Recent studies have described an ability of cancer cells to survive engagement of apoptotic pathways following chemical and therapeutic insults, challenging the prevailing model that caspase activation inevitably leads to cellular demise. Gasdermin E (GSDME), whose expression is frequently down-regulated or silenced in many tumors and tumor-derived cell lines, is a putative tumor suppressor capable of facilitating the induction of antitumor immunity. We found that GSDME expression precluded high caspase activity before cellular membrane rupture downstream of chemical and immune-mediated insults, and its absence allowed for enhanced activities downstream of caspase activation, including the DNA-damaging effects of caspase-activated deoxyribonuclease. Loss of GSDME allowed cells that had sustained DNA damage to survive, resulting in development and propagation of mutated clones. We conclude that GSDME functions as a key rheostat for determining cell death outcomes by tuning the tolerance to the activities of caspases and their substrates during apoptosis. In analyzing solid tumors in The Cancer Genome Atlas, we found that tumor mutational burden was higher in tumors with low GSDME expression and high immune signatures, supporting the possibility that the effects we describe affect tumor mutation in response to immune assault.

Hepatocellular carcinoma (HCC) remains a major challenge threatening global health. It has a high incidence with poor prognosis, and its response to current conventional therapies is not satisfactory, so we need to explore new effective therapies to address this problem. Targeted therapy represents a promising approach, but the therapeutic efficacy of targeting ion transporters and nuclear transport proteins, such as Na+/K+/2Cl- cotransporter 1 (NKCC1) and Karyopherin β1 (KPNβ1), remains poorly investigated. This study aims to assess the therapeutic efficacy of targeting NKCC1 and KPNβ1 individually and in combination. We also explored the roles of these transporters in tumor cell proliferation and HCC progression. To achieve this aim, an HCC rat model was used, induced by diethylnitrosamine and phenobarbital. The evaluation included histopathological examination and assessment of liver function biomarkers (alanine aminotransferase and aspartate aminotransferase), cell cycle regulators (Cyclin D1, p21, E2F1), proliferation (Ki-67), apoptosis (Caspase-3), and expression of NKCC1 and KPNβ1. This study revealed that NKCC1 and KPNβ1 were upregulated in the HCC group. This increase was associated with increased proliferation and suppressed apoptosis. Targeting these proteins, particularly in combination, significantly improved liver function. It also induced cell cycle arrest, reduced proliferative markers, and enhanced apoptosis. These findings indicate that NKCC1 and KPNβ1 could serve as possible therapeutic targets in HCC treatment.

Due to the late stage at which most gastric cancer patients are diagnosed, the prognosis is often poor. Current treatments have limited efficacy for advanced cases. This study delves into the involvement of circARID1A and the mechanisms behind its role in gastric cancer progression. GES-1 cell line and GC cell lines HGC-27, AGS, MKN45, and SNU-16 were cultured and subjected to various assays. RNA interference and overexpression techniques were used to modulate circARID1A and miR-147a levels in vitro, while xenograft tumor models in BALB/c nude mice were used to assess tumor growth in vivo. Cellular growth, migration, and invasion were assessed using CCK8, colony formation, and Transwell assays. Dual-luciferase reporter assays, qPCR and Western blot were utilized to investigate the interactions between circARID1A, miR-147a, and SNAI2. CircARID1A promotes GC cell proliferation, migration, and invasion by regulating the miR-147a/SNAI2 axis. In vivo, knockdown of circARID1A inhibits tumor growth in subcutaneous xenograft models.

Oral squamous cell carcinoma (OSCC) is represented as a major global health concern with few treatment options. Codon usage bias (CUB) is a non-random selection of synonymous codons. It offers information on gene expression patterns and molecular evolution.

This study examined CUB patterns in 1328 differentially expressed genes (651 up-regulated, 677 down-regulated) from oral cancer tissues. Nucleotide composition analysis, effective number of codons (ENC), Relative Synonymous Codon Usage (RSCU) analysis, neutrality plot analysis, and gene expression analysis were performed to assess codon usage patterns and their relationship to gene expression levels and pathway classification.

