Search Results (506)

Background: Metabolic reprogramming is increasingly recognized as a hallmark of endometrial cancer, yet tissue-based metabolic signatures remain insufficiently defined. Methods: Untargeted metabolomics was performed on paired endometrial cancer (n = 10) and adjacent normal tissues (n = 10). Differential metabolites were identified through multivariate and univariate analyses. KEGG enrichment characterized altered pathways, while Random Forest and SVM were used for machine-learning-based feature prioritization. ROC analyses were conducted to evaluate the discriminative potential of selected metabolites. Results: 300 metabolites were significantly altered. Tumor tissues showed increased sphingolipid metabolism, glutathione metabolism, and arachidonic acid metabolism, alongside decreased bile acid, phenylalanine, and steroid biosynthesis. Machine learning converged on six key metabolites that demonstrate strong tissue-discriminative capacity. Conclusions: Endometrial cancer exhibits a distinct metabolic profile characterized by lipid remodeling and redox adaptation. The six metabolites identified through machine-learning-based analyses represent candidate metabolic features associated with endometrial cancer and provide a foundation for future mechanistic studies and validation in larger, independent cohorts. Full article

Background and Objectives: Soft tissue sarcomas account for approximately 7% of all malignant tumors in the pediatric population. Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) measurements may provide early functional biomarkers of treatment response by reflecting changes in tumor cellularity. This study evaluated whether ADC-derived parameters can serve as quantitative biomarkers of neoadjuvant chemotherapy response in pediatric rhabdomyosarcoma. Materials and Methods: This retrospective single-center study included 14 patients aged ≤18 years with histopathologically confirmed rhabdomyosarcoma who underwent MRI before treatment and after three cycles of chemotherapy. Twenty-five patients were initially identified; eleven were excluded due to imaging artifacts or absence of baseline examination. ADC maps were generated on 1.5T and 3T scanners. Regions of interest were placed over the entire lesion and areas with the lowest ADC signal. Relative ADC (rADC) was calculated by normalizing tumor ADC to adjacent healthy muscle. Paired t-tests were used to compare pre- and post-treatment values. Results: At baseline, 13/14 patients (93%) demonstrated diffusion restriction. Mean ADC increased from 1.11 × 10⁻³ mm²/s (SD ± 0.48) at baseline to 1.63 × 10⁻³ mm²/s (SD ± 0.67) after treatment. The paired t-test for rADC yielded t = −3.089 (p = 0.0086, 95% CI: −0.79 to −0.14), indicating a statistically significant change. There was a significant difference between the ADC values of the entire lesion and the areas with the lowest signal in tumors with a heterogenic structure, t = 2.862, p = 0.013. Conclusions: ADC and rADC increased significantly after neoadjuvant chemotherapy in pediatric rhabdomyosarcoma, suggesting potential utility as early functional biomarkers of treatment response. These preliminary findings require validation in larger multicenter prospective studies with correlation to histopathological response and clinical outcomes before clinical implementation. Full article

Cancer remains one of the most common causes of death worldwide and imposes enormous social and economic burdens. Human tumor-associated NADH oxidase (ENOX2, also known as tNOX) is a cancer cell-specialized NADH oxidase that is expressed on the membranes of cancer cells. In this study, we investigated the potential role of ENOX2 in regulating stemness properties in oral cancer through a combination of in vitro, in vivo, and bioinformatics approaches. We found that ENOX2 physically interacted with the stem cell transcription factor, SOX2, in co-immunoprecipitation experiments. The expression and activity of ENOX2 were elevated in p53-functional SAS and p53-mutated HSC-3 oral cancer cell spheroids compared with their monolayer counterparts. Consistently, SIRT1, a downstream effector modulated by ENOX2 through NAD⁺ generation, was also upregulated in spheroid cultures. Functional studies further established that ENOX2 overexpression significantly enhanced spheroid formation, self-renewal properties, stem cell marker expression, and PKCδ expression, whereas ENOX2 knockdown produced the opposite effects. In xenograft models, ENOX2-overexpressing oral cancer cell spheroids exhibited enhanced tumorigenicity, while ENOX2-silenced spheroids formed significantly smaller tumors. Complementary analyses of public transcriptomic and proteomic datasets revealed elevated ENOX2 expression in human head and neck tumor tissues compared with adjacent normal tissues. Based on these findings and literature-supported correlations, we propose a putative ENOX2-SIRT1-SOX2 regulatory framework that may contribute to the acquisition and maintenance of stem-like properties of oral cancer cells. While the ENOX2–SOX2 interaction was experimentally validated, the roles of SIRT1 and other downstream components are inferred from bioinformatic analyses and prior studies; thus, this axis represents a hypothetical model that warrants further mechanistic investigation. Collectively, our results identify ENOX2 as a potential regulator of oral cancer stemness and provide a conceptual foundation for future studies aimed at elucidating its downstream pathways and clinical relevance in head and neck tumors. Full article

