Glioma is a particularly lethal central nervous system tumor. Identifying the boundary between gliomas and normal tissues is difficult due to their infiltrative and invasive growth characteristics. This can result in the inevitable recurrence of the tumor after surgery. Preventing the residual tumor from growing or spreading is a major obstacle in treating gliomas. An earlier study suggested that hypotaurine could enhance the invasion of glioma cells while inhibiting the activity of demethylases. The hypotaurine synthesis-deficient U251 cell line usage showed a decrease in the cells' invasion capability. Analysis of gene expression profiles showed that reducing the activity of a critical enzyme in hypotaurine production, 2-aminoethanethiol dioxygenase (ADO), had a notable effect on the extracellular matrix-receptor interaction. Decreased intracellular ADO expression led to a significant increase in Wnt5a expression. Cells exposed to hypotaurine exhibited decreased levels of both intracellular Wnt5a protein and its corresponding mRNA. The observed characteristic was linked to increased methylation of the Wnt5a gene promoter, possibly due to hypotaurine's ability to inhibit demethylase enzymes. To sum up, the research showed that U251 cells lacking hypotaurine synthesis were susceptible to epigenetic changes, and Wnt5a seemed to function as a cancer inhibitor in this scenario. It would be beneficial to reevaluate this tumor suppressive effect in real tumor samples, which may contribute to the development of new glioma interference strategies.

Breast cancer remains a significant concern worldwide, with a rising incidence in Indonesia. This study aims to evaluate the applicability of risk-based screening approaches in the Indonesian demographic through a case-control study involving 305 women. We developed a personalized breast cancer risk assessment workflow that integrates multiple risk factors, including clinical (Gail) and polygenic (Mavaddat) risk predictions, into a consolidated risk category. By evaluating the area under the receiver operating characteristic curve (AUC) of each single-factor risk model, we demonstrated that they retained their predictive accuracy in the Indonesian context (AUC for clinical risk: 0.67 [0.61,0.74]; AUC for genetic risk: 0.67 [0.61,0.73]). Notably, our combined risk approach enhanced the AUC to 0.70 [0.64,0.76], highlighting the advantages of a multifaceted model. Our findings demonstrate for the first time the applicability of the Mavaddat and Gail models to Indonesian populations, and show that within this demographic, combined risk models provide a superior predictive framework compared to single-factor approaches.

Survival is the gold standard in oncology when determining the real impact of therapies in patients outcome. Thus, identifying molecular predictors of survival (like genetic alterations or transcriptomic patterns of gene expression) is one of the most relevant fields in current research. Statistical methods and metrics to analyze time-to-event data are crucial in understanding disease progression and the effectiveness of treatments. However, in the medical field, data is often high-dimensional, complicating the application of such methodologies. In this study, we addressed this challenge by compressing the high-dimensional transcriptomic data of patients treated with immunotherapy (avelumab + axitinib) and a TKI (sunitinib) into latent, meaningful features using autoencoders. We applied a semi-parametric statistical approach based on the COX Proportional Hazards model, coupled with Breslow's estimator, to predict each patient's Progression-Free Survival (PFS) and determine survival functions. Our analysis explored various penalty configurations and their combinations. Given the complexity of transcriptomic data, we extended our model to incorporate both tabular data and its graph variant, where edges represent protein-protein interactions between genes, offering a more insightful approach. Recognizing the interpretability challenges inherent in neural networks, particularly autoencoders, we analyzed the mutual information between genes in the original data and their latent feature representations to clarify which genes are most associated with specific latent variables. The results indicate that different types of autoencoders are better suited for different tasks: denoising autoencoders excel at accurate reconstruction, while the sparse variant is more effective at producing meaningful representations. Additionally, combining these penalties enhances both reconstruction quality and the interpretability of latent features. The interpretable models identified genes such as LRP2 and ACE2 as highly relevant to renal cell carcinoma. This research underscores the utility of autoencoders in managing high-dimensional data problems.

Lung cancer remains the leading cause of malignant tumors worldwide in terms of the incidence and mortality, posing a significant threat to human health. Given that distant metastases typically occur at the time of initial diagnosis, leading to a poor 5-year survival rate among patients, it is crucial to identify markers for diagnosis, prognosis, and therapeutic efficacy monitoring. Abnormal glycosylation is a hallmark of cancer cells, characterized by the disruption of core fucosylation, which is predominantly driven by the enzyme fucosyltransferase 8 (FUT8). Evidence indicates that FUT8 is a pivotal enzyme in cancer onset and progression, influencing cellular glycosylation pathways. Utilizing bioinformatics approaches, we have investigated FUT8 in lung cancer, resulting in a more systematic and comprehensive understanding of its role in the disease's pathogenesis. In this study, we employed bioinformatics to analyze the differential expression of FUT8 between LUAD and LUSC. We observed upregulation of FUT8 in both LUAD and LUSC, associated with unfavorable prognosis, and higher diagnostic utility in LUAD. GO/KEGG analysis revealed a primary association between LUAD and the spliceosome. Immunologically, FUT8 expression was significantly associated with immune cell infiltration and immune checkpoint activity, with a notable positive correlation with M2 macrophage infiltration. Our analysis of FUT8 indicates that it may serve as a potential biomarker for lung cancer diagnosis and prognosis, and could represent a therapeutic target for LUAD and LUSC immunotherapy.

