Pancreatic ductal adenocarcinoma (PDAC) exhibits higher hypoxia level than most solid tumors, and the presence of intratumoral hypoxia is associated with a poor prognosis. However, the identification of hypoxia levels based on pathological images, and the mechanisms regulating ferroptosis resistance, remain to be elucidated. The objective of this study was to construct a deep learning model to evaluate the hypoxia characteristics of PDAC and to explore the role of Sulfide quinone oxidoreductase (SQOR) in hypoxia-mediated ferroptosis resistance.

Recent studies have increasingly reported abnormal glutathione (GSH) metabolism within the tumor microenvironment across various solid tumors. However, the specific mechanisms underlying aberrant GSH metabolism in pancreatic cancer (PC) remain unclear. This study aims to investigate the prognostic significance of GSH metabolism-related genes in PC and to identify key molecular targets, thereby providing novel perspectives for targeted PC therapy.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy with high survival rates in children; however, certain high-risk subtypes pose significant challenges due to poor prognosis and frequent relapse. Ubiquitination, a post-translational modification critical for protein regulation, has been implicated in various cancer processes, yet its role in ALL remains poorly understood.

The Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder affecting women's reproductive and metabolic health, faces diagnostic challenges due to heterogeneous clinical presentations and the absence of reliable biomarkers. This study investigates the role of Glucosaminyl (N-acetyl) transferase 2 (GCNT2) in modulating sex hormone-binding globulin (SHBG) and its potential as a therapeutic target in PCOS pathophysiology.

Aging is the greatest risk factor for breast cancer, and although epithelial cells are the source of carcinomas, epithelial changes alone do not fully explain cancer susceptibility. Fibroblasts and macrophages are key stromal constituents around the cells of origin for cancer in breast tissue. With age, macrophages surrounding terminal ductal lobular units (TDLUs) become increasingly immunosuppressive. CD105+ fibroblasts intercalate within TDLUs, drive luminal differentiation, and give rise to immunosuppressive cancer-associated fibroblasts in other tissues. We propose that differences in fibroblasts are a crucial component of the stroma that shapes cancer susceptibility.

Although neoadjuvant chemotherapy and immunotherapy show promise in treating oesophageal squamous cell carcinoma (OSCC), long-term survival data are limited. This randomized, multicenter phase 2 study evaluated the efficacy of perioperative Nivolumab with chemotherapy, followed by surgery and adjuvant immunotherapy, in patients with locally advanced resectable OSCC, and explored the prognostic role of circulating tumor DNA (ctDNA) status.

One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.

Hepatocellular carcinoma (HCC) is associated with a poor 5-year survival mainly due to detection at late stages. Better non-invasive surveillance methods are needed to improve early detection and maximize survival. We performed a strict assessment of DNA methylation markers (DMMs) for HCC detection.

Melanoma is one of the most commonly diagnosed malignancies and serves as a model for studying immunotherapy. The B16 melanoma model, resembling human cold tumors that lack T cell infiltration and show minimal response to PD-1 blockade, is widely used for studying melanoma and its resistance to immunotherapy. Therefore, understanding the molecular basis that prevents T cell-mediated anti-tumor activity in B16 melanoma is of great significance.

Small cell carcinoma of the esophagus (SCCE) is an aggressive and rare neuroendocrine malignancy with poor prognosis. Here, we firstly performed single-cell transcriptional profiling derived from 10 SCCE patients, with normal esophageal mucosa, adjacent non-malignant tissue and tumors from esophageal squamous cell carcinoma (ESCC) as reference. We observed enrichment of activated regulatory T cells and an angiogenesis-induced niche existed in SCCE compared with ESCC, revealing an immune suppressive and vessel-induced tumor microenvironment (TME) in SCCE. Totally, we identified five TME ecotypes (EC1 ~ 5). Notably, EC1 was highly enriched in SCCE, associating with molecular subtyping and survival outcomes. To dissecting heterogeneity of epithelium in SCCE, we constructed eight transcriptional metaprograms (MPs) that underscored significant heterogeneity of SCCE. High expression of MP5 was linked to neuroendocrine phenotype and poor clinical survival. Collectively, these results, for the first time, systematically deciphered the TME and epithelial heterogeneity of SCCE and provided evidences that SCCE patients might benefit from anti-angiogenesis therapy.

The pathogenesis of CRC requires primary genetic and epigenetic mechanisms including, methylation of CpG islands of the genes. In the current study, micro RNA-139-5p (miR-139-5p) promoter methylated DNA was evaluated in tumor tissue and plasma samples from CRC affected patients.

