricular zone (SVZ) of mice. Reserpine reduced leukocytosis in the blood and hematopoietic activity in the bone marrow of mice with TBI compared to untreated TBI mice. Furthermore, reserpine decreased neutrophilic and lymphocytic infiltration, as well as the number of Iba1⁺ microglial cells, including M1-polarized microglia, Caspase-3⁺ cells, and cells expressing myeloperoxidase (MPO) in the CC and SVZ of treated mice. The activity of degenerative processes was also reduced. Additionally, reserpine reduced the number of M2-polarized microglial cells in the SVZ. Conclusions: The sympatholytic drug reserpine may hold promise for the development of a novel approach to treating neuroinflammation and degeneration following a TBI. This is based on its ability to reduce hematopoiesis and mobilize inflammatory cells from the bone marrow into the bloodstream. Full article

Dry Anophthalmic Socket Syndrome (DASS) is a multifactorial condition that affects roughly half of all prosthetic eye wearers and remains frequently underrecognized. It is characterised by symptoms such as dryness, discomfort, discharge, and inflammation of the socket surface. Diagnostic criteria include validated symptom questionnaires (e.g., OSDI, DEQ-5, SANDE) and at least one clinical sign such as conjunctival staining, blepharitis, or reduced tear meniscus height. This review describes the anatomical, cellular, and molecular changes associated with DASS. Meibomian gland dysfunction is common, with a significant reduction in gland density and structure. Goblet cell density is also often decreased, particularly in the tarsal and bulbar conjunctiva, although findings may be affected by topical treatments. Increased conjunctival inflammation—evidenced by immune cell infiltration and elevated markers such as MMP-9 and ICAM-1—is frequently observed, particularly in the posterior socket lining. Oxidative stress, mediated by dysregulated NOX4, KEAP1, and NRF2 expression, appears to play a contributory role. Additional factors influencing DASS include eyelid malpositions such as entropion and ectropion, prosthesis smoothness and amount of tear film production. Poor hygiene practices and environmental factors may exacerbate symptoms. Given its multifactorial aetiology, DASS requires a complex management strategy targeting inflammation, tear film instability, mechanical irritation, eyelid position and patient education. Increased awareness, standardised diagnostics, and evidence-based care protocols are critical to improving outcomes for prosthetic eye wearers. Full article

Background: Standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer typically employs capecitabine or 5-fluorouracil. Gemcitabine, an alternative radiosensitizer, has a well-established immunomodulatory effect. The role of preoperative concurrent gemcitabine with radiotherapy on rectal cancer microenvironment and long-term survival has not been fully elucidated. Methods: In this phase II clinical trial update and secondary analysis, 40 adult patients with stage T3/T4 or node-positive, non-metastatic rectal cancer received neoadjuvant chemoradiotherapy consisting of external beam radiation (45–54 Gy) with weekly 24-hour infusional gemcitabine (100 mg/m², later 75 mg/m² for toxicity) followed by surgery and adjuvant capecitabine. The protocol was amended to analyse immune cell infiltration pre- and post-treatment using immunohistochemistry. The primary endpoint was pathological complete response (pCR); secondary endpoints included R0 resection rate, toxicity, immune infiltration, disease-free survival (PFS), and overall survival (OS). Results were compared to historical controls treated with capecitabine-based chemoradiation. Results: Of the 40 enrolled patients (83% high-risk features), 32 underwent surgery, and 31 were resected. The updated median PFS was 70 months (median follow-up: 87.4 months); median OS was not reached. The estimated 5-year PFS and OS were 54.4% and 67.5%, respectively. Infusional gemcitabine induced significantly higher total immune cell infiltration in resected tumors compared to controls (p = 0.026). CD8+ T cell density increased markedly in surgical specimens (p = 0.001), and PD-L1+ immune cells rose significantly post-therapy (p = 0.032). There was a trend toward increased CD56+ NK cell infiltration. Toxicities and pCR rates aligned with established regimens. Conclusions: Neoadjuvant chemoradiotherapy with infusional gemcitabine yields durable survival and robust immune cell infiltration in locally advanced rectal cancer, comparable to modern standards. The immunomodulatory effects of gemcitabine—particularly the enrichment of CD8+ T cells and PD-L1+ immune cells—support further evaluation of combination strategies incorporating immunotherapy to enhance systemic disease control. Full article

