Elderly non-small cell lung cancer (NSCLC) patients do not always benefit from standard treatments due to impaired organ function and/or multiple comorbidities. Our study aimed to determine the efficacy and safety of aumolertinib as a first-line therapy in NSCLC patients aged ≥65 and <65 years in clinical practice.We enrolled 100 patients with stage IIA-IVB epidermal growth factor receptor-mutant NSCLC who received aumolertinib alone as the first-line therapy. Efficacy and safety were compared between patients aged ≥65 and <65 years in different subgroups. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety.Overall, ORR and DCR were 76% and 98%, respectively. ORR was 69.4% and 82.4% for patients aged ≥ 65 and < 65 years, respectively (P = .27), and DCR was 98% and 98%, respectively (P = .93). The median PFS was 23.2 months. The median PFS was 26.9 months and 18.3 months in the ≥65 and <65 years groups, respectively (P = .377, and the median OS of all patients was 31.7 months. The median OS was 33.7 months and 30.7 months in the ≥65 and <65 years groups, respectively (P = .851). Adverse events were not statistically different between the 2 groups.The efficacy and safety profile of aumolertinib as a first-line therapy in elderly patients with epidermal growth factor receptor-mutant NSCLC were similar to those observed in the younger subgroup.

Lung cancer remains a leading cause of global morbidity and mortality, imposing a significant healthcare burden worldwide. To comprehensively investigate potential risk factors for lung cancer and provide a theoretical basis for its prevention and treatment, we utilized publicly available genome-wide association study data of European ancestry. We treated various traits as exposures and lung cancer as the outcome. Causal relationships were assessed using 5 Mendelian randomization (MR) methods: inverse-variance weighted, constrained maximum likelihood and model averaging, debiased inverse-variance weighted, contamination mixture, and Mendelian randomization-robust adjusted profile score. We subsequently performed meta-analysis and median-based MR to synthesize the roles of different risk factors in lung cancer development. Following outlier removal via radial MR and MR analyses, we identified 88, 113, 248, and 232 exposure datasets showing causal associations with lung adenocarcinoma, small cell lung cancer, lung cancer overall, and squamous cell lung cancer, respectively. Further integration via meta-analysis and median MR revealed that higher educational attainment may reduce lung cancer risk by delaying age at first sexual intercourse, increasing age at first childbirth, lowering body mass index and adiposity, and reducing smoking frequency. Our comprehensive analysis suggests that education may play a protective role against lung carcinogenesis, potentially mediated through behavioral changes such as reduced smoking and modifications in physical health indicators including body mass index and adiposity.

Endometrial carcinoma (EC) remains an ambiguous pathogenesis. This study aimed to investigate the potential of causal genes in predicting EC prognosis. The prognostic biomarkers of EC were identified using univariate Cox regression analyses based on data from The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC). Mendelian randomization (MR) analyses were conducted to infer causal relationships, utilizing expression quantitative trait loci (eQTLs) derived from prognostic genes as exposures, and a dataset from European populations with EC as outcomes. Single nucleotide polymorphisms (SNPs) that significantly influenced gene expression (eQTLs) were selected as instrumental variables. The inverse variance weighted (IVW) method was employed as the primary analytical approach. Sensitivity analyses were performed to ensure robustness of the findings. Causal genes with potential prognostic significance were further evaluated using multivariate Cox regression analysis, Kaplan-Meier (KM) overall survival curves, and receiver operating characteristic (ROC) curve analysis. Additionally, results from gene ontology (GO) and gene set enrichment analysis (GSEA) of differentially expressed genes (DEGs), along with immune infiltration analyses in the high- and low-risk groups, are presented. 18 genes exhibiting a negative correlation with EC demonstrated a protective effect, whereas 9 genes identified as risk factors for EC exerted an adverse effect on the disease. A prognostic model was developed consisting of 8 genes selected from 27 genes. According to the KM overall survival curve data, ECs classified with high-risk ratings exhibited significantly poor prognoses (P < .0001). The ROC curve analysis indicated that the area under the curve (AUC) for this risk model in predicting the 1-, 3-, and 5-year EC survival rates were 0.704, 0.735, and 0.766, respectively. Furthermore, GO and GSEA results of DEGs in both the high- and low-risk groups revealed strong associations with pathways related to cell motility and immune response, among others. In addition, an analysis of immune cell infiltration demonstrated significant differences between the high- and low-risk groups. A prognostic model for EC using causal genes identified using MR has good sensitivity and specificity. These findings provide new insights into ECs pathogenesis and suggest promising strategies for the diagnosis and treatment of ECs.

