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Background Ubiquitin-conjugating enzyme E2T (UBE2T) acts as an oncogene in various types of cancer. However, the mechanisms behind its oncogenic role remain unclear in lung cancer. This study aims to explore the function and clinical relevance of UBE2T in lung cancer. Methods Lentiviral vectors were used to mediate UBE2T depletion or overexpress UBE2T in lung cancer cells. CCK8 analysis and western blotting were performed to investigate the effects of UBE2T on proliferation, autophagy, and relevant signaling pathways. To exploit the clinical significance of UBE2T, we performed immunohistochemistry staining with an anti-UBE2T antibody on 131 NSCLC samples. Moreover, we downloaded the human lung adenocarcinoma (LUAD) dataset from The Cancer Atlas Project (TCGA). Lasso Cox regression model was adopted to establish a prognostic model with UBE2T-correlated autophagy genes. Results We found that UBE2T stimulated proliferation and autophagy, and silencing this gene abolished autophagy in lung cancer cells. As suggested by Gene set enrichment analysis, we observed that UBE2T downregulated p53 levels in A549 cells and vice versa. Blockade of p53 counteracted the inhibitory effects of UBE2T depletion on autophagy. Meanwhile, the AMPK/mTOR signaling pathway was activated during UBE2T-mediated autophagy, suggesting that UBE2T promotes autophagy via the p53/AMPK/mTOR pathway. Interestingly, UBE2T overexpression increased cisplatin-trigged autophagy and led to cisplatin resistance of A549 cells, whereas inhibiting autophagy reversed drug resistance. However, no association was observed between UEB2T and overall survival in a population of 131 resectable NSCLC patients. Therefore, we developed and validated a multiple gene signature by considering UBE2T and its relevance in autophagy in lung cancer. The risk score derived from the prognostic signature significantly stratified LUAD patients into low- and high-risk groups with different overall survival. The risk score might independently predict prognosis. Interestingly, nomogram and decision curve analysis demonstrated that the signature’s prognostic accuracy culminated while combined with clinical features. Finally, the risk score showed great potential in predicting clinical chemosensitivity. Conclusions We found that UBE2T upregulates autophagy in NSCLC cells by activating the p53/AMPK/mTOR signaling pathway. The clinical predicting ability of UBE2T in LUAD can be improved by considering the autophagy-regulatory role of UBE2T.

Background As urbanization accelerates across China, community-level sports governance is increasingly recognized as a critical factor in promoting public health through physical activity (PA). However, little is known about the specific mechanisms by which governance structures influence residents’ sports participation, particularly in the presence of sports infrastructure and public awareness. Methods This cross-sectional study surveyed 735 residents in Dongguan, China, using validated instruments to assess perceptions of community sports governance, sports infrastructure development, awareness of sports policies, and physical activity participation. A structural equation model (SEM) was constructed to test the hypothesized mediating effect of sports infrastructure and moderating role of awareness on the relationship between sports governance and physical activity behavior. Results The sports governance system (SGS) significantly influenced physical activity participation (β = 0.323, p  < 0.001), primarily through the mediating role of sports infrastructure development (SID) (indirect effect β = 0.147, p  < 0.001). Public awareness of sports (PAS) significantly moderated the impact of governance on infrastructure (interaction β = 0.377, p  < 0.001), with a smaller but significant total effect on physical activity (β = 0.063, p  < 0.001). The final model explained 41.0% of the variance in SID and 22.1% in PA participation. Conclusion Community sports governance indirectly promotes physical activity primarily by improving local infrastructure. This effect is further strengthened by residents’ awareness of sports programs and policies. Effective physical activity promotion requires not only investments in facilities but also efforts to raise public awareness. These findings support the need for multi-sectoral, system-level strategies integrating governance, infrastructure, and education to improve community health.