Colorectal cancer (CRC) is a major cause of cancer death, with the tumor microenvironment and gene expression influencing outcomes. Identifying survival-associated epithelial marker genes (EMGs) may improve prognosis and guide therapy. We obtained single-cell RNA-sequencing (scRNA-seq) data from CRC patients (n = 23,176 cells) from the TISCH database to identify EMGs through differential expression analysis. These were intersected with malignant cell markers. We used bulk RNA-seq data from TCGA-COAD (n = 375) to assess EMG prognostic value via univariable Cox analysis, followed by LASSO regression. Significant genes were evaluated using multivariable Cox models. An EMGs-based risk score was developed and validated using GSE39582 (n = 585) and GSE17536 (n = 177). Immune infiltration was assessed using xCELL and TIMER algorithms. A total of 107 EMGs were identified and assessed in TCGA data. Cox analysis identified 18 survival-related EMGs, which were narrowed by LASSO to SPINK1 and TIMP1. Multivariable analysis confirmed SPINK1 (HR: 0.88, 95% CI: 0.79–0.97, p = 0.009) and TIMP1 (HR: 1.66, 95% CI: 1.29–2.13, p < 0.001) as independent survival predictors. Patients were classified into high- (n = 187) and low-risk (n = 188) groups. The low-risk group had significantly better overall and disease-free survival. Immune profiling revealed distinct patterns, where the high-risk group showed higher dendritic cells, memory T-cells, macrophages, and immune checkpoint expression, while the low-risk group showed enrichment of NK cells, plasma cells, and CD4+ T-helper cells. These findings were validated in the GSE39582 and GSE17536 cohorts. EMGs have prognostic value in CRC, with SPINK1 and TIMP1 as independent survival predictors. Distinct immune patterns support integrating EMGs with immune profiling for improved risk stratification and personalized treatment. Full article

Background and Objectives: Although beaded filament structural protein 1 (BFSP1) may be involved in oncogenic mechanisms, its clinical relevance and functional role in liver hepatocellular carcinoma (LIHC) remain unclear. This study examined the prognostic significance, regulatory mechanisms, and potential therapeutic implications of BFSP1 in LIHC. Materials and Methods: Comprehensive bioinformatics analysis was performed across multiple platforms using datasets derived from The Cancer Genome Atlas. Differential gene expression, DNA methylation, copy number variation, immune cell infiltration, drug sensitivity, and co-expression networks were systematically examined. Functional enrichment analyses of protein–protein and gene–gene interaction networks were conducted using STRING and GeneMANIA. Additionally, short interfering RNA-mediated knockdown and wound-healing assays were performed in HepG2 cells to evaluate BFSP1 function in vitro. Results: The results showed that BFSP1 mRNA expression was significantly upregulated in tissues from LIHC patients. Elevated BFSP1 levels were associated with poorer prognostic patterns, which were further supported by detailed clinicopathological subgroup analyses. Furthermore, BFSP1 expression was correlated with promoter hypomethylation and associated with patterns of tumor-infiltrating immune cells, including specific immune cell subtypes such as M1 and M2 macrophages. Integrative analyses revealed strong associations between BFSP1 and drug sensitivity, as well as a regulatory network encompassing genes involved in the cell cycle, DNA repair, and metabolic processes. Functional knockdown of BFSP1 significantly reduced HepG2 cell migration in vitro, as assessed by wound healing assay, with decreased wound closure at 24 h (11.0% vs. 16.5%) and 48 h (7.4% vs. 12.5%) compared with the control (p < 0.05, n = 6 biological replicates). Conclusions: In conclusion, these findings suggest that BFSP1 functions as a multifaceted prognostic biomarker and a potential therapeutic target for LIHC. Full article