Ovarian cancer (OC) is the leading cause of gynecological cancer deaths. Current biomarkers of OC are not specific or sensitive enough. Extracellular vesicles (EVs), EV surface proteins and their cargo microRNA (miRNA) show potential as biomarkers. This study aimed to characterize the ability of EVs to identify early OC-biomarkers among blood donors six months before their diagnosis.

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I-deficient tumor cells cocultured with T cells were more susceptible to T cell-mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I-knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I-deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I-mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.

Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif-containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin-mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.

Alternative polyadenylation (APA) is a widespread post-transcriptional mechanism that diversifies gene expression by generating messenger RNA isoforms with varying 3' untranslated regions. Accurate identification and quantification of transcriptome-wide polyadenylation site (PAS) usage are essential for understanding APA-mediated gene regulation and its biological implications. In this review, we first review the landscape of computational tools developed to identify APA events from RNA sequencing (RNA-seq) data. We then benchmarked five PAS prediction tools and seven APA detection algorithms using five RNA-seq datasets derived from clear cell renal cell carcinoma (ccRCC) and adjacent normal tissues. By evaluating tool performance across genes with either single or multiple PASs, we revealed substantial variation in accuracy, sensitivity, and consistency among the tools. Based on this comparative analysis, we offer practical guidelines for tool selection and propose considerations for improving APA detection accuracy. Additionally, our analysis identified CCNL2 as a candidate gene exhibiting significant APA regulation in ccRCC, highlighting its potential as a disease-associated biomarker.

Colorectal cancer (CRC) remains a major contributor to cancer-related morbidity and mortality. While Dachshund homolog 1 (DACH1) was recognized as a critical regulator in cancer progression, its role in promoting or suppressing tumor development remains a subject of ongoing debate. This study aimed to elucidate the role of DACH1 in CRC progression and its underlying regulation mechanisms. The expression levels of Methyltransferase 1 (DNMT1) and DACH1, as well as its methylation status were assessed through a combination of TCGA data analysis and experimental validation using immunohistochemistry, PCR, methylation-specific PCR, and bisulfite sequencing RCR on 120 clinical samples, comprising normal mucosa, adenomas, and adenocarcinomas. The relationships among them were evaluated using Pearson or Spearman correlation analysis. The associations between the DACH1 and DNMT1 levels and clinicopathological parameters were examined to determine their clinical relevance. A progressive decrease in DACH1 expression and a concomitant increase in DACH1 promoter methylation and DNMT1 expression were observed from normal mucosa to adenoma and adenocarcinoma tissues. Higher DNMT1 expression and lower DACH1 expression were associated with poorer clinical outcomes, including worse tumor differentiation, lymphatic metastasis, and advanced tumor stages. Paired analysis of tissues from the same patient further validated their inverse expression patterns during CRC progression. DNMT1-mediated DACH1 epigenetic silencing plays a critical role in CRC progression, suggesting that the DNMT1-DACH1 regulatory axis may serve as a potential biomarker and therapeutic target in CRC.

Immune checkpoint blockade (ICB) therapy has shown promise in treating advanced colorectal cancer, particularly in patients with microsatellite instability-high (MSI-H) tumors. However, only a subset of these patients responds favorably, highlighting the need for strategies to improve immunotherapy efficacy.

RNA 5-methylcytosine (m5C) modification is a crucial epitranscriptomic mark that regulates RNA stability, processing, and translation. Emerging evidence highlights its essential role in various physiological processes, including cellular differentiation, stem cell maintenance, and immune responses. Dysregulation of m5C modification has been implicated in multiple pathological conditions, particularly in cancer, neurodegenerative disorders, and metabolic diseases. This review provides a comprehensive overview of the molecular mechanisms governing m5C deposition, its functional consequences in normal physiology, and its contributions to disease pathogenesis. Furthermore, we discuss the potential of m5C as a biomarker and therapeutic target, offering new insights into its biological significance and clinical relevance.

Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.