Acrolein, a highly reactive environmental toxicant widely present in urban air and tobacco smoke, has been implicated in the development of multiple malignancies. In oral tissues, chronic acrolein exposure induces oxidative stress, inflammation, and genetic mutations, all of which are closely linked to the development of oral squamous cell carcinoma (OSCC). Although accumulating evidence indicates a strong association between acrolein exposure and OSCC, its prognostic significance remains poorly understood. In this study, we analyzed transcriptome data to identify differentially expressed genes (DEGs) between tumor and adjacent normal tissues, and screened acrolein-related candidates by intersecting DEGs with previously identified acrolein-associated gene sets. Functional alterations of these genes were assessed using Gene Set Variation Analysis (GSVA), and a protein–protein interaction (PPI) network was constructed to identify key regulatory genes. A prognostic model was developed using Support Vector Machine–Recursive Feature Elimination (SVM-RFE) combined with LASSO-Cox regression and validated in an independent external cohort. Among the acrolein-related DEGs, four key genes (PLK1, AURKA, CTLA4, and PPARG) were ultimately selected for model construction. Kaplan–Meier analysis showed significantly worse overall survival in the high-risk group (p < 0.0001). Receiver operating characteristic (ROC) curve analysis further confirmed the strong predictive performance of the model, with area under the curve (AUC) values of 0.72 at 1 year, 0.72 at 3 years, and 0.75 at 5 years. Furthermore, the high risk score was significantly correlated with a ‘cold’ immune microenviroment, suggesting that acrolein-related genes may modulate the tumor immune microenvironment. Collectively, these findings highlight the role of acrolein in OSCC progression, suggesting the importance of reducing acrolein exposure for cancer prevention and public health, and call for increased attention to the relationship between environmental toxicants and disease initiation, providing a scientific basis for public health interventions and cancer prevention strategies. Full article

The transcription factor SOX11 is implicated in tumor progression across multiple types of cancers, including head and neck squamous cell carcinoma (HNSCC). However, its mechanistic role in HNSCC remains elusive. In this study, we found that the expression of SOX11 was induced by epidermal growth factor (EGF) but suppressed by an epidermal growth factor receptor (EGFR) inhibitor in HNSCC cells. The signal transducer and activator of transcription 3 (STAT3) bound to the Sox11 gene promoter and transcriptionally upregulated the expression of Sox11 in HNSCC cells. Meanwhile, analyses of The Cancer Genome Atlas (TCGA) gene expression datasets indicated that Sox11 gene expression was significantly overexpressed in HNSCC versus adjacent normal tissues and correlated with those of most epithelial–mesenchymal transition transcription factors (EMT-TFs) and marker genes. Knockdown of SOX11 significantly downregulated the expression of EMT-related genes, including EMT-TFs, vimentin, fibronectin, and N-cadherin, but significantly upregulated E-cadherin and vice versa when SOX11 was overexpressed. Collectively, our studies demonstrated that SOX11 was regulated by EGF-EGFR-STAT3 signals, promoting EMT in HNSCC. Full article