The high attrition rates in glioblastoma (GB) therapeutic development stem largely from preclinical models that fail to adequately recapitulate the dynamic tumor–host ecosystem. Unlike previous reviews that characterize glioma cell lines in isolation, this article integrates tumor biology with the distinct neuro-immune–endocrine landscapes of major laboratory rat strains. We critically evaluate standard rat malignant glioma cell lines (C6, F98, RG2, 9L) alongside transplantable tissue models (GB 101.8, GB 15/47), which offer enhanced translational relevance, demonstrating that the predictive value of any model is contingent upon the specific “glioma model and host strain” pairing and the individual physiological characteristics of the host. We provide evidence that strain-specific hypothalamic–pituitary–adrenal (HPA) axis reactivity (e.g., hyper-reactive Fischer 344 versus normo-reactive Wistar) acts as a decisive, yet often overlooked, modulator of the tumor microenvironment and therapeutic response. The review delineates the utility and limitations of these models, specifically addressing the MHC incompatibilities of the widely used C6 model in immunotherapy research, while contrasting it with the immune-evasive phenotypes of RG2 and the GB 101.8 tissue model. Furthermore, we highlight the superiority of tissue transplants in preserving cellular polyclonality and diffuse infiltration patterns compared to the circumscribed growth often observed in cell line-derived tumors. Consequently, we propose a strategic selection paradigm wherein immunogenic models serve as bioindicators of host immunocompetence, while invasive, non-immunogenic systems (F98, RG2, and GB 101.8) are utilized to investigate therapeutic resistance and systemic host-tumor interactions. Full article

High-grade gliomas—particularly glioblastoma (GBM)—remain refractory to standard-of-care surgery followed by chemoradiation, with a median overall survival of ~15 months. Oncolytic viruses (OVs), which selectively infect and lyse tumor cells while engaging antitumor immunity, offer a mechanistically distinct therapeutic modality. This review synthesizes clinical progress of OVs in GBM, with emphasis on oncolytic herpes simplex virus (oHSV) and coverage of other vectors (adenovirus, reovirus, Newcastle disease virus, vaccinia virus) across phase I–III trials, focusing on efficacy and safety. Key observations include the encouraging clinical trajectory of oHSV exemplars—T-VEC (approved for melanoma) and G47Δ (approved in Japan for recurrent GBM)—the multi-center exploration of the adenovirus DNX-2401 combined with programmed death-1 (PD-1) blockade, and the early-stage status of reovirus (pelareorep) and Newcastle disease virus programs. Emerging evidence indicates that oHSV therapy augments immune infiltration within the tumor microenvironment and alleviates immunosuppression, with synergy when combined with chemotherapy or immune checkpoint inhibitors. Persistent challenges include GBM’s inherently immunosuppressive milieu, limitations imposed by the blood–brain barrier, intrapatient viral delivery and biodistribution, and concerns about viral shedding. Future directions encompass programmable vector design, optimization of systemic delivery, biomarker-guided patient selection, and rational combination immunotherapy. Collectively, OVs represent a promising immunotherapeutic strategy in GBM; further gains will hinge on vector engineering and precision combinations to translate mechanistic promise into durable clinical benefit. Full article

Background: Reliable analgesia is essential to ensure animal welfare and experimental validity in preclinical disease models. However, evidence on the efficacy and side effects of analgesics remains limited. This study investigated the effects of three commonly used analgesics on animal well-being in a murine model of cholestasis. Methods: Thirty male C57BL/6J mice underwent transmitter implantation followed by bile duct ligation (BDL) and received continuous metamizole (3 g/L), tramadol (1 g/L), or carprofen (0.15 g/L) via drinking water before and after surgery. Welfare was evaluated using multiple parameters, including body weight, a distress score, drinking volume, burrowing and nesting behavior, mouse grimace scale (MGS), and telemetric data (heart rate, heart rate variability: SDNN and RMSSD, core body temperature, and locomotion). Additionally, liver and gastrointestinal tissues were analyzed histologically for necrosis and immune cell infiltration. Results: Even prior to surgery, analgesic-specific reductions in body weight, drinking behavior, and burrowing and nesting activity were observed. After transmitter implantation, metamizole treatment led to significantly reduced body weight, drinking volume, and locomotion compared to the other two analgesics. Following BDL, all treatment groups exhibited pronounced distress, weight loss, and reduced activity. Tramadol treatment resulted in slightly improved MGS and SDNN values, indicating minor benefits without sustained welfare restoration. In contrast, carprofen treatment was associated with reduced survival and inflammatory alterations in the forestomach. Conclusions: None of the tested analgesic regimens fully restored animal welfare after BDL. However, tramadol provided modest advantages, suggesting it may represent the most suitable option among the tested analgesics for the BDL model. Full article