CXC motif chemokine receptor type 4 (CXCR4) has an association with normal and abnormal progression. Previous studies have demonstrated the involvement of CXCR4 in breast cancer (BC), particularly in promoting metastatic progression. However, most of the existing evidence originates from basic research. Our study aims to evaluate novel the expression profiles of CXCR4 in BC. Computerized literature search was done on the online accessible databases, including ONCOMINE, Kaplan-Meier plotter, TCGA database and Breast Cancer Gene-Expression Miner v4.3 to explore the expression profile and prognostic roles of CXCR4. CXCR4 overexpression was associated with BC versus normal control. Elevated CXCR4 expression predicted better PFS, but no survival rate benefit in BC patients. Moreover, there is a survival rate benefit with high expression of CXCR4 mRNA in the negative ER but the positive ER group. CXCR4 was more frequently overexpressed in BC patients with negative expression of ER and PR and negative expression of HER-2. For molecular subtypes analysis, higher expression of CXCR4 was associated with Basal-like and HER-2 subtypes than luminal A and luminal B subtypes. Moreover, we demonstrate a positive correlation between high expression of CXCR4 and low expression of LASP1 and EIF4A1 via gene correlation targeted analysis, which is consistent with the result among the triple-negative breast cancer patients. Our results suggest that CXCR4 can be used as a biological factor to predict the prognosis of BC patients, especially those with triple-negative breast cancer, and is also a tumor marker with potential value in the future treatment of BC.

The ECT2 gene, encoding a guanine nucleotide exchange factor, plays crucial roles in cell cycle progression and cytoskeletal dynamics, implicating its involvement in various cancers. However, a comprehensive pan-cancer analysis integrating genomic data is still lacking. This study employed an integrated approach using data from multiple cancer genomics databases to assess ECT2 across various malignancies. Expression profiles of ECT2 were analyzed for differential expression across tumor stages and its association with clinical outcomes. Correlation analyses examined the relationship between ECT2 expression and immune cell infiltration levels. Pathway enrichment analysis identified biological processes influenced by ECT2 dysregulation in cancer progression. These methods facilitated a comprehensive exploration of ECT2's role in cancer biology, revealing potential implications for diagnosis, prognosis, and therapy. Analysis across 33 tumor types consistently shows elevated ECT2 expression. ECT2 correlates with tumor staging in 8 cancers and molecular subtypes in 13 cancers, and shows associations with immune subtypes in 22 cancers, suggesting its role in cancer progression and immune modulation. ECT2 demonstrates strong diagnostic potential (the area under the ROC curve > 0.9) in 16 cancers and correlates with poorer overall survival in 11 cancers. ECT2 expression correlates positively with microsatellite instability in STAD, MESO, UCEC, and READ, and negatively in DLBC; it correlates positively with tumor mutational burden in STAD, PAAD, ACC, LGG, and LUAD, and negatively in THYM. ECT2 also exhibits diverse correlations with immune checkpoint genes and specific immune cell types identified through CIBERSORT analysis. ECT2 interacts with proteins like RACGAP1, KIF23, enriched in pathways involving cell polarity, Ras signaling, and tight junctions, impacting cancer progression and stemness in various cancer types. This study offers comprehensive insights into ECT2's role in cancer biology through integrative bioinformatics analyses. The results advocate for ECT2 as a potential biomarker and therapeutic target in diverse malignancies, suggesting avenues for personalized oncology strategies.

