Head and neck cancer, particularly oral squamous cell carcinoma (OSCC), remains a major global health burden, with especially high incidence and mortality in Taiwan due to the widespread habit of betel quid chewing. Betel nut mediated OSCC (BN-OSCC) is characterized by aggressive clinical behavior, including increased risks of recurrence, metastasis, and poor survival outcomes, and exhibits limited responsiveness to conventional chemoradiotherapy. Therefore, the development of novel therapeutic agents and radiosensitizers is urgently needed. Evodiamine (EVO), a bioactive quinolone alkaloid isolated from Evodia rutaecarpa, has demonstrated broad anti-tumor activities across multiple cancer types, including inhibition of proliferation, suppression of metastasis, and induction of apoptosis. Although previous studies have reported the anti-OSCC effects of EVO through modulation of pathways such as Akt, EPRS1, and RAGE, its specific impact on BN-OSCC remains unclear. In this study, we investigated the anti-cancer effects of EVO in BN-OSCC and non-BN-OSCC cell lines. Our results demonstrate that EVO significantly inhibits cell viability and proliferation in a dose-dependent manner in BN-OSCC rather than non-BN-OSCC cells. Importantly, EVO induces apoptosis through activation of the caspase-dependent pathway, as evidenced by increased cleavage of caspase-3, caspase-9, and PARP. Furthermore, EVO treatment leads to mitochondrial dysfunction and enhances pro-apoptotic signaling, suggesting involvement of the intrinsic apoptotic pathway. Collectively, these findings indicate that EVO exerts potent anti-tumor effects in BN-OSCC cells by triggering caspase-dependent apoptosis. This study provides novel insights into the therapeutic potential of EVO and supports its development as a promising candidate for the treatment of betel nut mediated oral cancer.
Background:Cutaneous melanoma (CM) is a highly aggressive skin cancer with poor prognosis in advanced stages. Efferocytosis, the process by which apoptotic cells are cleared by phagocytes, plays a dual role in tumor immunity and progression. However, the comprehensive role of efferocytosis-related genes (EFRGs) in CM remains unclear. Methods:We conducted a multi-omics analysis by integrating transcriptomic data from TCGA, GEO and GTEx databases, identifying differentially expressed genes and performing WGCNA to define EFRG signatures. Based on the expression profiles of differentially expressed EFRGs, we identified molecular subtypes, evaluated immune infiltration using ESTIMATE and ssGSEA. A prognostic EFRG risk scoring model was further constructed and validated using multiple machine learning algorithms. Western blot, CCK8 assay, colony formation assay and Transwell assays were performed to validate the functional role of the screened EFRG. Results:21 DE-EFRGs with significant prognostic value were identified and three distinct molecular subtypes were subsequently defined. The EFRG-based scoring model effectively stratified patients into high- and low-risk groups with distinct survival outcomes and immune microenvironment characteristics. The low-risk group exhibited a more immune-activated phenotype and greater sensitivity to immunotherapy and chemotherapeutic agents. In vitro functional validation revealed that knockdown of one screened EFRG, TTYH3, significantly inhibited melanoma cell proliferation and migration. Conclusions:Our study comprehensively characterizes EFRG patterns in CM and proposes a robust EFRG-based prognostic model. TTYH3 is identified as a potential oncogenic effector and therapeutic target. These findings may guide personalized immunotherapy and improve prognostic assessment in melanoma.
Background/Objectives: The central role of G-protein coupled receptors (GPCRs) in tumor biology is becoming acknowledged. Yet their involvement in cancer stem cells (CSCs) niche is unknown. Molecular mechanisms of CSCs allow self-formation capacity, resistance to chemotherapy and immune therapy. Methods:Western blots, Co-immunoprecipitation (co-IP) analysis, RT-PCR, Lef/Tcf luciferase activity and Alpha Fold3 HANDDOCK v2.4 protein-protein docking interactions. Results:It is demonstrated that protease-activated receptor 4 (PAR4) induces β-catenin levels, co-associates with LRP6 coreceptor and promotes DVL nuclear translocation. PAR4 induced β-catenin transcriptional activity is shown by TOPflash luciferase assay and enhanced downstream target genes levels. Significantly, PAR4 co-binds leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) as determined by co-IP and protein-protein docking analyses. We show also that another GPCR namely, GPR25 specifically expressed in the gastrointestinal tract cells, elicits β-catenin stabilization and co associates with LGR5. Conclusions:As was previously shown for PAR2 also PAR4 and GPR25 elicit β-catenin stabilization and they co-link with LGR5. We propose that GPCRs that potently induce β-catenin stabilization are potentially involved in the regulation of CSCs niche. Our data may provide future directions for potential partners in the cancer stem cell niche.