Breast cancer significantly affects women's lives globally. While PAX7 (Paired Box 7), a regulatory protein linked to muscle growth, has been connected to various cancers, its role in breast cancer is not well understood. This study explores PAX7's significance in breast cancer and its mechanisms. RNA-seq data from the TCGA database assessed PAX7 expression across cancer types. Prognostic value in breast cancer was evaluated using Kaplan-Meier and Cox regression analyses. Functional experiments, including high-throughput sequencing, cell growth analysis, colony formation, Transwell assays, and Western blot analysis, were conducted on PAX7 knockdown cell lines (MDA-MB-468 and MDA-MB-231). Results showed high PAX7 expression in breast cancer linked to lower survival rates. PAX7 knockdown affected over 2000 genes and inhibited cancer cell proliferation, migration, and invasion, involving the Wnt/β-catenin pathway. SKL2001 reversed these effects. PAX7 is a potential prognostic biomarker and therapeutic target, with elevated levels indicating a poor prognosis. Further research on PAX7-targeted therapies is needed.

Methyl eugenol (ME), a natural compound found in various essential oils, has recently been classified as a Group 2A carcinogen by the International Agency for Research on Cancer.

Emerging evidence highlights the critical involvement of dysregulated circular RNAs (circRNAs) in non-small cell lung cancer (NSCLC) pathogenesis. Nevertheless, the precise functional role and mechanistic contributions of circ-MBOAT2 in NSCLC remain poorly characterized. The purpose of this study was to investigate the pathogenesis of NSCLC based on circ-MBOAT2.

Our aim was to identify crucial RNA-binding proteins (RBP) genes associated with Ewing sarcoma (EwS) in order to provide valuable insights into its mechanisms of tumorigenesis and to enhance therapeutic intervention.

Ovarian Cancer (OC) is a gynecological malignant tumor with an extremely high mortality rate, seriously endangering women's health. Due to its insidious clinical manifestations, most patients are diagnosed in the advanced stage of the disease. The currently clinically relied CA125 has limited specificity for the early diagnosis of ovarian cancer. Hence, identifying new promising biomarkers is crucial for the early screening, diagnosis, and treatment of ovarian cancer. Based on differential expression analysis, WGCNA and survival analysis, we identified a centromere-associated gene, WDR62, which is highly expressed in ovarian cancer and highly correlated with ovarian cancer, as well as the poor prognosis of ovarian cancer patients with high expression, suggesting that WDR62 may be a potential biomarker for ovarian cancer. Previous studies have shown that WDR62 is closely associated with the occurrence, development and prognosis of a variety of tumors. However, its role in ovarian cancer has not been studied in depth.

T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive.

Mutations in ESR1 play a critical role in resistance to endocrine therapy (ET) in hormone receptor-positive (HR +)/HER2- metastatic breast cancer (MBC). Testing for ESR1 mutations is essential for guiding treatment with novel oral selective estrogen receptor degraders (SERDs) like elacestrant or camizestrant. While most studies have utilized liquid biopsy (LB) for mutation detection, the role of formalin-fixed paraffin-embedded (FFPE) tissue biopsy in this context remains unclear. In this study, we analyzed a cohort of HR + /HER2- MBC patients who experienced resistance to ET and CDK4/6 inhibitors. Next-generation sequencing (NGS) was performed on FFPE biopsy samples obtained from metastatic sites at the time of disease progression. ESR1 mutations were detected in 24 out of 38 patients (63.2%), with p.D538G identified in 10 patients (45.5%) and p.Y537S in 6 patients (27.2%) as the most frequent alterations. One patient exhibited dual ESR1 mutations, and a recurrent ESR1-CCDC170 gene fusion was identified, underscoring the diversity and potential interplay of genetic alterations driving resistance in HR + /HER2- MBC. Notably, lung metastases were significantly more common in ESR1 mutant cases (8/24, 33.3%) compared to wild-type cases (1/14, 7.1%), while liver metastases showed no difference between mutant (12/24, 50.0%) and wild-type groups (7/14, 50.0%). Co-mutations in actionable pathways, particularly PIK3CA, were observed in n = 10 ESR1 mutant tumors (41.6%), highlighting their contribution to resistance mechanisms and posing significant challenges for treatment selection, as these alterations may necessitate combination therapies to effectively target multiple resistance pathways. This study presents new insights into the prevalence and clinical significance of ESR1 mutations in HR + /HER2- MBC, highlighting the potential utility of FFPE biopsy samples as a viable alternative or complementary approach to LB for mutation detection, particularly in resource-limited settings where access to ctDNA analysis may be constrained.

Several studies have suggested that chemotherapy-free regimens consisting of blinatumomab and a BCR::ABL1 tyrosine kinase inhibitor are highly effective in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, the clinical and molecular characteristics that predict for relapse with these chemotherapy-free regimens are largely unknown.