PRMT5, a type II methyltransferase catalyzing symmetric dimethylation of arginine residues, has emerged as a promising therapeutic target in various cancers. However, the precise mechanism by which PRMT5 mediated the tumor immune microenvironment, particularly CD8⁺ T cell recruitment in cervical cancer remains elusive. Analysis of data from The Cancer Genome Atlas (TCGA) revealed elevated PRMT5 mRNA levels in cervical cancer tissues, which correlated with reduced immune cell infiltration and poorer patient prognosis. To further investigate the role of PRMT5 in tumor development, a CD8 knockout (KO) mouse tumor model was utilized. Significant inhibition of tumor growth was observed in cervical cancer using a mouse model lacking PRMT5. Notably, this antitumor effect was attenuated in CD8 KO mice lacking functional CD8⁺ T cells. Mechanistically, RNA sequencing (RNA-seq) analysis was conducted to explore how PRMT5 regulates immune cell recruitment. Disruption of PRMT5 was found to increase the secretion of chemokine CXCL10 by tumor cells. CXCL10 binds to its receptor CXCR3, thereby recruiting T cells to the tumor. Furthermore, in CXCR3 KO mice, PRMT5 knockdown failed to enhance T cell infiltration into tumors. These findings indicate that PRMT5 knockdown promotes CD8⁺ T cell recruitment to the tumor microenvironment via CXCL10 signaling. Furthermore, the therapeutic efficacy of the selective PRMT5 inhibitor EPZ015666 was evaluated in a cervical cancer xenograft mouse model. Treatment with EPZ015666 effectively suppressed tumor growth. In summary, these findings elucidate a novel mechanism whereby PRMT5 depletion in cervical cancer cells triggers a CXCL10-mediated chemotactic response, enhancing CD8⁺ T cell infiltration and restricting tumor progression. Thus, our study provides compelling evidence supporting the potential targeting of PRMT5 as a viable immunotherapeutic strategy for cervical cancer. Full article

Background/Objectives: Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US. The presence of deficient DNA mismatch repair and microsatellite instability (dMMR/MSI) in CRC is linked to responses to immune checkpoint inhibitors (ICIs). This study investigates the impact of metformin on the tumor microenvironment (TME) and clinical outcomes of patients with dMMR/MSI CRC treated with ICIs, aiming to better understand its potential role in enhancing ICI efficacy. Methods: Of 25,011 CRC patients in Caris database, 47 received both metformin and ICI therapy (Met-ICI group), and 475 patients received ICI therapy alone (ICI group). Samples underwent genomic or transcriptome sequencing at Caris Life Sciences. Immune cell fractions were estimated using quanTIseq. Univariate and multivariate survival analyses were conducted using the Cox proportional model. Results: The TME analysis of CRC patient samples revealed that TMB-High (≥10 mut/Mb) was more prevalent in the “ICI” group compared to the “Met-ICI” group (99.1% vs. 95.6%, p = 0.036). Mutation rates for most genes between the two groups were similar, but CIC gene mutations were more common in the “ICI” group than in the “Met-ICI” group (23.2% vs. 4.8%, p = 0.006). No significant differences were observed in the PD-L1 positivity rate or immune checkpoint gene expression (including IDO1, IFNG, TIM3, and CTLA4). M1 macrophages and neutrophils showed the highest infiltration among immune cells. However, the fractions of infiltrated immune cells were similar between the two cohorts. Univariate and multivariate analyses showed that there was no significant difference in patient survival between “ICI” and “Met-ICI” cohorts. Conclusions: In this retrospective analysis of real-world clinical outcomes, the concurrent use of metformin with ICIs in patients with dMMR/MSI CRC did not reveal an impact on clinical outcomes. Full article