Objective:Nucleosome assembly protein 1-like 1 (NAP1L1) plays an important role in the development and progression of several types of cancer. Subject and Methods:This study investigated the association between NAP1L1 polymorphisms, particularly rs11180813, and susceptibility to oral squamous cell carcinoma (OSCC). Results:Our study showed that betel quid chewing and cigarette smoking were significantly associated with OSCC risk (p < 0.001). No significant correlation was found between NAP1L1 SNPs and overall OSCC susceptibility. However, among OSCC patients, patients with rs11180813 variant genotypes (GC/CC) were associated with lymph node metastasis (adjusted OR = 1.565, 95% CI = 1.042-2.350, p = 0.031) and poor tumor differentiation (adjusted OR = 2.284, 95% CI = 1.126-4.635, p = 0.022). In buccal OSCC, the rs11180813 variant was associated with lymph node metastasis (adjusted OR = 2.349, 95% CI = 1.213-4.549, p = 0.011). TCGA analysis revealed that high NAP1L1 expression correlated significantly with lymph node metastasis and poor tumor differentiation (p < 0.0001). Conclusion:These findings suggest that NAP1L1 and its rs11180813 polymorphism may be associated with certain clinicopathological characteristics of OSCC, particularly lymph node metastasis and tumor differentiation. Further studies are required to validate their clinical significance.
Nasopharyngeal carcinoma (NPC) is mainly treated with radiotherapy. With the advancements of imaging and radiotherapy techniques, the delineation of NPC target areas has evolved from empirical field setting in the two-dimensional era to three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), and image-guided adaptive radiotherapy (ART), significantly improving treatment accuracy and safety. This review systematically explores the development process of target area delineation in NPC, focusing on the evolution and standardization of target areas in the nasopharynx and neck lymph nodes, and combines the role of multimodal imaging such as MRI and PET-CT in target area delineation. The article further examines the clinical response strategies and research trends of target area changes after induction chemotherapy (IC), and looks forward to the potential of ART and artificial intelligence in future target area delineation. The review aims to provide clinical practitioners with a scientific, rational, and personalized approach to target delineation, optimizing treatment plans and improving clinical outcomes.
Background: Lung adenocarcinoma (LUAD) exhibits extensive molecular heterogeneity and poor prognosis, necessitating novel epigenetic biomarkers. N6-methyladenosine (m6A) modification, a pivotal epigenetic regulator of RNA, is frequently dysregulated in LUAD, yet its systematic roles in clinical prognosis and the tumor microenvironment (TME) remain poorly elucidated. Methods: Transcriptomic profiles and clinical data from large-scale cohorts were integrated and analyzed. Unsupervised consensus clustering based on 47 m6A-related genes (MRGs) was performed to distinguish distinct molecular subtypes. A prognostic model was developed via LASSO-Cox regression algorithm and further validated in multiple independent cohorts. Immune infiltration, tumor mutational burden (TMB), immunotherapy response (TIDE/IPS), and chemotherapy sensitivity were analyzed, complemented by single-cell RNA sequencing. Results: Two distinct m6A-related gene clusters (mRGclusters A and B) were identified. Patients in cluster B exhibited inferior survival outcomes, higher m6A pathway activity, and significant enrichment of cell cycle-related pathways. The eight-gene signature successfully stratified patients into high-risk (HR) and low-risk (LR) subgroups. Patients in the HR group presented significantly worse overall survival (P < 0.05), higher TMB levels, and upregulated expression of multiple immune checkpoint genes such as LAG3 and PDCD1. CSMD3 mutations were capable of improving the survival of HR patients by facilitating the infiltration of natural killer cells and follicular helper T cells. The signature independently predicted prognosis (AUC: 0.70-0.84) and treatment response: LR patients favored immunotherapy (lower TIDE, higher IPS), while HR patients were sensitive to chemotherapy (e.g., Bosutinib, Tozasertib). Conclusion: This transcriptome-derived m6A-associated prognostic model can effectively predict clinical survival outcomes and therapeutic response in LUAD patients. Combined with immune landscape, genomic mutation profiles and single-cell transcriptomic evidence, this signature provides a reliable basis for personalized risk stratification and rational treatment choice.
