Search Results (22,296)

Epoxide hydrolases (EHs) constitute a conserved enzyme family that catalyzes the hydrolysis of epoxides into less reactive diols. Beyond their canonical roles in xenobiotic detoxification, EHs have emerged as critical regulators of lipid metabolism, redox balance, and inflammatory signaling. Accumulating evidence implicates EH family members, particularly Ephx1 (microsomal EH) and Ephx2 (soluble EH), in cardiovascular diseases, cancer, neurodegeneration, metabolic disorders, and other pathological conditions. More recently, studies have uncovered specialized functions of Ephx3 and Ephx4, broadening our understanding of EH biology and highlighting their tissue-specific roles in skin homeostasis and lipid signaling. Here, we systematically review the structural features, catalytic mechanisms, and physiological functions of EHs, with an emphasis on their regulatory networks in human diseases. We further discuss advances in genetic, epigenetic, and translational studies that connect EHs to disease susceptibility and progression. Finally, we evaluate the therapeutic potential and challenges of targeting EHs, particularly soluble EH inhibitors, and propose future research directions to bridge basic discoveries with clinical translation. This review aims to provide a comprehensive framework for understanding the multifaceted roles of EHs and to inspire novel strategies for precision medicine. Full article

This review evaluates recent progress in nanozyme-based biosensors for detecting circulating tumour cells, nucleic acids, and protein biomarkers, with particular attention to how peroxidase-, oxidase-, and catalase-like reactions enhance signal generation across electrochemical, optical, and microfluidic platforms. The roles of iron oxide–gold composites, silica nanostructures, quantum dots, and hybrid nanomaterials in improving analytical performance, enabling multiplexed detection, and facilitating assay miniaturization are critically assessed. Advances such as amplification-free detection approaches, smartphone-compatible point-of-care systems, and AI-assisted data analysis are discussed in relation to their translational potential. Key barriers, including regulatory requirements, reproducibility concerns, and manufacturing scalability, are also evaluated. By integrating mechanistic understanding with practical considerations for clinical deployment, this review outlines how next-generation nanozyme-based biosensors may strengthen early cancer detection, real-time monitoring, and precision oncology. Full article

Background: Liquid biopsy-based biomarkers provide valuable insights into tumor biology, dynamics, burden, relapse prediction and therapeutic responsiveness. The stress-inducible heat shock protein 70 (Hsp70), which is frequently overexpressed in highly aggressive solid tumors and is presented on the cell membrane of tumors but not normal cells, is found in the circulation either as a free protein originating from dying cells or in the context of extracellular vesicles (EVs) that are actively released by viable tumor cells. This study demonstrates the potential value of circulating Hsp70 (eHsp70) levels across multiple solid tumor entities as an entity- and stage-dependent diagnostic biomarker reflecting tumor burden and disease stage. Methods: Circulating eHsp70 levels, as determined using the Hsp70-exo ELISA which detects free and EV-associated Hsp70, in plasma samples collected from patients with different tumor entities (n = 389) prior to the initiation of any oncological therapy and healthy controls (n = 108) between 2021 and 2025, were analyzed retrospectively. Tumor stages were categorized as early, locally advanced, or metastatic. The Kruskal–Wallis test was used for group comparisons and the Receiver Operating Characteristic (ROC) curve was used to evaluate the diagnostic performance of eHsp70 levels. DeLong’s test was used to calculate differences between AUC values. Results: In tumor patients (n = 389), circulating eHsp70 levels were significantly higher than those in healthy controls (n = 108) (Kruskal–Wallis, p < 0.001). eHsp70 levels progressively increased from early-stage to locally advanced and metastatic disease in a stage-dependent manner. Although ROC analysis demonstrated the limited discriminatory performance of eHsp70 levels in early-stage disease (AUC 0.569), increased discrimination was apparent in locally advanced disease (AUC 0.751), metastatic tumors (AUC 0.784) and combined advanced tumor diseases (AUC 0.765; significant by DeLong’s Test comparing early-stage to locally advanced and metastatic tumors), irrespective of the tumor entity with the highest AUC values in metastatic breast cancer (AUC 0.872), sarcoma (AUC 0.861) and non-small cell lung cancer (NSCLC) (AUC 0.835). Apart from minor entity-specific differences, the correlation of eHsp70 levels with the tumor stage remained consistent across all measured tumor entities. Conclusions: Circulating eHsp70 levels are markedly elevated in patients with highly malignant solid tumors and show a consistent, stage-dependent increase across multiple tumor types. These findings suggest that circulating eHsp70, as an indicator of tumor-associated cellular stress and overall tumor burden, represents a valuable biomarker for assessing disease stage, monitoring disease progression, and evaluating therapeutic responses. Full article