Background Ubiquitin-conjugating enzyme E2 T (UBE2T) is a potential oncogene. However, Pan-cancer analyses of the functional, prognostic and predictive implications of this gene are lacking. Methods We first analyzed UBE2T across 33 tumor types in The Cancer Genome Atlas (TCGA) project. We investigated the expression level of UBE2T and its effect on prognosis using the TCGA database. The correlation between UBE2T and cell cycle in pan-cancer was investigated using the single-cell sequencing data in Cancer Single-cell State Atlas (CancerSEA) database. The Weighted Gene Co-expression Network analysis (WGCNA), Univariate Cox and Least absolute shrinkage and selection operator (LASSO) Cox regression models, and receiver operating characteristic (ROC) were applied to assess the prognostic impact of UBE2T-related cell cycle genes (UrCCGs). Furthermore, the consensus clustering (CC) method was adopted to divide TCGA-lung adenocarcinoma (LUAD) patients into subgroups based on UrCCGs. Prognosis, molecular characteristics, and the immune panorama of subgroups were analyzed using Single-sample Gene Set Enrichment Analysis (ssGSEA). Results derived from TCGA-LUAD patients were validated in International Cancer Genome Consortium (ICGC)-LUAD data. Results UBE2T is highly expressed and is a prognostic risk factor in most tumors. CancerSEA database analysis revealed that UBE2T was positively associated with the cell cycle in various cancers(r > 0.60, p < 0.001). The risk signature of UrCCGs can reliably predict the prognosis of LUAD (AUC 1 year  = 0.720, AUC 3 year  = 0.700, AUC 5 year  = 0.630). The CC method classified the TCGA-LUAD cohort into 4 UrCCG subtypes (G1–G4). Kaplan–Meier survival analysis demonstrated that G2 and G4 subtypes had worse survival than G3 (Log-rank test P TCGA training set  < 0.001, P ICGC validation set  < 0.001). A comprehensive analysis of immune infiltrates, immune checkpoints, and immunogenic cell death modulators unveiled different immune landscapes for the four subtypes. High immunophenoscore in G3 and G4 tumors suggested that these two subtypes were immunologically “hot,” tending to respond to immunotherapy compared to G2 subtypes (p < 0.001). Conclusions UBE2T is a critical oncogene in many cancers. Moreover, UrCCG classified the LUAD cohort into four subgroups with significantly different survival, molecular features, immune infiltrates, and immunotherapy responses. UBE2T may be a therapeutic target and predictor of prognosis and immunotherapy sensitivity.

Observations reveal that, in summer, westward extension of the Bermuda high enhances the Great Plains low-level jet (LLJ) that transports more moisture northward, causing precipitation increases in the Midwest and decreases in the Gulf States. Meanwhile, more warm air advection from the Gulf of Mexico to the southern Great Plains and stronger clear-sky radiative heating under high pressures over the Southeast result in warmer surface temperatures across the Gulf states. The enhanced LLJ transport of cleaner marine air from the Gulf reduces surface ozone across the southern Great Plains–Midwest. In contrast, larger transport of more polluted air from the Midwest to New England and more frequent air stagnation under high pressures in the Southeast increase ozone over most of the eastern coastal states. This Bermuda high–induced ozone change reversal between the southern Great Plains–Midwest and eastern coastal states, with a magnitude of 6 and 13.5 ppb, respectively, in summer-mean maximum daily 8-h average, exhibits strong decadal variations that should be considered in the U.S. air quality dynamic management. The observed Bermuda high signatures over the Gulf states can be well captured by regional climate and air quality models. Notable model deficiencies exist over the northern Great Plains–Midwest that are more remote to the Bermuda high and LLJ control. The regional models largely reduce these deficiencies from general circulation models (GCMs). Only 7 out of 51 GCMs can represent all key regional signatures of the Bermuda high, while none can simulate its strong association with planetary sea surface temperature anomalies. The result indicates a great challenge for GCMs to predict Bermuda high variability and change.

Neuroblastoma is a commonly occurring extracranial pediatric solid tumor without defined etiology. Polymorphisms in pre-miRNAs have been demonstrated to associate with the risk of several cancers. So far, no such polymorphism has been investigated in neuroblastoma. With this in mind, we performed a two-center case-control study to assess the association of genetic variants in pre-miRNAs and neuroblastoma susceptibility in Chinese children, including 393 cases and 812 controls. We found that miR-34b/c rs4938723 T > C polymorphism was significantly associated with decreased neuroblastoma risk (TC versus TT: adjusted odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.39–0.67; TC/CC versus TT: adjusted OR = 0.62, 95% CI = 0.48–0.79). We also observed the significant association between the miR-218 rs11134527 A > G polymorphism and decreased neuroblastoma risk (AG versus AA: adjusted OR = 0.73, 95% CI = 0.56–0.96). Stratified analysis further demonstrated that the protective effect of the rs4938723 T > C polymorphism remained prominent in the subgroups, regardless of age, gender, and clinical stages. In term of sites of origin, this polymorphism significantly reduced the risk of tumors originating from the adrenal gland. We further validated the significant results using false-positive report probability analyses. Overall, the miR-34b/c rs4938723 T > C and miR-218 rs11134527 A > G polymorphisms displayed a protective role from neuroblastoma. These findings need further validation.