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, and diabetes mellitus has been recognized as both a risk factor for and a potential consequence of PDAC. However, the epidemiological trends and shared molecular mechanisms underlying this association are not completely understood. Methods: We conducted an integrative analysis combining population-level epidemiological data and transcriptomic datasets. Global trends in PDAC incidence, PDAC-related mortality, and diabetes incidence from 2013 to 2023 were obtained from the Global Burden of Disease (GBD) database. A meta-analysis was performed to quantify the association between diabetes and PDAC risk. In addition, gene expression datasets focusing on PDAC (GSE15471) and type 2 diabetes mellitus (T2DM; GSE20966) were obtained from the Gene Expression Omnibus database, differentially expressed genes were identified, and upregulated genes associated with both PDAC and T2DM were examined using heatmaps. Results: Continuous increases in global PDAC incidence, mortality due to PDAC, and the incidence of diabetes were identified in the GBD data. The meta-analysis of eight studies demonstrated that diabetes was significantly associated with an increased risk of PDAC (pooled relative risk = 1.94, 95% CI: 1.78-2.11). Transcriptomic analyses identified five genes-FXYD3, LAMC1, MDFIC, SOCS3, and TREM2-that were consistently upregulated in both PDAC and T2DM-affected tissues. Conclusion: This integrative epidemiological and transcriptomic analysis demonstrates that diabetes and PDAC share not only similar global disease trends but also a significant epidemiological association and common molecular alterations. The identified shared genes may represent molecular links between diabetes and PDAC, providing new insights applicable to risk stratification and mechanistic studies.
Exosomes are small extracellular vesicles (EVs) that play an important role in intercellular communication among multiple cell types. In recent years, they have emerged as a novel and promising class of cancer biomarkers, offering significant potential to increase diagnostic and therapeutic strategies. These bilayer nano-vesicles are actively secreted by living cells into various biological fluids and carry a diverse cargo of proteins, nucleic acids, and other biomolecules that reflect the physiological and pathological state of their cells of origin. The molecular composition of exosomes mirrors the dynamic processes and unique cargo of molecular and genetic data, reflecting the complex activities within cancer cells, making them a promising alternative for cancer detection and treatment monitoring. Although the mechanisms underlying exosome biogenesis, secretion, and cargo selection in cancer remain incompletely understood, growing evidence highlights their importance in tumor progression and therapeutic response. Exosomal proteins have gained considerable attention as potential therapeutic targets. These proteins can regulate immune responses, reshape the tumor microenvironment, and influence cancer cell proliferation and survival. Consequently, targeting exosome-associated proteins represents a promising strategy for developing innovative anticancer therapies. Advances in exosomal protein analysis have provided a promising approach for unraveling the complex molecular networks underlying cancer biology. A wide range of analytical techniques is available to identify and quantify exosomal proteins, enabling characterization of cancer-specific molecular signatures. As an expanding field in cancer research, exosomes have the potential to revolutionize both therapies and diagnostics. By deciphering the diverse molecular and functional cargos of exosomes, exosomes offer new insights that may lead to more precise, effective, and personalized approaches to cancer management.
Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with poor clinical outcomes due largely to recurrence and therapy resistance. Dehydroleucodine (DhL) is a sesquiterpene lactone derived from Asteraceae species, which has demonstrated anticancer activity in several tumor models. However, its therapeutic relevance in OSCC has not been established. This study investigated the antitumor effects of DhL and the mechanisms underlying its activity in OSCC using complementary in vitro and in vivo approaches. DhL significantly suppressed cell viability and clonogenic growth in HSC3 and SCC4 cells, with relatively low cytotoxicity toward normal gingival fibroblasts (HGF-1) under the tested conditions. The underlying mechanisms involved apoptotic cell death and G2/M phase arrest, accompanied by reduced cyclin B1 and CDK1 expression. DhL was also shown to promote mitochondrial dysfunction, as indicated by loss of mitochondrial membrane potential, increased Bax/Bcl-2 ratio, elevated cleaved caspase-3 expression and activity, and increased intracellular reactive oxygen species (ROS) generation. Pretreatment with the antioxidant N-acetylcysteine partially attenuated apoptosis and cell cycle arrest, suggesting that ROS plays a role in both responses. Systemic DhL treatment in an in vivo xenograft model significantly inhibited tumor growth and increased cleaved caspase-3 expression in tumor tissue without a significant loss of body weight. Together, these findings identify DhL as a potent suppressor of OSCC growth, which acts through ROS-associated mitochondrial apoptosis and G2/M arrest, supporting further preclinical evaluation of DhL as a candidate therapeutic agent for OSCC.