Background/Objectives: Cancer cachexia (CC) is a metabolic syndrome characterized by the progressive loss of skeletal muscle and adipose tissue during tumor progression. Despite its clinical prevalence, effective therapeutic options are currently lacking. Phloretin, a natural flavonoid with potent anti-inflammatory and antioxidant properties, has unclear efficacy against CC. This study investigates the therapeutic potential of phloretin in ameliorating cancer cachexia. Methods: Mouse models of CC were established using BALB/c mice implanted with C26 colon carcinoma cells and C57BL/6 mice implanted with Lewis lung carcinoma (LLC) cells. Upon the detection of palpable tumors, phloretin (10 mg/kg) was administered daily via intraperitoneal injection. At the endpoint, hind limb skeletal muscle, inguinal white adipose tissue (iWAT), and hearts were harvested and weighed. Lean body mass was assessed by analyzing the weight of the carcass following the excision of skin, subcutaneous fat, and visceral organs. Gene expression and protein levels in muscle tissues were subsequently quantified. Results: Phloretin administration significantly alleviated tumor-induced loss of tumor-free body weight. It effectively preserved skeletal muscle mass in both C26 and LLC cachexia models, while significantly attenuating adipose tissue depletion in the C26 model. In vitro, phloretin treatment mitigated myotube atrophy induced by C26 conditioned medium. Mechanistically, phloretin inhibited STAT3 activation in skeletal muscle. This inhibition suppressed the expression of the E3 ubiquitin ligases MuRF-1 and Atrogin-1. Furthermore, phloretin concurrently modulated the autophagy pathway. Conclusions: Phloretin effectively ameliorates cancer cachexia-induced muscle wasting by targeting STAT3-mediated protein degradation and autophagy pathways. These findings suggest that phloretin represents a promising therapeutic agent for the clinical management of cancer-associated cachexia. Full article

Background/Objectives: Active surveillance (AS) has become the gold standard for managing men diagnosed with low-risk or favorable intermediate-risk prostate cancer. However, both patients and healthcare providers often face a lack of clear, evidence-based guidance regarding lifestyle choices during this period. This systematic review was designed to determine whether specific lifestyle modifications—including dietary changes, physical activity, weight control, and use of supplements—can tangibly impact oncologic outcomes or improve patient-reported quality of life during surveillance. Methods: The research followed PRISMA protocols, searching PubMed, Cochrane, and Scopus for studies published between 2000 and 2025. The team included diverse methodologies, from randomized controlled trials to qualitative interviews, specifically focusing on men on AS. To ensure high standards, two independent reviewers performed data extraction and quality assessments using CASP tools, and the review was formally registered with PROSPERO. Results: The review synthesized data from over 30 heterogeneous studies. The findings suggest that lifestyle interventions are safe and highly feasible. Physical exercise emerged as the most effective intervention, consistently improving cardiorespiratory fitness and reducing psychological burdens such as fatigue and “PSA anxiety.” While dietary changes and weight loss successfully improved metabolic health markers, they did not show a consistent ability to prevent biopsy upgrading or MRI progression. Similarly, supplements showed only minor, short-term effects on PSA kinetics without providing reproducible oncologic protection. Conclusions: For men undergoing active surveillance, lifestyle interventions may be considered as supportive measures, as they appear feasible and may improve physical fitness, metabolic health, and selected patient-reported outcomes. However, current evidence remains insufficient to demonstrate a consistent effect on biopsy upgrading, MRI progression, or long-term deferral of definitive treatment. Full article