Nucleotide composition analysis indicated a clear GC-rich tendency with base frequencies arranged as C > G > A > T for up-regulated genes and C > A > G > T for down-regulated genes. The average ENC values were 47.21 (up-regulated) and 49.08 (down-regulated), suggesting a low codon usage bias. RSCU analysis revealed 25 more frequently used (mean RSCU >1.0) and 34 less frequently used (mean RSCU <1.0) codons in up-regulated genes, while down-regulated genes had 30 more frequently used and 29 less frequently used codons. Neutrality plot analysis showed that both gene groups were predominantly shaped by selective constraints rather than mutational pressure (slopes of 0.202 and 0.228 for up- and down-regulated genes, respectively), though these slopes provide only indirect, qualitative evidence and should not be interpreted as exact quantitative contributions. Gene expression analysis revealed 1328 differentially expressed genes with functional enrichment in metabolic pathways and cellular components.

These discoveries offer molecular insights into the genetic pathways that support oral cancer development. It implies that codon optimization could affect the translation efficiency of cancer-promoting genes.

Protein inhibitor of activated STAT 2 (PIAS2) is highly expressed in various solid tumors. Its precise function as a ferroptosis regulator in hepatocellular carcinoma (HCC) is still unknown. The purpose of this work was to determine whether PIAS2 overexpression attenuates erastin-induced ferroptotic changes and, in turn, is associated with the development of HCC in a manner that correlates with changes in Glutathione Peroxidase 4 (GPX4) protein levels and small ubiquitin-like modifier 3 (SUMO3) modification signals.

Erastin (Era) was used to induce ferroptosis in HepG-2 and H22 cells, while Ferrostatin-1 (Fer-1) was employed for validation. Western blotting, qPCR, and co-immunoprecipitation (Co-IP) were used to examine the expression and interaction of PIAS2 and GPX4. Ferroptosis markers (lipid-reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), Fe²⁺), cell viability, migration, and invasion were all analyzed. Functional rescue experiments were performed using PIAS2 overexpression (oe-PIAS2) and GPX4 knockdown (sh-GPX4). In addition, a murine model of H22 cells in the right groin/lateral abdomen was established for in vivo validation. Tumor weight and volume were measured in these animals. Additionally, tumor tissues were collected and subjected to immunohistochemical staining for Ki-67 expression, as well as biochemical analysis of ferroptosis-related markers (GSH, MDA, Fe²⁺).

In HCC cells, Era-induced ferroptosis resulted in a significant downregulation of PIAS2 and GPX4 expression, as well as elevated levels of lipid ROS, MDA, and Fe²⁺, decreased GSH content, and decreased cell viability, migration, and invasion. Under Era-treated conditions, overexpression of PIAS2 effectively reversed these changes, suppressing ferroptosis and partially restoring malignant phenotypes within the context of Era challenge. Co-treatment with Fer-1 significantly reversed Era-induced ferroptotic changes and rescued cell viability, migration, and invasion, without affecting PIAS2 expression, while also restoring GPX4 levels. Mechanistic studies revealed that PIAS2 and GPX4 co-immunoprecipitate in HCC cells, and PIAS2 overexpression was associated with increased SUMO3 modification signals and higher remaining GPX4 protein levels at the examined 12- and 24-h CHX time points. GPX4 knockdown attenuated the phenotypes observed under PIAS2 overexpression, suggesting possible involvement of GPX4 in the effects of PIAS2. In Era-treated tumor-bearing mice, PIAS2 overexpression was associated with increased tumor growth, elevated Ki-67 and GPX4 levels, and reduced ferroptosis indicators.

PIAS2 overexpression was associated with increased GPX4 SUMO3 modification signals and higher GPX4 protein levels at the examined CHX time points, together with reduced ferroptotic changes under Era-treated conditions.

Accumulating evidence suggests that neddylation contributes to tumor initiation and progression. Nonetheless, its biological functions and regulatory mechanisms in lung adenocarcinoma (LUAD) remain poorly understood.

Bioinformatics analyses integrated single-cell RNA sequencing (scRNA-seq) datasets from the Gene Expression Omnibus (GEO) with bulk RNA-seq data from The Cancer Genome Atlas (TCGA). The Seurat package was used for scRNA-seq processing, including cell clustering, annotation, cell-cell interaction analysis, and pseudotime trajectory inference. The survival and pROC packages were used for Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) analyses, respectively. Tissue microarray (TMA) and immunohistochemistry (IHC) analyses were performed to validate biomarker expression. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell assays, were conducted in A549 and NCI-H1975 cells with DNAJB1 knockdown.