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally and play crucial roles in cancer biology and immune function. Among them, miR-150-5p has emerged as a key regulator with complex, context-dependent roles in both tumorigenesis and immune cell differentiation. This review provides a comprehensive synthesis of current knowledge on miR-150-5p, highlighting its dual function as a tumor suppressor or oncogene depending on cancer type and cellular context. We examine its involvement in hematologic malignancies and solid tumors, detailing the molecular mechanisms through which it influences proliferation, apoptosis, and metastasis. Particular emphasis is placed on the role of extracellular vesicle (EV)-associated miR-150-5p as a modulator of the tumor microenvironment (TME), including its impact on angiogenesis, immune evasion, and intercellular communication. We further explore miR-150-5p's regulation of key immune cell subsets-such as macrophages, dendritic cells, T cells, and natural killer cells-and its implications for anti-tumor immunity. Finally, we discuss the therapeutic potential and challenges of targeting miR-150-5p, including delivery barriers, off-target effects, and opportunities for personalized medicine. By integrating recent findings, this review underscores miR-150-5p's value as both a biomarker and a therapeutic target in cancer immunology.
Oncolytic virotherapy represents an innovative therapeutic modality in oncology, exploiting the selective tropism of viruses to target and eradicate malignant cells. Unlike conventional cancer treatments such as chemotherapy and radiotherapy, oncolytic viruses (OVs) exhibit a dual mechanism of action: direct tumor cell lysis and potent immune activation. This approach transforms tumors into in situ vaccines, generating durable anti-tumor immune memory. The field has garnered substantial attention following the regulatory approval of talimogene laherparepvec (T-VEC), a genetically engineered herpes simplex virus, for metastatic melanoma treatment-a watershed moment in oncolytic virotherapy. Recent advances in genetic engineering have significantly enhanced OV specificity and efficacy, addressing critical challenges including tumor-selective targeting and immune evasion. This review comprehensively examines the complex mechanisms underlying OV therapeutic action, clinical applications, and recent developments that position oncolytic virotherapy as a transformative strategy in contemporary cancer treatment.
Voltage-gated calcium channels (VGCCs) are crucial membrane proteins that mediate calcium influx. The CACNA gene family, which encodes the alpha subunits of VGCC complexes, is essential for forming functional calcium channels and plays significant roles in various cancers. This review focuses on the CACNA1E gene, which encodes the Cav2.3 channel α1E subunit, and systematically elaborates its role in cancer. Studies have identified CACNA1E as a key prognostic stemness-related gene in bladder cancer. Its somatic mutations are associated with the development of air pollution-related lung cancer and non-small cell lung cancer. In breast cancer, genetic variations and DNA methylation differences in CACNA1E have also been reported. Functionally, CACNA1E drives tumor progression by regulating calcium signaling. For example, in osteosarcoma, METTL3-mediated m⁶A modification stabilizes CACNA1E mRNA, activating the WNT7B/Ca²⁺ signaling pathway and thereby promoting tumor progression and chemoresistance. The expression of CACNA1E is closely linked to patient prognosis, with its amplification and overexpression correlating with relapse in favorable histology Wilms' tumor. Additionally, CACNA1E is involved in therapy resistance, as evidenced by its downregulation being associated with temozolomide resistance in glioblastoma. Collectively, this evidence suggests that CACNA1E, along with other VGCC members, may serve as a potential prognostic biomarker and therapeutic target in cancer. Future research should further explore their molecular mechanisms, interactions with the tumor microenvironment, and clinical translation potential.