Background and Objectives: Chromobox protein homolog 2 (CBX2), a member of the polycomb group of proteins that plays a role in chromatin remodeling, has been associated with multiple types of cancer. However, its characterization in liver hepatocellular carcinoma (LIHC) has not been fully elucidated. This study aims to systemically evaluate the expression, prognostic value, epigenetic regulation, and ncRNAs of CBX2 in LIHC. Materials and Methods: We performed a comprehensive in silico analysis to assess CBX2 expression at mRNA and protein levels, correlate its expression with clinical characteristics and prognosis, and explore DNA methylation and ncRNA-mediated regulatory networks. Multiple public databases (TIMER2.0, UALCAN, Human Protein Atlas, KM Plotter, MethSurv, miRNet, and ENCORI) were utilized to conduct expression, survival analysis, and construct a network encompassing miRNAs, lncRNAs, and pseudogenes. Results: CBX2 expression was found to be elevated in LIHC at both the mRNA and protein expression level. Increased CBX2 expression was closely linked with unfavorable clinical outcome. Methylation analysis indicated that various CpG sites, exhibiting both hypermethylation and hypomethylation patterns, were correlated with CBX2 expression and patient prognosis. Among the identified ncRNAs, hsa-miR-101-3p tended to be downregulated, whereas hsa-miR-222-3p was significantly upregulated in LIHC, and both were associated with CBX2 expression and clinical outcomes. The constructed ncRNA interaction network suggested potential associations among miRNA, lncRNAs, and pseudogenes that may be linked to tumor progression. Conclusions: Our results suggest that CBX2 was overexpressed in LIHC and may be associated with epigenetic alterations and ncRNA-related regulatory interactions. Its expression shows a relationship with clinical prognosis, suggesting that CBX2 could serve as a candidate biomarker. The proposed CBX2-associated ncRNA network represents a potential framework for further investigation, although additional experimental validation is required to confirm its biological and clinical relevance. Consequently, our findings suggest that CBX2 may serve as a potential prognostic biomarker and therapeutic target in LIHC, potentially influenced by specific epigenetic and post-transcriptional mechanisms. Full article

Pharmacokinetic modeling in Positron Emission Tomography (PET) imaging has become a cornerstone in cancer research, offering insights into tumor development and progression. These models facilitate the quantification of radiotracer distribution and metabolism, enabling precise measurement of physiological parameters essential for cancer diagnosis, staging, and treatment monitoring. However, accurate pharmacokinetic modeling depends on reliable input function acquisition and partial volume correction techniques to minimize biases in quantitative PET metrics. This review provides a comprehensive overview of current methodologies and advancements in pharmacokinetic modeling for PET oncology imaging. We discuss techniques for acquiring input functions, including arterial, venous, and image-derived input functions (IDIFs), along with population-based input functions (PBIFs). Their strengths, limitations, and clinical applications are critically evaluated. Additionally, we examine quantitative methods such as partial volume correction (PVC) that mitigate the spatial resolution limitations of PET, improving radiotracer quantification in small or heterogeneous tumors. Furthermore, we explore advanced kinetic modeling techniques, including compartmental models, graphical approaches, and data-driven methods, highlighting recent innovations such as machine learning and Bayesian modeling. Key areas for future research in PET pharmacokinetic modeling include integrating hybrid imaging modalities, developing robust patient-specific input functions, and leveraging machine learning to streamline modeling processes. These advancements aim to enhance the precision and clinical utility of PET imaging in oncology, leading to more personalized cancer treatment strategies. Full article