The main goal of this study was to clarify the causal link between dietary habits and the occurrence of oral cancer via a Mendelian randomization (MR) approach. This method offers valuable insights that can inform the creation of effective management strategies in clinical settings. This investigation involved a comprehensive dataset that included 8,943,774 dietary samples and 3,723,373 oral cancer cases sourced from genome-wide association studies. To explore the possible causal relationship between dietary habits and the occurrence of oral cancer, various statistical methods, such as inverse variance weighted MR analysis, the weighted median approach, and MR-Egger regression analysis, have been employed. The variability in the results was evaluated via the Cochran Q statistic, and to address the issue of multiple comparisons, the MR-Egger and MR-PRESSO methods were utilized. Additionally, sensitivity analysis was conducted via the leave-one-out technique to ensure the reliability of the findings. Among 59 instrumental variables, inverse variance weighted analysis revealed an inverse relationship between oily fish intake and oral cancer risk (odds ratio = 0.998; 95% confidence interval: 0.997-1.000; P = .024). Nonsignificant results emerged from MR-Egger (P = .171) and weighted median (P = .483). Cochran Q testing confirmed no single-nucleotide polymorphism heterogeneity (P > .05), while MR-Egger (intercept = 3.776E-05, P = .389) and MR-PRESSO (P = .534) detected no horizontal pleiotropy. Leave-one-out analysis demonstrated robustness, with no single single-nucleotide polymorphism significantly influencing outcomes. Oily fish intake may reduce the incidence of oral cancer.

Since the causal relationship between cholelithiasis and serum bilirubin levels and hepatobiliary and pancreatic malignancies has been inconclusive and inconsistent for a long time, to control confounding factors and reverse causality as much as possible, this paper adopted a Mendelian randomization (MR) study to reveal further the causal relationship between different exposure factors and hepatobiliary and pancreatic malignancies. This study selected 4 exposure factors, including cholelithiasis, serum total bilirubin, direct bilirubin, and indirect bilirubin, by double-sample and bidirectional MR method. The results were as follows: gallbladder carcinoma, liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PADC) were selected as the outcome, and significance level (P < 5e-08) was used as the filtering criterion to select genetic variation as the instrumental variable for follow-up analysis. Then, we calculated the odds ratio between exposure and outcome to show the causal relationship between different exposure factors and outcome. A series of sensitivity analyses were conducted to verify the conclusions' reliability. There was a causal relationship between direct bilirubin and gallbladder cancer, and direct bilirubin was a risk factor for gallbladder cancer (odds ratio = 3.07, 95% confidence interval = 1.02-9.22, P = .04). We then performed a reverse MR analysis on this analysis to further analyze the possible reverse causality between the 2 and found no reverse causality between the 2 (P = .22). At the same time, other exposure factors in the study did not show a causal relationship with the outcome. This study showed that serum direct bilirubin is a risk factor for gallbladder cancer. The conclusion was statistically significant (P = .04), and reverse MR excluded the reverse causal association between the 2. Cholelithiasis, serum total bilirubin, and indirect bilirubin were not causally associated with gallbladder cancer, and none of the exposure factors in the study showed a causal association with hepatocellular carcinoma and pancreatic cancer.

Epigenetic modifications such as DNA methylation play a fundamental role in oncogenesis and the progression of neoplasms neoplasias. DNA methyltransferase inhibitors (DNMTi) constitute a family of therapeutic agents that impede the methylation at the 5-position on cytosine nucleotides, thereby modulating the epigenetic regulation of tumor suppressor genes, oncogenes, and other key regulatory genes. The first-generation DNMTi azacitidine and decitabine have demonstrated substantial efficacy in the treatment of medically non-fit, older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy (IC), by virtue of their favorable safety profile. Despite these clinical achievements, however, single-agent DNMTi treatment has faced challenges such as limited, non-durable response rates and remissions as well as the emergence of secondary resistance. These limitations have driven broad efforts to identify more effective, dual treatment combinations, such as now attained with the DNMTi-BCL-2 (B-cell lymphoma 2) inhibitor combination. This review aims to provide a comprehensive overview and analysis of the pivotal role of DNMTi in both mono- and combination therapies for myeloid malignancies over the last 40 years, while also exploring their potential applicability in lymphoid malignancies. Additionally, this review assesses the therapeutic potential of DNMTi in the management of solid tumors. Through these discussions, we intend to enhance the understanding of the mechanistic and therapeutic implications of DNMTi across a diverse array of malignancies.