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a congenital cardiac disorder, but its severity has been increasingly linked to inflammatory processes. This study aimed to investigate gene expression profiles in ARVC to identify genes potentially driving inflammation in affected individuals. Methods: Publicly available gene expression datasets comprising 12 ventricular tissue samples from six clinically confirmed ARVC patients (paired left and right ventricular biopsies) and 12 ventricular samples from six non-failing donor hearts were analyzed to identify differentially expressed genes. Immune infiltration was assessed to determine the proportions of immune cells in the ARVC condition. Correlation analysis between immune cell proportions and gene expression profiles was further performed to identify genes linked with inflammation-specific immune cells. Functional enrichment analysis of associated genes was performed to pinpoint the key involvement of genes in different inflammatory-specific pathways. Finally, the key gene associated with inflammation-specific immune cells and its active involvement in inflammatory pathways was further subjected to molecular docking against a curated library of marine-derived phytochemicals, followed by 100 ns molecular dynamics simulations to evaluate ligand stability. Results: A total of 141 significantly upregulated genes were identified in ARVC. Immune infiltration analysis revealed elevated proportions of regulatory T cells, CD8⁺ T cells, plasma cells, M2 macrophages, resting mast cells, and activated NK cells in the ARVC phenotype, indicating an immunologically active microenvironment. Correlation analysis identified four genes—LIFR, SCN2B, RGCC, and PIK3R1—showing significant positive associations with these immune cells. Functional enrichment analysis highlighted PIK3R1 (LogFC > 2.00) as a central regulator in the PI3K/AKT and mTOR pathways, which govern immune activation, cell survival, and fibrosis. Molecular docking identified two marine compounds, CMNPD18967 and CMNPD756, with strong binding affinities (−5.9 and −5.7 kcal/mol, respectively). Molecular dynamics simulations confirmed stable ligand binding within the PIK3R1 active site. Conclusions: PIK3R1 emerges as a key inflammation-associated gene in ARVC, with strong involvement in immune-regulatory pathways. Marine-derived phytochemicals CMNPD18967 and CMNPD756 demonstrate promising inhibitory potential through stable interaction with PIK3R1. While these findings present potential anti-inflammatory leads, validation in larger clinical cohorts and experimental models is essential to confirm translational applicability. Full article

High mobility group A1 (HMGA1) is a chromatin-associated protein that regulates transcription and drives cancer progression. In this pan-cancer study, we analyzed multi-omics data to comprehensively characterize HMGA1’s expression patterns, prognostic significance, epigenetic regulation, and immunotherapy roles. We found that HMGA1 was markedly upregulated in most cancers, mainly driven by promoter hypomethylation and copy number alterations. Elevated HMGA1 expression was consistently associated with unfavorable patient survival, stemness features, and the activation of oncogenic signaling pathways. Crucially, HMGA1 expression correlated with an immune-excluded tumor microenvironment, characterized by suppressed stromal and immune scores. Even in tumors with immune infiltration, high HMGA1 predicted poor prognosis, likely mediated by enhanced regulatory T-cell (Treg) recruitment and impaired effector immune function. Moreover, HMGA1 levels were positively correlated with tumor mutational burden (TMB), and microsatellite instability (MSI), and immunotherapy-related checkpoints including PD-1, CTLA-4, and TIGIT. Drug sensitivity analysis further revealed that HMGA1 predicted resistance to AKT inhibitors, which was experimentally validated in breast cancer cells treated with Capivasertib. Collectively, our findings establish HMGA1 as a pivotal oncogenic regulator and a promising biomarker for prognosis and for guiding strategies in immunotherapy and overcoming targeted therapy resistance. Full article

Chronic inflammation is a well-established hallmark of cancer, playing a critical role in the initiation and progression of gliomas. Recent evidence underscores the importance of anti-inflammatory natural products as chemotherapeutic and potentially as chemopreventive agents, offering a safe and multifaceted approach to mitigate tumor-promoting inflammation in the brain. This review explores the interplay between major inflammation-related pathways—such as NF-κB, COX-2, and the NLRP3 inflammasome—and key bioactive compounds derived from natural sources such as polyphenols, isothiocyanates, terpenes/lignans, and omega-3-derived mediators. We provide evidence on the effect of these compounds on the above inflammatory triangle. We discuss emerging in vitro, in vivo preclinical and translational evidence in the context of glioma biology and highlight how these compounds may pass the blood–brain barrier (BBB) and modulate the tumor microenvironment (TME), including immune cell infiltration and cytokine profiles that may act in a pro- or anti-inflammatory manner, highlighting their capacity to inhibit GBM-associated inflammation. Each substance may differentially influence the components of the inflammatory triangle. Overall, we position these agents as low-toxicity, formulation-aware adjuncts to standard care. The ultimate goal is offering novel insights on low-toxicity, inflammation-targeting interventions against malignant brain tumors. Full article