Background: Conventional absorption-based computed tomography has a limited ability to resolve lung microarchitectures that are critical for histological subtype discrimination. This study evaluated the potential of X-ray Dark-Field Imaging Computed Tomography (XDFI CT) using synchrotron radiation for non-destructive, three-dimensional visualization of human lung cancer microstructures. Methods: Surgically resected human lung cancer specimens (n = 4) were examined, including acinar-predominant adenocarcinoma (n = 1), adenocarcinoma after concurrent chemoradiation therapy (n = 1), keratinizing squamous cell carcinoma (n = 1), and metastatic hepatocellular carcinoma in the lung (n = 1). Image acquisition was performed at beamline BL-14B of the Photon Factory (Tsukuba, Japan), using a monochromatic 19.8 keV synchrotron X-ray beam and a crystal analyzer-based refraction-contrast optical system. Imaging findings were qualitatively correlated with corresponding histopathological sections. Results: Synchrotron radiation XDFI CT enabled clear visualization of normal distal lung microanatomy, including alveolar walls and associated vascular structures, which served as internal references adjacent to tumor regions. Distinct microstructural features—such as invasive growth patterns, fibrotic or keratinized stroma, necrosis, and treatment-related remodeling—were identifiable and varied according to histological subtype. Tumor–normal tissue transitional zones were consistently delineated in all specimens. Conclusions: Synchrotron radiation XDFI CT provides high-resolution, non-destructive volumetric imaging of lung cancer tissues and reveals subtype-associated microarchitectural features. This technique may complement conventional histopathology by enabling three-dimensional virtual histologic assessment of lung cancer specimens. Full article

Background/Objectives: Colorectal cancer (CRC) is the third most commonly occurring cancer. Apoptosis is a fundamental cellular process of programmed cell death, and although many pathways for inducing apoptosis may exist, only the intrinsic and the extrinsic pathways have been demonstrated in detail. This study investigated the expression of BAD, BID, BCL2, MDM2, p53, Ki-67, and PUMA in primary CRC, paired lymph node metastases, and adjacent normal mucosa and explored their associations with clinicopathologic features and patient outcomes. Methods: One hundred thirty patients who underwent surgery for resectable CRC were included in the study. FFPE tumor tissue samples were prospectively collected and used for the construction of the TMA blocks from the primary tumor, paired lymph node metastasis, and paired normal mucosa. Immunohistochemistry for BAD, BID, BCL2, MDM2, p53, Ki-67, and PUMA antibodies was performed. Results: Univariate analysis showed reduced cancer-specific (CSS), disease-free (DFS), and overall survival (OS) in patients with lymphatic invasion, ≥4 positive lymph nodes, poorly differentiated tumors, older age (≥65), right-sided tumors, stage IIIC disease, or no chemotherapy. Multivariate analysis identified lymphovascular invasion, ≥4 metastatic nodes, and high Ki-67 as independent predictors of worse DFS and CSS, with low BAD expression additionally predicting DFS. For OS, adverse predictors included nodal burden, tumor location, absence of chemotherapy, and high p53, MDM2, and Ki-67 expression. Notably, combined high PUMA and low p53 expression independently predicted poorer CSS and OS. Conclusions: High expression of PUMA combined with low expression of p53 and a high expression of Ki-67 were independent unfavorable prognostic indicators for both OS and CSS. Further studies are required to clarify the prognostic and therapeutic role of these markers in CRC. Full article

Background/Objectives: Synovial sarcoma (SS) is a malignant soft tissue neoplasm with good outcomes in adolescents with localized tumors, but poor outcomes in older adults and in advanced or metastatic cases. Targeting cancer metabolism, such as glutamine metabolism, is a promising therapeutic strategy. In this study, we investigated glutamine dependency in SS and assessed the therapeutic potential of inhibiting the glutamine transporter ASCT2 using V9302. Methods: Immunohistochemistry (IHC) was used to evaluate ASCT2 expression in SS and liposarcoma (LPS) specimen. The effects of glutamine deprivation and V9302 were examined in a SS cell line (HS-SY-II), patient-derived SS cells (SSH1), and a normal cell line (HEK293). Cell viability, apoptosis, and protein expression were assessed using the CCK-8 assay, flow cytometry, and Western blotting, respectively. The therapeutic efficacy of V9302 was evaluated in a xenograft model using IHC. Results: ASCT2 expression was elevated in SS tumor tissues compared with adjacent normal tissues and LPS specimens. Both the HS-SY-II cell line and SSH1 cells exhibited strong glutamine dependency for proliferation. V9302 selectively reduced HS-SY-II cell viability by suppressing the AKT/mTOR signaling pathway and inducing apoptosis via caspase-3 activation, with minimal effects on control cells. In vivo, V9302 administration significantly inhibited tumor growth without inducing systemic toxicity, and IHC of the treated tumors confirmed the suppression of the mTOR pathway and induction of apoptosis. Conclusions: Our findings suggest that SS is a glutamine-dependent malignancy and validate ASCT2 as a promising therapeutic target. The ASCT2 inhibitor V9302 demonstrated therapeutic efficacy both in vitro and in vivo, supporting its potential as a therapeutic agent for SS. Full article