It is currently understood that the characteristic loss of the repressive histone mark H3K27me3 in PFA ependymoma and diffuse midline glioma (DMG) are caused by complementary mechanisms mediated by EZHIP and the oncohistone H3K27M, respectively. To support the complementarity of these mechanisms, rare H3K27M-negative DMGs express EZHIP. Interestingly, EZHIP is one of the few genes recurrently mutated in PFA. The significance of EZHIP mutations in PFA, and whether EZHIP has wider functions in addition to repression of H3K27me3 deposition, are not known. Here, we investigated the mutational landscape of EZHIP in pediatric brain tumors. We found that EZHIP mutations occur not only in PFA, but also in rare medulloblastoma and pediatric high-grade glioma (HGG), including in H3K27-positive DMG. Contrary to current expectations, we show that mutant EZHIP is expressed in H3K27M-positive DMG. All the EZHIP-mutated HGG cases also have EGFR mutations. Further, we pursued better understanding of the function of EZHIP by expressing it in human-derived neural models. Our transcriptomic analyses indicate that EZHIP expression potentiates neuronal-like gene programs associated with synaptic function. Metabolomics data indicate that EZHIP leads to repression of methionine and polyamine metabolism, suggesting links between metabolic and epigenetic changes that are observed in PFA. Collectively, our results expand the repertoire of tumor types known to harbor EZHIP mutations and shed light on EZHIP-dependent metabolic and transcriptional programs in relevant neural models.

This case-control study aimed to investigate the relationship between plasma EVs LncRNAs, specifically Xist, MALAT1, and NEAT1, and MetS in PCOS patients, to identify a novel biomarker for early MetS diagnosis in these patients.

Hypoxia and angiogenesis are crucial hallmarks of cancer that play key roles in the development and progression of colorectal cancer (CRC). However, the transcriptional mechanism underlying hypoxia induced angiogenesis (HIA) remain elusive. This study aimed to explore the regulatory networks, molecular mechanisms, and prognostic value of HIA-related genes.

Castration-resistant prostate cancer (CRPC) represents the terminal stage of prostate cancer (PCa), yet the molecular mechanisms driving its development remain unclear. Members of the histone lysine demethylase (KDM) family regulate histone methylation and thereby modulate transcriptional programs during malignant progression, contributing to PCa pathogenesis. While the function of KDM3B in PCa has been described, its involvement in CRPC remains uncertain. This study investigated the mechanistic role of KDM3B in CRPC progression.

Chemoresistance remains a major challenge in addressing T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL), underscoring the necessity for novel strategies to unravel the molecular factors driving resistance. Through transcriptomic profiling, circBPTF was found to be markedly overexpressed in chemoresistant samples. Further functional experiments demonstrated that BPTF-665aa, the protein product of circBPTF, plays a pivotal role in mediating resistance. Notably, BPTF-665aa prevents the ubiquitination degradation of full-length BPTF, and promotes chromatin accessibility at key promoter sites, such as that of c-Myc promter 2 (P2), facilitating transcriptional activation crucial for cellular survival and proliferation under therapeutic stress. Structural studies confirmed the motifs of BPTF-665aa, including the Plant Homeodomain (PHD) finger and Bromodomain, essential for its chromatin remodeling function. HY-B0509 was identified as a small-molecule inhibitor of BPTF-665aa, with molecular docking and dynamics simulations showing stable binding to critical residues within the protein's active site. Overall, this study introduces a new mechanism where circBPTF affects chromatin accessibility, causing chemoresistance, making BPTF-665aa as a potential therapeutic target for treating T-LBL/ALLs.

A subset of multiple myeloma (MM) patients exhibited worse survival and higher tumor burden. STAiR18 has been found to be highly expressed in MM cell lines. However, the precise mechanisms underlying the upstream and downstream regulation of STAiR18 have remained unclear.

Reliable biomarkers to identify inoperable limited stage small-cell lung cancer (LS-SCLC) benefiting from post-definitive chemoradiotherapy (dCRT) immunotherapy is valuable. This study aims to develop a circulating tumor DNA (ctDNA)-based algorithm to stratify progression risk and predict survival benefit from consolidation immunotherapy.

The development of drug resistance in cancer is associated with multiple malignant properties, including proliferative progression, metastasis, and stemness. Long noncoding RNAs (lncRNAs) reportedly contribute to multidrug resistance in lung cancer. However, functional and mechanistic studies of key lncRNAs associated with lung cancer are lacking.