Background: Reliable biomarkers that capture tumor–host interactions and predict treatment resistance in extensive-stage small cell lung cancer (SCLC) remain limited. We evaluated the prognostic and predictive value of the pretreatment lactate dehydrogenase-to-albumin ratio (LAR), an integrative biomarker reflecting metabolic activity, systemic inflammation, and host nutritional status. Methods: This multicenter, retrospective cohort study included patients with extensive-stage SCLC treated at five tertiary centers between 2016 and 2024. Pretreatment LAR was calculated using baseline serum lactate dehydrogenase and albumin levels and dichotomized using a Youden index-derived cut-off at the 12-month overall survival (OS) horizon. Time-dependent receiver operating characteristic (ROC) analyses using inverse probability weighting were performed to assess discriminative performance. Survival outcomes were evaluated using Kaplan–Meier estimates and Cox proportional hazards models. Associations with platinum resistance and lack of objective treatment benefit (defined as progressive disease as best response) were examined using logistic regression models. Results: A total of 223 patients were included. Elevated LAR was associated with inferior OS (median, 15.8 vs. 25.2 months; log-rank p < 0.001) and progression-free survival (7.9 vs. 11.5 months; p < 0.001). In multivariable analysis, LAR remained independently associated with OS (HR, 1.43; 95% CI, 1.04–1.95; p = 0.028). LAR demonstrated modest but consistently superior discriminative performance compared with other inflammatory indices for both 12-month OS (area under the curve [AUC], 0.692) and 6-month progression-free survival (PFS) (AUC, 0.646), with statistically significant differences in DeLong comparisons. Higher LAR was independently associated with increased odds of platinum resistance (adjusted odds ratio [aOR], 2.31; 95% CI, 1.41–3.81; p = 0.001) and lack of objective treatment benefit (adjusted OR, 2.04; 95% CI, 1.33–3.14; p = 0.001). Conclusions: Pretreatment LAR is a clinically accessible and biologically integrative biomarker associated with survival and treatment resistance in extensive-stage SCLC. By capturing tumor–host interactions, LAR may support risk stratification and identify patients at increased risk of early treatment failure. Prospective validation is warranted to define its role in biomarker-driven clinical decision-making. Full article

Objectives: This study aimed to investigate the biological role and molecular mechanism of the RNA m⁵C methyltransferase NSUN4 in cervical cancer progression, with a focus on its involvement in ferroptosis regulation. Methods: Differential expression and survival analyses were performed using TCGA and GEPIA datasets. Functional enrichment and GSEA identified pathways associated with NSUN4 dysregulation. NSUN4 expression was validated in clinical tissues by qRT-PCR, Western blot, and immunohistochemistry. Gain- and loss-of-function assays, including CCK-8, colony formation, and Transwell assays, were conducted to assess cell proliferation and invasion. Furthermore, a nude mouse subcutaneous xenograft model was established to validate the oncogenic role of NSUN4 in vivo. Ferroptosis was evaluated using specific inhibitors and measurement of GSH and ferroptosis-related proteins. RIP, m⁵C-RIP, RNA stability, and dual-luciferase assays were performed to explore the underlying mechanism. Results: NSUN4 was markedly upregulated in cervical cancer tissues and correlated with poor prognosis. Functionally, NSUN4 enhanced tumor cell growth, migration, and invasion while inhibiting ferroptosis. Mechanistically, NSUN4 bound to and stabilized C-MYC mRNA via m⁵C methylation, activating the PI3K/Akt signaling pathway and promoting ferroptosis resistance. Conclusions: NSUN4 promotes cervical cancer progression by stabilizing C-MYC mRNA through m⁵C modification, leading to PI3K/Akt activation and suppression of ferroptosis. These findings identify NSUN4 as a novel oncogenic regulator and potential therapeutic target in cervical cancer. Full article

Background: Cytokine-like receptor family 1 (CRLF1) has been implicated in tumor progression, yet its prognostic function and mechanistic actions in prostate cancer (PCa) remain elusive. Objective: This investigation sought to clarify the functional role, molecular mechanisms, and clinical relevance of CRLF1 in the progression of PCa. Methods: We conducted extensive bioinformatics analyses utilizing the protein interaction networks and the TCGA-PRAD dataset. CRLF1 and cartilage oligomeric matrix protein (COMP) expression were validated in clinical samples by qRT-PCR and Western blot (WB). Functional assessments, including Transwell invasion, flow cytometry, CCK-8, and wound healing, were conducted in vitro. An in vivo xenograft tumor model was used for further validation. Mechanistic investigations involved genetic perturbation (overexpression and inhibition) of CRLF1 and COMP. Results: Compared to benign tissues, the levels of CRLF1 and COMP were markedly elevated in PCa tissues. Bioinformatics assessments illustrated a robust positive relationship between CRLF1 and COMP, suggesting COMP may function as a downstream mediator. In vitro and in vivo investigations illustrated that silencing CRLF1 significantly suppressed PCa cell growth, invasion, and tumor progression, while enhancing apoptosis. Importantly, suppressing COMP counteracted the cancer-promoting effects triggered by CRLF1 overexpression. At the mechanistic level, CRLF1 facilitates tumor progression by modulating COMP to activate the FAK/PI3K/AKT signaling cascade. Conclusions: Our outcomes demonstrate that CRLF1 promotes PCa progression by targeting COMP to stimulate the FAK/PI3K/AKT signaling axis. This newly identified CRLF1/COMP/FAK/PI3K/AKT pathway underscores CRLF1 as a potential biomarker and therapeutic target for PCa. Full article