Eight major cell populations were identified at the single-cell level, among which T/NK cells, particularly CD8+ effector memory T cells (CD8+ Tem), exhibited strong associations with neddylation. T/NK cells displayed extensive ligand-receptor-mediated interactions with other cell types. A transcription factor (TF)-target regulatory network was constructed, revealing that Surfactant Protein C (SFTPC), Lipopolysaccharide-Induced TNF Factor (LITAF), Serine/Threonine Kinase 17B (STK17B), Enah/Vasp-Like Protein (EVL), FYN Proto-Oncogene, Src Family Tyrosine Kinase (FYN), and Lymphocyte-Specific Protein 1 (LSP1) were associated with favorable prognosis, whereas DNAJB1 correlated with poor survival in LUAD patients. Pseudotime trajectories further delineated dynamic differentiation pathways of T/NK subsets and differential TF target expression across states. IHC analysis showed elevated DNAJB1 expression in tumors compared with adjacent normal tissues. Moreover, silencing DNAJB1 significantly inhibited proliferation, migration, and invasion in A549 and NCI-H1975 cells.

This study identifies neddylation-associated cellular phenotypes and clinically relevant biomarkers in LUAD, providing new mechanistic insights and highlighting potential therapeutic targets for LUAD treatment.

Renal cell carcinoma (RCC) is a common urological malignancy, yet the cytokine landscape of the tumor microenvironment, especially in early-stage tumors, remains poorly defined. Using antibody arrays, 174 tumor-related cytokines were measured in 20 sets of normal, para-cancerous, and tumor tissues from early-stage RCC patients. Selected cytokines were validated by ELISA. Functional enrichment was analyzed via DAVID, while transcriptional expression, survival outcomes, and immune infiltration were assessed using GEPIA, Kaplan-Meier Plotter, and TIMER databases. Thirty-four differentially expressed cytokines were identified in tumors versus controls, enriched in cytokine signaling, TNF, PI3K-Akt, Ras, HIF-1, and Toll-like receptor pathways. ELISA confirmed reduced IL-2, IL-15, IGFBP-2, HGF, ErbB3, and FLT3LG, and increased CCL4, CXCL9, and Angiopoietin-2 in tumors. Serum levels of HGF, ErbB3, and CCL4 were decreased in RCC patients, while urinary ErbB3 was also reduced. IL-2, IL-15, and CCL4 were upregulated in T1-T2 metastatic tumors. Several cytokines correlated with poor survival, except ErbB3, which associated with improved outcomes. Several cytokine-related genes, including CXCL9 and CCL4, correlated with inferred immune cell infiltration patterns. These findings suggest that early-stage RCC may be associated with a cytokine expression profile characterized by reduced immune-stimulating factors and elevated pro-angiogenic and inflammatory signals. Urinary ErbB3 emerged as a candidate non-invasive biomarker requiring further validation.

Environmental exposures, such as per-and polyfluoroalkyl substances (PFAS), are suspected to play a role in the significant increase in incidence of some early-onset cancers. PFAS are chemicals of concern due to their persistence in the environment, long biological half-lives, and potential carcinogenic properties. Exposure during sensitive windows of development may exert durable effects on cancer-related biological pathways leading to greater risks of early-onset cancers. This review summarizes the current evidence of PFAS exposure and early-onset carcinogenesis, with an emphasis on potential exposure routes, early-onset cancer development in humans linked with PFAS exposure, and mechanistic pathways. Emerging evidence supports a potential role for PFAS exposure in carcinogenesis during early life, particularly through prenatal and early postnatal windows of susceptibility. While epidemiologic studies increasingly link PFAS to several types of cancer, the evidence specifically addressing early-onset cancers remains limited and heterogeneous. Future research should prioritize prospective, longitudinal cohort studies with repeated exposure measurements spanning prenatal, infancy, and childhood periods, coupled with long-term follow-up into early adulthood to capture early-onset cancer outcomes.