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-smokers in China accounting for over 40% of cases. Despite the proven efficacy of low-dose computed tomography (LDCT) in early detection and reduction of lung cancer mortality, the current paradigm of lung cancer screening, heavily focused on smoking status and age, may inadequately address the unique risk factors associated with non-smokers, particularly those with a family history of the disease. This study evaluates the cost-effectiveness of LDCT screening for non-smokers with a first-degree relative (FDR) history of lung cancer, a group at particularly high-risk.

Colorectal cancer is the fourth most deadly cancer, with a high mortality rate and a high probability of recurrence and metastasis. Since continuous examinations and disease monitoring for patients after surgery are currently difficult to perform, it is necessary for us to develop a predictive model for colorectal cancer metastasis and recurrence to improve the survival rate of patients.

Recent decades have witnessed a steady decrease in the use of race categories in genomic studies. While studies that still include race categories vary in goal and type, these categories already build on a history during which racial color lines have been enforced and adjusted in the service of social and political systems of power and disenfranchisement. For early modern classification systems, data collection was also considerably arbitrary and limited. Fixed, discrete classifications have limited the study of human genomic variation and disrupted widely spread genetic and phenotypic continuums across geographic scales. Relatedly, the use of broad and predefined classification schemes-e.g. continent-based-across traits can risk missing important trait-specific genomic signals.

The centrosome, a vital component in mitosis in eukaryotes, plays a pivotal role in cancer progression by influencing the proliferation and differentiation of malignant cells, making it a significant therapeutic target. We collected genes associated with centrosomes from existing literature and established a prognostic model for 85 osteosarcoma patients from the TARGET database. Genes associated with prognosis were identified through univariate Cox regression. We then mitigated overfitting by addressing collinearity using LASSO regression. Ultimately, a set of five genes was selected for the model through multivariable Cox regression. Model performance was assessed using ROC curves, which yielded a training set AUC of 0.965 and a validation set AUC of 0.770, indicating satisfactory model performance. We further identified genes with differential expression in high and low-risk groups and conducted functional enrichment analysis using KEGG, GO, Progeny, GSVA, and GSEA. Results revealed significant variances in various immune-related pathways between high and low-risk cohorts. Analysis of the immune microenvironment using ssGSEA and ESTIMATE indicated that individuals with unfavorable prognoses had lower immune scores, stromal scores, and ESTIMATE scores, coupled with higher tumor purity. This suggests that high-risk individuals have compromised immune microenvironments, potentially contributing to their unfavorable prognoses. Additionally, drug sensitivity and molecular docking analysis revealed increased responsiveness to paclitaxel in high-risk individuals, implying its prognostic value. The JTB-encoded protein exhibited a negative binding energy of - 5.5 kcal/mol when interacting with paclitaxel, indicating its potential to enhance the patient's immune microenvironment. This framework enables patient prognosis prediction and sheds light on paclitaxel's mechanism in osteosarcoma treatment, facilitating personalized treatment approaches.

Lung cancer is one of the most commonly diagnosed cancers worldwide and the leading cause of cancer-related deaths worldwide. In recent years, an increasing number of studies have shown that the tumor immune microenvironment (TIME) has a significant impact on the development of lung cancer. Interleukin-7 (IL-7) is an essential cytokine for the adaptive immune system and plays an important immunoregulatory role in different types of tumors. However, the relationship between IL-7 and TIME in non-small cell lung cancer (NSCLC) is not yet known. This study found that the expression of MCP-1 and CD11b was correlated with the expression of IL-7/IL-7R. MCP-1, IL-7R, tumor differentiation and tumor stage were the strongest predictors of survival. In addition, IL-7 upregulates MCP-1 through JAK1/STAT3 pathway to affect the migration of MDSCs and exert tumor immunosuppressive effect. Furthermore, CCR2 inhibitor and depletion of MDSCs suppressed the promoting effect of IL-7 mediated development of lung cancer. These findings provided the important mechanism that IL-7 upregulate MCP-1 through JAK1/STAT3 pathway to recruit MDSCs and put forth blockage of CCR2 inhibitor and MDSCs recruitment as a prospective immunotherapy strategy for the treatment of NSCLC.