Lung cancer poses severe threats to human health. It is indispensable to discover more druggable molecular targets. We identified a novel dysregulated long non‐coding RNA (lncRNA), LINC00669, in lung adenocarcinoma (LUAD) by analyzing the TCGA and GEO databases. Pan‐cancer analysis indicated significantly upregulated LINC00669 across 33 cancer types. GSEA revealed a tight association of LINC00669 with the cell cycle. We next attempted to improve the prognostic accuracy of this lncRNA by establishing a risk signature in reliance on cell cycle genes associated with LINC00669. The resulting risk score combined with LINC00669 and stage showed an AUC of 0.746. The risk score significantly stratified LUAD patients into low‐ and high‐risk subgroups, independently predicting prognosis. Its performance was verified by nomogram (C‐index = 0.736) and decision curve analysis. Gene set variation analysis disclosed the two groups' molecular characteristics. We also evaluated the tumor immune microenvironment by dissecting 28 infiltrated immune cells, 47 immune checkpoint gene expressions, and immunophenoscore within the two subgroups. Furthermore, the risk signature could predict sensitivity to immune checkpoint inhibitors and other anticancer therapies. Eventually, in vitro and in vivo experiments were conducted to validate LINC00669's function using qRT‐PCR, CCK8, flow cytometry, western blot, and immunofluorescence staining. The gain‐ and loss‐of‐function study substantiated LINC00669's oncogenic effects, which stimulated non‐small cell lung cancer cell proliferation but reduced apoptosis via activating the Wnt/β‐catenin pathway. Its oncogenic potentials were validated in the xenograft mouse model. Overall, we identified a novel oncogenic large intergenic non‐coding RNA (lincRNA), LINC00669. The resulting signature may facilitate predicting prognosis and therapy responses in LUAD. We identified and validated a novel oncogenic lincRNA of LINC00669. The resulting signature based on LINC00669‐assoicated cell cycle genes may facilitate predicting prognosis and therapy responses in LUAD.

Background Activated Cdc42-associated kinase 1 (ACK1) is a promising druggable target for cancer, but its inhibitors only showed moderate effects in clinical trials. The study aimed to investigate the underlying mechanisms and improve the antitumor efficacy of ACK1 inhibitors. Methods RNA-seq was performed to determine the downstream pathways of ACK. Using Lasso Cox regression analysis, we built a risk signature with ACK1-related autophagy genes in the lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) project. The performance of the signature in predicting the tumor immune environment and response to immunotherapy and chemotherapy were assessed in LUAD. CCK8, mRFP-GFP-LC3 assay, western blot, colony formation, wound healing, and transwell migration assays were conducted to evaluate the effects of the ACK1 inhibitor on lung cancer cells. A subcutaneous NSCLC xenograft model was used for in vivo study. Results RNA-seq revealed the regulatory role of ACK1 in autophagy. Furthermore, the risk signature separated LUAD patients into low- and high-risk groups with significantly different prognoses. The two groups displayed different tumor immune environments regarding 28 immune cell subsets. The low-risk groups showed high immune scores, high CTLA4 expression levels, high immunophenoscore, and low DNA mismatch repair capacity, suggesting a better response to immunotherapy. This signature also predicted sensitivity to commonly used chemotherapy and targeted drugs. In vitro, the ACK1 inhibitors (AIM-100 and Dasatinib) appeared to trigger adaptive autophagy-like response to protect lung cancer cells from apoptosis and activated the AMPK/mTOR signaling pathway, partially explaining its moderate antitumor efficacy. However, blocking lysosomal degradation with chloroquine/Bafilamycine A1 or inhibiting AMPK signaling with compound C/shPRKAA1 enhanced the ACK1 inhibitor’s cytotoxic effects on lung cancer cells. The efficacy of the combined therapy was also verified using a mouse xenograft model. Conclusions The resulting signature from ACK1-related autophagy genes robustly predicted survival and drug sensitivity in LUAD. The lysosomal degradation inhibition improved the therapeutic effects of the ACK1 inhibitor, suggesting a potential role for autophagy in therapy evasion.

To date, the relationship between METTL1 gene polymorphisms and Wilms tumor has never been described. [...]we carried out a large case-control study to explore their relationship and the etiology of Wilms tumor. [...]the METTL1 gene not only served as a potential oncogene but also acted as a tumor suppressor. [...]it is reasonable to speculate that METTL1 may be involved in the occurrence of Wilms tumor, but we have not confirmed that METTL1 gene SNPs play a cancer-suppressing or cancer-promoting role in Wilms tumor. [...]most variants of SNPs that are associated with cancer susceptibility are always located in non-coding regulatory regions, suggesting that transcriptional regulation plays a key role in cancer susceptibility.