Cardiac surgery patients are at particular risk of postoperative acute respiratory distress syndrome (ARDS), with an estimated incidence of 5% to 10%. Cardiopulmonary bypass (CPB), ischemia-reperfusion injury, and blood product transfusions are well-recognized contributing factors. Asymptomatic carriage of respiratory viruses has been hypothesized to prime the lungs and potentiate ARDS development when combined with the pulmonary insults of cardiac surgery. However, no study has directly assessed the relationship between preoperative asymptomatic viral carriage and postoperative ARDS.

The VIRUS-ATTAC study aims to determine whether asymptomatic carriage of influenza or other respiratory viruses is independently associated with postoperative ARDS following elective cardiac surgery under CPB.

VIRUS-ATTAC is a prospective, multicenter, low-interventional clinical study conducted across 5 French university hospitals and sponsored by Rennes University Hospital. Adult patients scheduled for elective cardiac surgery under CPB are eligible. A nasopharyngeal flocked swab is collected at anesthesia induction and tested using a multiplex reverse transcription polymerase chain reaction assay detecting 16 respiratory viruses. Results are kept blinded to the clinical team. The primary outcome is ARDS within 7 postoperative days, defined using the Berlin criteria and adjudicated by an independent blinded committee. Secondary outcomes include reintubation, postoperative pulmonary complications, pneumonia, ventilator-free days, intensive care unit-free days, hospital-free days, and 28-day mortality. The primary analysis uses a causal inference framework with a directed acyclic graph for confounder selection and g-computation to estimate the average treatment effect of viral carriage on ARDS risk. A sample size of 1250 patients (including 250 asymptomatic influenza carriers) provides 80% power to detect a 5% absolute risk increase in ARDS (2-sided α=.05).

The VIRUS-ATTAC study received ethics approval from the Comité de Protection des Personnes Sud-Est VI, and recruitment was initiated in February 2021 across 5 French university hospitals. Data collection was completed on March 10, 2023. Of the 1258 patients assessed as eligible, 1204 provided written informed consent and were enrolled. The study database was locked on April 9, 2026. Statistical analysis began after database lock, and the results are expected to be reported in a separate publication in 2027.

VIRUS-ATTAC is the first prospective multicenter study to directly evaluate the association between preoperative asymptomatic respiratory viral carriage and postoperative ARDS in cardiac surgery patients. If confirmed, this association would provide a rationale for evaluating preventive strategies, such as systematic preoperative vaccination or postponement of elective surgery in carriers, in future interventional studies aiming to reduce postoperative respiratory complications.

Neonatal acute respiratory distress syndrome (NARDS) carries high morbidity and mortality. Preterm infants at risk need to be identified early so that treatment is not delayed. We aimed to identify factors associated with NARDS in preterm infants. Clinical data of 548 preterm infants admitted to the NICU between 2019 and 2023 were retrospectively analyzed. Preterm infants were categorized into the NARDS group (n = 275) and the control group (n = 273) according to the Montreux definition. Univariate analysis and multivariable logistic regression were used to identify factors independently associated with NARDS; the results are shown in a forest plot. The study was reported in accordance with the STROBE guidelines. Six factors were independently associated with NARDS in preterm infants: male sex (OR = 1.895, 95% CI 1.051-3.420), premature rupture of membranes (PROM) (OR = 6.784, 95% CI 3.415-13.478), chorioamnionitis (OR = 11.143, 95% CI 5.460-22.742), cesarean delivery (OR = 2.104, 95% CI 1.125-3.935), higher PaCO2 (OR = 1.188 per mmHg, 95% CI 1.143-1.234), and lower gestational age (OR = 0.715 per week, 95% CI 0.587-0.871).

Male sex, lower gestational age, PROM, chorioamnionitis, cesarean delivery, and elevated early postnatal PaCO2 were independently associated with NARDS in preterm infants. All six are available in routine practice and could help clinicians flag preterm infants who need closer monitoring.

• NARDS is a severe, recently defined form of acute respiratory failure in neonates, and evidence on its risk factors in preterm infants remains limited.

• Male sex, lower gestational age, premature rupture of membranes, chorioamnionitis, cesarean delivery, and elevated PaCO2 within 15 min of birth were independently associated with NARDS in preterm infants.