Background:Obesity's impact on cancer treatment outcomes is poorly understood, especially in the context of immuno-oncology. This study explores how obesity and medical comorbidities are associated with overall survival in cancer patients receiving immune checkpoint inhibitors (ICIs). Additionally, considering the influence of sex on body composition in obesity, this study examines the relationship between sex, obesity, medical comorbidities, and survival. Methods:This cohort study involved 688 patients with metastatic cancer received ICIs as first- or second-line therapy. Obesity was assessed using body mass index (BMI). Cox proportional hazard models and Kaplan-Meier survival analysis were used to examine associations between predictors and overall survival. Results:Patients with higher BMI had longer overall survival, and hazard ratio (HR) for death was 0.83 (95% CI 0.73-0.95) for every 10 units increased in BMI. Additionally, patients belonged to the highest BMI group (≥ 40) had the lowest risk of death when comparing to patients with BMI 18.5 to < 30 with HR 0.58 (95% CI 0.37-0.90). In subgroup analysis, a significant association between high BMI and decreased HR for death was predominantly observed in the male cohort. In multivariate analysis, the prognostic value of BMI remained significant after adjusting for performance status, line of therapy, age-adjusted medical comorbidities, and cancer type. Conclusions:Obesity was associated with decreased mortality risk for cancer patients who had received ICIs. There could be a sex-dependent association between survival benefit and obesity.
Introduction: Genomic alterations have been reported to correlate with patients' response to immune checkpoint inhibitor (ICI) therapy in hepatocellular carcinoma (HCC). The present study aimed to examine whether single nucleotide polymorphism (SNP) is associated with ICI treatment-related side effects and progression-free survival (PFS) in HCC patients. Methods: This retrospective study included 96 patients with HBV-related HCC receiving ICI (atezolizumab plus bevazizumab) therapy between 2020 and 2023. Five SNPs derived from a previous genome-wide association study linking to chemotherapy responses in HCC patients were included. Their predictive values for PFS and side effects were examined. Results: After ICI therapy, patients with GALNT14-rs9679162 "GG" genotype (median PFS = 19.7 months, 95% confidence interval [CI]: 12.3-35.7; p = 0.032) had a longer PFS, whereas GALNT14-rs675230, BMP7-rs6025211, WWOX-rs13338697 or WWOX-rs13333314 were not associated with PFS (all p > 0.05). GALNT14-rs9679162 "GG" genotype (odds ratio [OR] = 0.298, 95% CI: 0.096-0.926; p = 0.036) was also associated with a decreased risk of post-treatment high-grade aspartate aminotransferase (AST) elevation. Multivariate analysis showed that GALNT14-rs9679162 "GG" genotype (hazard ratio [HR] = 0.433, 95% CI: 0.212-0.886; p = 0.022) and high initial albumin-bilirubin (ALBI) grade (HR = 2.053, 95% CI: 1.153-3.590; p = 0.014) were independently associated with PFS. Conclusions: Genetic variant of an SNP, GALNT14-rs9679162, predicts post-treatment PFS and side effect in HBV-related HCC patients receiving ICIs therapy.
Introduction:The best tissue sample is still very important for the diagnosis of mesothorax lymphadenopathy. In the past 20 years endobronchial ultrasound (EBUS) has been used efficiently in most cases of primary lung cancer disease or metastatic disease. Several new type of needles have been created such 19G, 18G and hybrid biopsies with cryoprobes. Rapid on-site evaluation (ROSE) is used as an additional initial diagnostic tool. Confocal microscopy is a method of rapid on-site evaluation. Patients and Methods:One hundred patients with mesothorax lymphadenopathy were biopsied with ebus and two groups were created one with rapid on-site evaluation with confocal microscopy and one by an operator with microscopic evaluation with sample preparation on cytoglasses. Our main objective was to assess parameters such as time, false negative results between the two techniques and technical issues such as the accessibility and evaluation between the two techniques. Safety was also evaluated. Results:Rapid on-site evaluation is more cost efficient with a cytologist on site, however; with a higher rate of false negative results. Accessibility with the Cellvizio® catheter was less possible in a few cases due to rigid angles within the airways especially for small lymphnodes ≤ 1.5 cm (L4L mainly). Discussion:Confocal is a safe and time-efficient technique for mesothorax lymphadenopathy. A high level of training is required for pulmonary physicians in order to assess the novel imaging technique. Definitely different parts of the lymphnode have to reached and evaluated in order to have a proper initial evaluation.