Background: MicroRNAs (miRNAs) such as miR-155-5p and miR-221-3p are key regulators of gene expression in cancer. Although both have been implicated in colorectal cancer (CRC) and papillary thyroid carcinoma (PTC), data on their regional expression profiles and clinical associations remain scarce, particularly in the Middle East. This study assessed the expression patterns and clinical relevance of miR-155-5p and miR-221-3p in CRC and PTC patients from Sulaymaniyah Province, Iraq. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and adjacent normal tissue samples were collected from 60 CRC patients and 50 PTC patients. miRNA expression levels were quantified using real-time quantitative PCR (RT-qPCR) and analyzed by the ΔΔCt method, adjusted for tumor cellularity. Statistical analyses were conducted to evaluate associations between miRNA expression and clinicopathological parameters. Results: miR-155-5p and miR-221-3p were frequently overexpressed in both CRC (65%) and PTC (72% and 68%, respectively). In CRC, miR-155-5p expression correlated significantly with histological grade, tumor location, and TNM stage (p < 0.05), while miR-221-3p did not show significant associations with clinicopathological features. In PTC, miR-155-5p exhibited a trend toward association with TNM stage (p = 0.02). No significant differences in expression levels of these miRNAs were observed between CRC and PTC samples. Conclusions: Overall, miR-155-5p and miR-221-3p are consistently overexpressed in CRC and PTC, indicating their potential as diagnostic biomarkers. miR-155-5p, in particular, shows promise as a marker of disease progression in CRC. These findings underscore the importance of region-specific studies in advancing our understanding of the molecular landscape of cancer. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide. While immune checkpoint blockade (ICB) has transformed cancer therapy, its clinical benefit in CRC is often limited by an immune-excluded tumor microenvironment (TME). MicroRNA-21-5p (miR-21-5p) is a well-established oncomiR in CRC; however, its role in immune resistance remains incompletely elucidated. In this study, we explored the potential immunoregulatory role of miR-21-5p in CRC by integrating transcriptomic profiling of TCGA-COAD and TCGA-READ cohorts with experimental validation of its target PTEN in CRC cell models. MiR-21-5p was markedly upregulated in tumors compared with adjacent normal tissues and was associated with reduced infiltration of CD8⁺ T cells and dendritic cells. Functional assays confirmed that miR-21-5p directly targets PTEN; transcriptomic correlations further suggested potential links to PI3K/AKT activation and alterations in JAK–STAT and Th17-associated signaling. Elevated miR-21-5p was associated with transcriptomic signatures indicative of altered Th1/Th2 balance, reduced IgA-related immune responses, and features of an immune-excluded TME. Therapeutically, the inhibition of miR-21-5p has been reported in previous studies to restore PTEN and modulate signaling pathways. However, our study did not evaluate immune reactivation or checkpoint-blockade efficacy; thus, such therapeutic implications remain hypothetical. Collectively, these findings suggest that the miR-21–PTEN–PI3K/AKT axis may contribute to shaping immune-related features in CRC. These findings provide a rationale for future studies investigating whether targeting miR-21-5p could enhance antitumor immunity or improve immunotherapy response in CRC. Full article