Rearrangement of Cyclin D1 (CCND1-R) is the hallmark genetic lesion of mantle cell lymphoma (MCL). However, recently diffuse large B-cell lymphomas (DLBCL) have been described carrying a CCND1-R, often with additional rearrangements of BCL2, BCL6 and/or MYC raising the question if these are bona fide DLBCL or pleomorphic MCL. Protein expression and fluorescence in situ hybridisation (FISH) screening of 708 aggressive B-cell lymphomas failed to disclose CCND1-R, demonstrating the rarity of such cases. Fifteen large B-cell tumours, with CCND1-R were collected from different institutions and characterized by immunohistochemistry and for their molecular features. Three of 15 cases were CD5 positive, and all cases were negative for SOX11 but exhibited cyclin D1 staining and CCND1-R by FISH. In 10/15 cases IG could be determined as rearrangement partner by FISH or WGS with occurrence of both aberrant VDJ rearrangement and IGH class-switch recombination (CSR). Eight of 15 tumours had additional translocations involving MYC, BCL2, or BCL6. 8/12 evaluable cases showed significantly mutated IGHV genes and evidence of intraclonal variations in their rearranged IGHV genes. WES disclosed a mutational spectrum typical of DLBCL in 14/14 evaluable cases. We conclude that DLBCL CCND1-R do exist and that CCND1-R in DLBCL can occur without additional translocations.

Triple-negative breast cancer (TNBC) represents a formidable subtype with a grim prognosis. This study aims to pinpoint the molecular targets of Glycosyltransferases (GTs) in TNBC, with the goal of improving prognostic accuracy and boosting the effectiveness of immune therapies. Using publicly available datasets, we combined differentially expressed and correlated genes based on AUCell scores from single-cell sequencing. These were then subjected to enrichment analysis and utilized for constructing a risk model. A total of 780 genes were identified as being closely associated with GTs. Using 101 algorithm combinations, a 17-gene signature emerged with predictive capabilities for TNBC patient prognosis. At the same time, we examined the role of these model genes in the tumor microenvironment(TME). We identified key transcription factors correlating with GTs, including CREB3L1, which showed significant association with the CERCAM gene. Subsequently, the pro-cancerous effects of GTs were validated through a series of experiments, including CCK-8 cell viability assays, scratch wound healing assays, and Transwell migration and invasion assays. This research lays the foundation for targeted drug therapies, offering new opportunities to enhance clinical outcomes in TNBC.

Metabolic syndrome is a major risk factor for hepatocellular carcinoma (HCC) progression, yet the role of metabolic syndrome-related genes in HCC remains incompletely understood. Using bioinformatics approaches, we investigated the influence of these genes on HCC prognosis and tumor biology. Two distinct patient clusters (C1 and C2) were identified based on metabolic gene expression, with C2 exhibiting poorer survival, increased stemness, and higher risk scores. A risk model further revealed that high-risk patients had worse outcomes, elevated immunosuppressive cell infiltration, and distinct phenotypic features. Experimental validation via qRT-PCR confirmed upregulation of risk model genes (particularly KIAA1841 and TUBA1B) in HCC cell lines and patient blood samples. Notably, post-surgical declines in KIAA1841 and TUBA1B levels were observed. Our findings highlight the clinical relevance of metabolic syndrome-related genes in HCC, linking them to prognosis, tumor microenvironment remodeling, cancer stemness, and immunotherapy response.

Claudin 18.2 (CLDN18.2) is a novel treatment target for patients with unresectable or stage IV gastric cancer. However, it remains unclear whether the expression of CLDN18.2 affects survival outcomes. In total, 586 patients with GC were enrolled in this study. CLDN18.2 expression in cancer cells was analyzed by immunohistochemistry. Correlations between CLDN18.2 expression and several clinicopathological factors and survival outcomes were investigated. We also performed a systematic review and a meta-analysis. CLDN18.2 expression was mainly observed in the cell membrane. The CLDN18.2 expression was not significantly correlated with any clinicopathological factor. In all patients, CLDN18.2 did not significantly affect OS. In patients with the diffuse type, the overall survival of patients with CLDN18.2-high expression was worse than that of patients with CLDN18.2-low expression, although the difference was not significant (p = 0.092). Meta-analyses revealed that CLDN18.2 was not significant prognostic factor in resected cases, although CLDN18.2 negative cases showed a trend for worse survival. In, conclusion, CLDN18.2 was not a significant prognostic factor in general, although CLDN18.2 negative cases showed a trend for worse survival. We revealed that patients with CLDN18.2 high expression showed worse survival outcomes especially in the diffuse type.