Background:Genetic and environmental factors regulate many physiological processes in the human body, and alterations in these processes may contribute to the development of various diseases, including breast cancer (BC), which is considered the most prevalent cancer among women and a leading cause of cancer-related mortality in the Jordanian population. Genes such as ACE, SOD1 and PER3 play important roles in regulating essential biological functions. These genes are involved in key physiological pathways, including blood pressure regulation, oxidative stress response and circadian rhythm maintenance, and genetic variants within them may influence susceptibility to cancer. Therefore, this study investigates the association between polymorphisms in the ACE, SOD1 and PER3 genes and the risk of breast cancer, with the aim of evaluating how these genetic variations relate to breast cancer susceptibility and clinical outcomes in Jordanian women. Methods:Blood samples of 300 women diagnosed with breast cancer, along with 300 healthy participants, were collected, and DNA was extracted from them. Genetic variants in the ACE (rs1799752), SOD1 (rs36232792) and PER3 (rs57875989) genes are examined through employing direct PCR to amplify the target regions. Results:The ACE (rs1799752) variant was observed to be associated with breast cancer susceptibility, with the I/I genotype increasing risk of breast cancer (OR = 5.138, 95% CI = 1.38-19.03, p = 0.014). No associations were observed for SOD1 (rs36232792) and PER3 (rs57875989) variants. Conclusion:The rs1799752 polymorphism is suggested to have the potential of serving as a biomarker for breast cancer susceptibility in Jordanian women, as it is associated with elevating the risk.
Background: As cancer survival improves, a growing number of patients experience functional decline and require supportive care and long-term care after hospitalization. However, the relationship between functional severity and post-discharge long-term care utilization in patients with cancer remains insufficiently characterized. This study examined long-term care service patterns across functional severity levels, as classified by a Case-Mix System, among hospitalized patients with cancer undergoing discharge planning. Methods: We conducted a retrospective single-center study of adult patients with cancer who received structured discharge planning at a tertiary hospital in Taiwan between January and December 2024. Discharge outcomes and applications for government-funded long-term care services were described for the full cohort. Exploratory multivariable analyses were restricted to patients who applied for long-term care and had complete Case-Mix System assessment data. Modified Poisson regression with robust variance was used for binary service outcomes, Poisson regression for the number of requested service types, and log-linear regression for length of stay. Results: Among 207 hospitalized patients with cancer who received discharge planning, 141 (68.1%) returned home, 26 (12.6%) were transferred to long-term care facilities, 1 (0.5%) was transferred to another hospital, and 39 (18.8%) died during hospitalization. Of 167 patients discharged home or to care facilities, 75 (44.9%) applied for long-term care services. Among applicants, 19 (25.3%) had mild disability, 36 (48.0%) moderate disability, and 20 (26.7%) severe disability according to Case-Mix System categories. Long-term care utilization showed a non-linear pattern across functional strata. After adjustment for age, sex, and length of stay, moderate disability was associated with a higher number of requested service types than mild disability (adjusted relative risk [aRR] 1.47, 95% CI 1.16-1.87; p = 0.001). Severe disability was associated with greater respite care use (aRR 2.40, 95% CI 1.40-4.09; p = 0.001), lower home-care use (aRR 0.40, 95% CI 0.17-0.95; p = 0.038), and longer hospitalization (ratio 2.82, 95% CI 1.71-4.65; p < 0.001). Conclusions: Functional stratification using a Case-Mix System was associated with distinct long-term care service patterns among discharged patients with cancer. Moderate disability was linked to broader multi-service needs, whereas severe disability was more strongly associated with respite-oriented care and prolonged hospitalization. In this single-center exploratory cohort, these findings support further validation of functional stratification approaches for post-discharge cancer care transitions.