Background/Objectives: The Notch signaling pathway regulates cell fate, proliferation, and differentiation, and its dysregulation has been implicated in various cancers, including breast cancer. MicroRNAs (miRNAs) are critical post-transcriptional regulators that can modulate Notch pathway components. The aim of this study was to identify miRNAs that may potentially regulate the expression of Notch pathway-related genes across five molecular subtypes of breast cancer in Polish women. Methods: Tumor and adjacent normal tissue samples were collected from 405 patients with five breast cancer subtypes: luminal A (n = 130), HER2-negative luminal B (n = 100), HER2-positive luminal B (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (n = 43). Gene expression was profiled using mRNA microarrays and validated with RT-qPCR and ELISA. Candidate regulatory miRNAs were identified by miRNA microarrays and confirmed using the miRDB database. Results: APH1A, CTBP1, DTX1, HEY1, HEY2, JAG2, NOTCH4, TLE2, and TLE4 were consistently dysregulated across all breast cancer subtypes. Overexpression of HEY1 and JAG2 may be driven by decreased levels of miR-145, miR-98, and miR-381. Conversely, downregulation of TLE4 may be associated with elevated expression of miR-196a and miR-155. No regulatory miRNAs meeting the selection criteria were identified for APH1A, CTBP1, DTX1, HEY2, NOTCH4, or TLE2. Conclusions: The consistent alterations suggest the presence of a shared Notch-driven oncogenic signature in breast cancer, potentially driving cell proliferation, stemness, and resistance to therapy. These findings enhance our understanding of Notch signaling in breast cancer and propose novel miRNA–Notch interactions as candidate targets for therapeutic intervention. Full article

Background: Connexin43 (Cx43) is recognized as a transmembrane protein; its precise expression profile and molecular mechanisms in triple-negative breast cancer (TNBC) remain unclear. Methods: We systematically analyzed Cx43 expression in over 60 breast cancer cell lines from the CCLE and HPA databases. Immunohistochemical evaluation compared Cx43 expression between TNBC tissues and adjacent normal tissues. Cx43 expression was assessed in normal breast epithelial cells (MCF-10A) and two TNBC cell lines (MDA-MB-231 and BT-549) using qRT-PCR and Western blot. Functional assays (CCK8, wound healing, transwell) evaluated TNBC progression following Cx43 interference or overexpression. Rab31, a Cx43-interacting protein, was identified via bioinformatics, immunofluorescence, and Co-IP. Autophagy-related proteins (ULK1, ATG5, LC3, and p62) were analyzed after Cx43 or Rab31 modulation. Finally, a nude mouse model validated Cx43’s in vivo effects on tumor growth and associated molecular changes. Results: Cx43 was upregulated in TNBC tissues and cell lines. Overexpression enhanced proliferation, migration, and invasion, while knockdown suppressed these effects. Cx43 co-expressed with Rab31, regulating its protein levels and autophagy. Rab31 interference reversed Cx43-mediated autophagy and oncogenic behaviors. In vivo, Cx43 promoted tumor growth and modulated Rab31/autophagy pathways. Conclusions: The Cx43/Rab31 axis drives autophagy to facilitate TNBC progression, highlighting Cx43 as a potential therapeutic target. Our findings provide mechanistic insights for improving TNBC treatment. Full article

Background/Objectives: Breast cancer is the leading cause of cancer-related mortality in women, highlighting the urgent need for robust prognostic tools to enable individualized risk stratification. Methods: Transcriptomic data from 1075 breast cancer and 113 adjacent normal tissues in The Cancer Genome Atlas (TCGA) were integrated with clinical information. Differential expression analysis identified 531 immune-related genes, which were further selected by univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression to construct a 13-gene prognostic signature. The model was validated in an independent cohort (n = 327). Tumor immune microenvironment and single-cell RNA sequencing data were analyzed to explore underlying biological differences. Results: The 13-gene signature effectively stratified patients into low- and high-risk groups with significantly different overall survival in both the TCGA cohort (log-rank p < 0.0001; C-index = 0.678; 5-year AUC = 0.72) and the validation cohort (log-rank p < 0.0001; C-index = 0.703; 3-year AUC = 0.81). Low-risk tumors exhibited an antitumor immune microenvironment enriched in CD8⁺ T cells, T follicular helper (Tfh) cells, and M1 macrophages, whereas high-risk tumors were dominated by immunosuppressive regulatory T cells and M2 macrophages (all p < 0.0001). Single-cell analysis revealed expansion of malignant epithelial cells and inflammatory cancer-associated fibroblasts (iCAFs) in high-risk tumors, with higher iCAF scores significantly associated with poorer survival (log-rank p = 0.00036). Conclusions: Collectively, this study delivers a rigorously validated 13-gene immune signature whose prognostic utility is rooted in distinct immune microenvironmental features, while unveiling iCAF-targeted therapeutic strategies as a promising intervention avenue. Full article