Cancer threatens the health and lives of people around the world and causes a heavy economic burden on families and society. Dysbiosis of the gut microbiota has been observed in cancer patients and is an important factor in cancer progression. Quercetin, a widely distributed dietary flavonol, exhibits pleiotropic anti-cancer activities in preclinical models. Importantly, recent studies reveal a bidirectional crosstalk between quercetin and the gut microbiota that may critically shape its biological effects. Specifically, gut microbiota enzymes mediate quercetin biotransformation and produce tumor-suppressive quercetin metabolites. On the other hand, quercetin remodels specific gut microbial species and their metabolites to promote anti-tumor activity. This review provides a timely and systematic synthesis of the latest findings regarding quercetin, gut microbiota, and cancer. Furthermore, we discuss strategies to enhance this interaction for improved cancer therapy. By highlighting the pivotal role of the gut microbiota, this review offers novel insights and a refined theoretical framework to guide future research and potential clinical translation of quercetin in cancer prevention and treatment. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Emerging evidence highlights the role of the gut microbiota in the development and progression of CRC. Microbial dysbiosis is hypothesized to contribute to chronic inflammation through a variety of mechanisms, such as the production of free radicals, which induce mutagenesis and immune dysregulation in the host, ultimately leading to diseases such as cancer. Methods: Tumor tissue samples or healthy mucosa tissue were collected for bacterial DNA extraction. The V3–V4 region of the 16S rRNA gene was amplified and sequenced using the Illumina MiSeq platform. Bioinformatics analysis was performed with QIIME2, including quality control, DADA2 denoising, alpha and beta diversity calculation, and taxonomic classification using the SILVA database. Results: Differences in microbial composition were observed between groups. The healthy controls exhibited high relative abundances of beneficial genera such as Faecalibacterium, Bacteroides, and Asteroleplasma, whereas the patients with CRC showed enrichment of atypical genera including Novosphingobium, Bradyrhizobium, and Undibacterium. Alpha diversity was lower in the CRC group, and clear clustering by group was observed in the beta diversity analysis. LEfSe analysis identified potential bacterial biomarkers associated with CRC at both the species and genus levels. Conclusions: The findings of this study support the hypothesis that colorectal cancer is associated with distinct alterations in gut microbiota composition, such as an increase in the Novosphingobium genus and a decrease in the Bacteroides genus. An exploratory description of these microbial profiles may aid in the development of microbiome-based diagnostic and therapeutic strategies and contribute to current knowledge of the role of the gut microbiota in CRC in southern Peru. Full article

Background: Prostate cancer (PCa) is one of the most prevalent malignancies in men, and active surveillance (AS) is the recommended management strategy for low- and favourable intermediate-risk disease. Predicting which patients will progress during AS remains a clinical challenge. MRI-derived radiomics has shown promise for risk stratification, but conventional machine learning approaches treat radiomic features as independent variables and may not capture the complex inter-feature dependencies within imaging data. This study evaluates the application of Synolitic Graph Neural Networks (SGNNs) to baseline MRI-derived radiomic features for predicting prostate cancer progression on active surveillance. Methods: We studied 343 AS patients (73 progressors, 270 non-progressors) from a single-centre cohort prospectively enrolled between 2013 and 2019 and retrospectively analysed. Seventy-two radiomic features were extracted from baseline 3T MRI (T2-weighted imaging and apparent diffusion coefficient maps), together with three clinical variables (prostate volume, PSA, PSA density). The SGNN pipeline transformed each patient’s feature profile into a weighted graph encoding pairwise feature relationships via logistic regression classifiers trained within each cross-validation fold. GCN and GATv2 architectures were evaluated with multiple sparsification strategies and compared against Gradient Boosting, SVM, Random Forest, and logistic regression using 5-fold stratified cross-validation. Results: Among conventional methods, Gradient Boosting achieved the highest ROC-AUC (0.634 ± 0.080). The SGNN pipeline with GATv2, confidence-based sparsification (p = 0.8), and extended node features incorporating graph centrality measures achieved the best performance (ROC-AUC = 0.699 ± 0.044), an absolute improvement of 0.065 over the best conventional method. The addition of topological node features consistently improved performance by 3–5% across configurations. GATv2 outperformed GCN in matched settings. Conclusions: As a proof of concept, the SGNN framework achieved the highest mean ROC-AUC among the evaluated single-timepoint approaches, though results require confirmation in independent external cohorts. By encoding inter-feature relationships as patient-specific graphs, SGNN offers a complementary modelling paradigm for radiomic data in clinical oncology. Future work should incorporate longitudinal data and graph explainability methods. Full article