Background:Gastric carcinogenesis involves progressive molecular and metabolic alterations, yet non-invasive biomarkers for early detection and risk stratification remain limited. This study aimed to characterize systemic metabolomic changes across the gastric carcinogenesis spectrum and to investigate potential associations between serum metabolites and gastric microbiome-related pathways. Methods:In this exploratory study, untargeted serum metabolomics was performed on samples from patients with gastric dysplasia or early gastric cancer (n = 40) and healthy controls (n = 14). Differential metabolite analysis, principal component analysis, and k-means clustering were used to identify metabolic alterations and potential metabolic subgroups. Microbial pathway associations were examined using metabolite origin inference based on gastric-resident taxa reported in prior studies. Results:Eighteen metabolites were significantly altered in gastric carcinogenesis compared with healthy controls. Six metabolites displayed distinct profiles that suggest two metabolic subgroups, including one subgroup showing a metabolic pattern closer to that of healthy controls, independent of histologic severity. Microbial pathway inference suggested contributions from Pseudomonadota, Actinomycetota, and Bacillota, with ornithine-related metabolites emerging as a key metabolic link previously implicated in dysplasia-to-carcinoma progression. These findings highlight inter-patient heterogeneity and potential metabolic-microbial interactions underlying gastric carcinogenesis. Conclusion:These findings suggest that serum metabolomic profiling may capture metabolic heterogeneity across the gastric dysplasia-early gastric cancer spectrum and generate hypotheses regarding microbiome-related metabolic alterations. While exploratory in nature, this study provides preliminary evidence supporting the potential of serum metabolites as non-invasive indicators of early gastric carcinogenesis, warranting validation in larger and longitudinal cohorts.
Objective: This study aims to systematically evaluate phenome-wide clinical factors contributing to radiation-induced toxicities (RITs) and provide evidence to identify acute RITs-associated risk factors for personalized radiation treatment stratification. Methods: Leveraging genome-wide association study data from 12,042 patients with prostate, head and neck, breast, or lung cancer, we conducted MR-PheWAS (phenome-wide association study integrated with Mendelian randomization) to evaluate the impact of 22,872 phenotypic traits on the susceptibility to acute RITs. Results: MR-PheWAS pinpointed diverse acute RITs-associated phenotypic traits, including previously noted and novel ones. Proteins related to infection and immunity, like C-reactive protein and Interleukin-4 receptor alpha, were found to augment the risk of acute RITs, whereas growth differentiation factor 15, fibroblast growth factor-2 and Interleukin-16 seemingly reduce it. Notably, systolic/diastolic blood pressure, and lipoprotein or cholesterol levels could elevate the risk, but fatty acids, lipids and body mass index-adjusted leptin levels offered protection. Real-world validation in 1,078 breast cancer patients who underwent radiotherapy in our department showed that red blood cell count (lowering risk), serum urea and uric acid levels (increasing risk) before radiotherapy were linked to acute RITs. Moreover, we estimated the direct causal link between the associated traits and acute RITs through multivariate MR analyses, and unveiled that systemic lupus erythematosus, and high-density lipoprotein cholesterol levels remained significantly associated with acute RITs. Conclusion: This study identified the phenome-wide risk factors linked to acute RITs, and future research was needed to clarify their underlying mechanisms for effective prevention of acute RITs.
Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer, with a globally increasing incidence. The disease exhibits significant sex-related clinical and biological differences: while incidence is approximately three times higher in women, men face a greater risk of lymph node metastasis, recurrence, and mortality. This gender disparity may be associated with hormonal factors, particularly estrogens, which are known to modulate cellular proliferation, invasion, migration, and adhesion in thyroid tumor cells. However, the molecular pathways underlying these effects remain poorly understood. In this context, the hallmarks of cancer proposed by Hanahan-such as sustained proliferative signaling, evasion of cell death, and reprogramming of the tumor microenvironment-provide a valuable framework to investigate sex-based disparities. This study assessed, via immunohistochemistry, the expression of molecular markers related to ferroptosis (GPX4, ALOX5, ACSL4, TFRC), the NLRP3 inflammasome and its components (NLRP3, ASC, caspase-1, caspase-5, caspase-8, IL-1β, and IL-18), proliferation (IRS-4), and tumor suppression (KLOTHO) in PTC samples from 25 men and 25 women. Our results demonstrated increased expression of ferroptosis-related markers, components of the NLRP3 inflammasome, and IRS-4 in female-derived samples, whereas male samples exhibited higher KLOTHO expression levels. These findings support the hypothesis of a molecular basis for sexual dimorphism in PTC and highlight the need for further research with larger cohorts and mechanistic approaches to elucidate these pathways and their therapeutic potential.