Background Wilms tumor, a prevalent pediatric kidney cancer, has been extensively studied to elucidate its genetic mechanisms. NAT10 ( N-acetyltransferase 10 ) is a gene encoding acetyltransferase, which is involved in various cellular processes, including RNA modification, DNA repair, and protein acetylation. The oncogenic role of NAT10 in cancer has garnered significant attention. However, research on NAT10 genetic variants and their associations with cancer is nascent. Methods This study investigated the link between NAT10 genetic variants and Wilms tumor risk via a case‒control design with genomic DNA from 414 patients and 1199 controls. Genotyping was performed via the TaqMan method, and logistic regression statistical analysis was conducted to identify significant associations, followed by extra analysis to minimize false positive significant results. Results Our findings revealed that the rs8187 G > A polymorphism in the NAT10 gene is significantly correlated with a decreased risk of developing Wilms tumor (GA vs. GG, adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI) = 0.46–0.77, P  < 0.0001; GA/AA vs. GG, AOR = 0.74, 95% CI = 0.59–0.93, P  = 0.011). Stratified analyses further revealed a significant association in children aged 18 months or under and in subgroups with stage II, stage IV, or combined stage I + II tumors. Conclusion These results highlight the potential of NAT10 rs8187 G > A polymorphism as genetic markers for Wilms tumor susceptibility. This study clarifies the genetic basis of Wilms tumor susceptibility and highlights the role of NAT10 rs8187 G > A polymorphism in early detection and risk assessment. Graphical Abstract

Neuroblastoma tightly linked with genetic abnormality. The core genes responsible for RNA N 1 -methyladenosine (m 1 A) modification are critical in tumor development. Nevertheless, few reports revealed the function of m 1 A modification core gene polymorphisms and the neuroblastoma risk. We carried out this study to verify the association of 12 single-nucleotide polymorphisms (SNPs) with neuroblastoma susceptibility. This study recruited 898 cases with newly diagnosed neuroblastoma and 1734 Healthy controls from eight medical centers. We selected 12 SNPs from m 1 A modification genes ALKBH1 , TRMT6 , TRMT61B , and TRMT10C , and genotypes were determined by the TaqMan method. We used univariable and multivariable logistic regression models to analyze the association of SNPs with neuroblastoma risk, followed by stratified analysis. Statistical analysis showed that TRMT6 rs236170 GG (AOR = 1.23, 95% CI = 1.02–1.50, P  = 0.034), rs451571 CC (AOR = 1.46, 95% CI = 1.01–2.11, P  = 0.043), rs236188 AA (AOR = 2.65, 95% CI = 1.16–6.07, P  = 0.021), rs236110 AA (AOR = 1.91, 95% CI = 1.29–2.82, P  = 0.001), and ALKBH1 rs6494 AA (AOR = 4.27, 95% CI = 1.31–13.93, P  = 0.016), rs176942 GG (AOR = 1.98, 95% CI = 1.35–2.89, P  = 0.0005) were neuroblastoma risk variants; the ALKBH1 rs1048147 CC (AOR = 0.80, 95% CI = 0.68–0.94, P  = 0.007) was inverse associated with neuroblastoma risk. The eQTL analysis showed that functional annotation of rs6494 T > A may be potential function variants through decreasing ALKBH1 gene expression mRNA, rs451571 T > C, rs236188 G > A, rs236110 C > A are associated with neuroblastoma risk through increasing the expression of its nearby genes RP5-967N21.11 and lowering the expression of MCM8 . Our research showed some SNPs in the m 1 A modification core genes are related to neuroblastoma. Clinical perspectives (i) Few reports have revealed the function of m 1 A modification core gene polymorphisms in neuroblastoma risk. (ii) After genotyping 12 SNPs with potential functions in four m 1 A modification core genes in children with neuroblastoma and healthy controls, we found several neuroblastoma predisposition loci, including TRMT6 rs236170, rs451571, rs236188, rs236110, and ALKBH1 rs6494, rs176942, and rs1048147. The eQTL assessment demonstrated that rs6494 T > A may be a potential functional variant by decreasing ALKBH1 mRNA expression. (iii) Our research is the first to reveal m 1 A modification core gene SNPs and neuroblastoma risk. Graphical Abstract