Miniprobe endoscopic ultrasonography (mEUS) combines high-resolution imaging of the gastrointestinal (GI) wall and bile ducts with ease of applicability during routine endoscopy. This narrative review aims to provide an overview of known and emerging fields of application for mEUS in gastrointestinal endoscopy. After its initial development in pancreatobiliary scenarios in the early 1990s, mEUS has been recently reconsidered a third-space endoscopic technique that is progressively developing and spreading for the treatment of early gastrointestinal neoplastic lesions. The high spatial resolution of mEUS provides an accurate assessment of the degree of submucosal invasion in early esophageal, gastric, and colorectal neoplasia, while the small caliber of catheters allows for mEUS employment in settings where standard echoendoscopes are impractical (e.g., severe stenoses or proximal colonic lesions). Beyond cancer staging, mEUS offers point-of-care characterization of subepithelial lesions by defining the layer of origin and echo-pattern, eventually defining endoscopic resectability, but definitive diagnosis remains histological. In pancreatobiliary diseases, miniprobe intraductal ultrasonography (IDUS) shows its strongest application for indeterminate biliary strictures when endoscopic retrograde cholangiopancreatography (ERCP)-based sampling strategies and brushing cytology show inconclusive diagnoses, and in choledocholithiasis, particularly for the detection of small stones/sludge and confirmation of duct clearance. IDUS is also valuable for the staging of ampullary tumors, for longitudinal extension mapping in hilar cholangiocarcinoma and for selected portal biliopathy scenarios. Overall, mEUS and IDUS are high-resolution adjuncts that can meaningfully refine local decision-making in the treatment of superficial epithelial/subepithelial tumors or lesions involving the bile ducts. Limitations include shallow penetration, lack of tissue acquisition capability, a relative increase in post-ERCP pancreatitis risk for intraductal use, and substantial cost with limited availability in lower-volume centers. Full article

Hepatocellular carcinoma (HCC) is the most common type of liver cancer that is mostly preceded by cirrhosis, with a high mortality rate. Therefore, diagnosis is critical in the early stages. In this study, we explored the liver expression of metabotropic glutamate receptor 3 (mGluR3), a group II mGluR, during the progression from fibrosis to cirrhosis and, ultimately, to HCC induced by diethylnitrosamine (DEN) in rats. We found that mRNA expression of mGluR3 (Grm3) was upregulated in HCC, while the protein level was significantly increased from the cirrhosis stage, and even more in HCC. Grm3 correlated with interleukin-6 (Il6) and transforming growth factor-β (Tgfb) mRNA expression. Furthermore, serum and intrahepatic glutamate concentrations were augmented in HCC. Immunohistochemical analysis revealed that mGluR3 is expressed in hepatocytes and non-parenchymal cells (endothelial cells and macrophages), and we observed a positive signal in the cytoplasmic membrane, cytoplasm, and nuclei of tumor and non-tumor cells. We confirmed that normal hepatocytes (C9 cell line) express low levels of mGluR3 protein and HCC-derived cells (HepG2) express high levels of this receptor. Using HepG2 cells, we observed that mGluR3 activation by glutamate and the group II-selective agonist LY354740 treatments were functional, as both inhibited cAMP generation induced by forskolin and increased cellular viability with no effect on dead cells. These results showed that mGluR3 is differentially expressed throughout the progression of liver pathologies, is associated with the inflammatory environment, and plays a role in HCC cell survival, with potential utility as an early biomarker and therapeutic target. Full article