Background: Considering the increased need to deliver adjuvant radiotherapy (RT) after pleurectomy/decortication (P/D) for malignant pleural mesothelioma (MPM) without exceeding the tolerance of the adjacent normal tissue, new advanced RT technologies have been developed. However, radiation to the whole hemithorax presents a challenge because of the increased risk of toxicity occurring with two intact radiosensitive lungs. The aim of this study is to systematically review the literature in order to assess the role of radiotherapy after P/D for MPM, based on the evidence published so far. Methods: We conducted this systematic review according to PRISMA guidelines and registered in an international public register of systematic review (PROSPERO). A PubMed and Cochrane database search was performed to identify articles published from 2005 to 2024 regarding the role of adjuvant radiotherapy after P/D for MPM. We included only level I–III-evidence studies according to the Oxford Centre for Evidence-Based Medicine’s guidance. Results: We selected 11 level II studies. Based on published reports, delivery of high-dose external beam ‘conventional’ RT to the entire hemithorax is not recommended in a P/D setting and hemithoracic intensity-modulated radiotherapy (IMRT) may be considered an encouraging and reasonable therapeutic option, leading to excellent loco-regional control and survival results. Conclusions: Data and experience strongly support that the ideal platform to define potential indication of the adjuvant RT is a multidisciplinary team. Moreover, given the technical difficulty of IMRT treatment, we recommend considering this treatment in experienced centers with dedicated protocols for MPM due to their ability to detect and manage side effects resulting from the disease and the treatment as well as to ensure the best and the latest treatment plan for each patient. Full article

Background: Ultrasound is the primary imaging modality for evaluating thyroid nodules, with echogenicity and nodule size serving as parameters for malignancy risk stratification. Though the TI-RADS classification system is standardized, interpretation varies among observers due to subjectivity, and can affect diagnostic consistency. This study aimed to evaluate the diagnostic and interobserver agreement of quantitative ultrasound gray-scale analysis and nodule area in differentiating benign from malignant solid thyroid nodules. Methods: This retrospective study reviewed 600 patients who underwent thyroid ultrasound at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, in 2023 and 2024. Of these 600, 107 adult patients with 116 solid thyroid nodules (96 benign and 20 malignant) who subsequently underwent ultrasound-guided fine-needle aspiration were included in the final analysis. From B-mode ultrasound images, the grayscale median (GSM) values of each nodule and adjacent normal thyroid tissue were measured using Adobe Photoshop. The GSM ratio (GSMr) was calculated by dividing nodule GSM by normal tissue GSM. Nodule size, taken as cross-sectional area, was assessed using ImageJ software version 1.53. The Mann–Whitney U test was used to compare GSMr and the area between benign and malignant nodules. Inter-observer agreement was evaluated using the intraclass correlation coefficient (ICC). Results: Malignant nodules had significantly lower GSMr compared to benign nodules (malignant: median 0.76, IQR 0.27; benign: median 0.88, IQR 0.55, p = 0.02). Malignant nodules were also significantly larger than benign nodules (malignant: median 2.77 cm², IQR: 5.08; benign: median 1.78 cm², IQR 1.65, p = 0.02). Inter-observer reproducibility was excellent for both GSMr (ICC = 0.998) and area (ICC = 0.997). Conclusions: Quantitative ultrasound assessment of grayscale echogenicity and nodule area provides valuable diagnostic information for differentiating benign from malignant solid thyroid nodules. These objective measures may enhance diagnostic confidence and support more precise clinical decision-making in thyroid nodule evaluation. Full article