Hepatocellular carcinoma (HCC) is a highly lethal malignancy associated with poor prognosis due to late-stage diagnosis and high recurrence rates. The MEX3 family genes has been implicated in various cancers; however, their roles in HCC remain largely unexplored. This study aims to systematically analyze the expression patterns, prognostic significance, and immune-related functions of MEX3A, MEX3B, MEX3C, and MEX3D in HCC using comprehensive bioinformatics approaches. We conducted a multi-level bioinformatics analysis to investigate the expression, prognostic significance, clinicopathological correlations, genetic alterations, immune associations, and functional mechanisms of MEX3 family members in HCC. Transcriptomic data from TCGA and GEO databases, along with experimental validation via qRT-PCR and Western blotting, were used to assess expression profiles. Kaplan-Meier, ROC curve, and Cox regression analyses were employed for prognostic evaluation. Co-expression, enrichment, and immune infiltration analyses further elucidated the functional and immunological relevance of MEX3 family genes. A prognostic model based on co-expressed genes was constructed and validated using LASSO and time-dependent ROC analyses. MEX3A, MEX3B, MEX3C, and MEX3D were significantly upregulated in HCC tissues compared to normal liver tissues (P < 0.05). ROC curve analysis demonstrated high diagnostic accuracy, particularly for MEX3A (AUC = 0.915). Kaplan-Meier survival analysis indicated that elevated MEX3A and MEX3C expression was associated with poorer overall survival (OS) and disease-specific survival (DSS) (P < 0.05). Mutation analysis revealed that MEX3A exhibited the highest alteration frequency (11%), primarily through gene amplifications. Immune infiltration analysis demonstrated significant correlations between MEX3 expression and multiple immune cell populations, including regulatory T cells (Tregs), cytotoxic T cells, and macrophages. Moreover, MEX3B, MEX3C, and MEX3D expression correlated with key immune checkpoint genes, including PDCD1, CD274, and CTLA4. Functional enrichment analysis revealed that MEX3 co-expressed genes were significantly involved in RNA metabolism, immune response regulation, and oncogenic signaling pathways. A 17-gene MEX3 co-expression-based prognostic model stratified patients into high- and low-risk groups with significantly different survival outcomes (AUC = 0.791 at 1 year). This study highlights the oncogenic potential of MEX3 family members in HCC and their associations with immune regulation. The findings suggest that MEX3 family genes could serve as potential biomarkers for HCC prognosis and immunotherapy responsiveness. Further experimental validation is warranted to elucidate the mechanistic roles of MEX3 family genes in HCC progression and immune evasion.

Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignant tumor, with the aberrantly activated EGFR signaling pathway playing a crucial role in its development. However, resistance to tyrosine-kinase inhibitors (TKIs) targeting EGFR significantly limits the efficacy of LUAD clinical therapy. Therefore, it is imperative to identify novel therapeutic targets and elucidate the regulatory mechanisms of EGFR for improving LUAD treatment outcomes. In this study, we discover that DNAJC5 functions as an oncogene in LUAD. We observe elevated protein levels of DNAJC5 in tissues from LUAD patients, which are strongly associated with poor prognosis among these individuals. Furthermore, overexpression of DNAJC5 promotes proliferation and migration of LUAD cells both in vitro and in vivo. Mechanistic investigations reveal that DNAJC5 interacts with the intracellular domain of EGFR and enhances its endocytosis and recycle, thereby augmenting EGFR activity and downstream signaling pathways. Additionally, we find that DNAJC5 binds to AP2A1 protein-a key player in EGFR endocytosis-and strengthens its interaction with EGFR. Knockdown experiments targeting AP2A1 attenuate the ability of DNAJC5 to promote proliferation and migration of LUAD cells. Collectively, our findings unveil a functional role for DNAJC5 in regulating EGFR trafficking and driving LUAD progression.

Lung cancer remains a significant global health challenge, with advanced stages often limiting surgical options and necessitating systemic therapies, such as radiotherapy. Resistance to radiotherapy frequently undermines the treatment efficacy. This study explored the role of miR-7-5p in modulating the expression and radiosensitivity of plakophilin-2 (PKP2) in non-small cell lung cancer (NSCLC). Using clonogenic assays, CCK-8 assays, immunofluorescence staining, western blotting, and reporter gene assays, we assessed the effects of miR-7-5p overexpression and inhibition on A549 NSCLC cells. The results show that miR-7-5p overexpression enhanced radiosensitivity by increasing DNA damage (evidenced by higher γ-H2AX foci) and inhibiting non-homologous end joining (NHEJ) repair. Bioinformatic and experimental validation identified PKP2 as a direct target of miR-7-5p. PKP2 overexpression mitigated the radiosensitizing effects of miR-7-5p, confirming the miR-7-5p/PKP2 axis's role in regulating radiosensitivity. This study highlights the potential of targeting the miR-7-5p/PKP2 pathway to overcome radiotherapy resistance in NSCLC and offers a promising therapeutic approach to enhance treatment outcomes.

Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI > 25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1, HBA2, MT-RNR1, MT-RNR2, EGFL6 and FDCSP expression to be differentially expressed in breast tissues from metformin-treated postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that postmenopausal breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors.Trial registration: MetBreCs trial is registered at European Union Clinical Trials Register (EudraCT Protocol # 2015-001001-14) on 07/10/2015.