Epigenetic regulatory genes (epiRG) are pivotal in the epigenetic regulation of the human genome, primarily through DNA and histone modifications. These genes are frequently mutated in human cancers, particularly bladder cancer (BC). However, the functional impact of epiRG mutations on patient outcomes remains poorly understood.

In this study, we developed gene signatures for the most frequent genomic aberrations of epiRG using The Cancer Genome Atlas Bladder Carcinoma (TCGA-BLCA) dataset and validated these signatures with independent tumor expression profiles for prognostic relevance. Furthermore, we evaluated the role of these signature scores in the immune system within the tumor microenvironment (TME). Finally, we assessed the correlation between epiRG and global DNA methylation.

Our results indicated that the inferred aberration-specific signature scores were more predictive of patient stratification than the genomic aberrations. Notably, certain signature scores were significantly associated with patient progression, whereas others correlated with the tumor immune microenvironment via interactions with the immune system. Patients with mutations had high signature scores in CREBBP-mut and EP300-mut, which revealed poor overall survival. Conversely, KDM6A-mut signatures showed an opposite trend, with low scores linking to favorable prognosis through enhanced immune activity. Also, other epiRG signature scores were strongly correlated with the immune system in TME and successfully predicted patients who responded to immunotherapy. Global methylation analysis revealed that high signature scores of KDM6A-mut are associated with hypomethylation.

These findings collectively establish epiRG signature scores as powerful biomarkers that integrate genomic, epigenetic, and immune microenvironment features for improved prognostic prediction in bladder cancer. This integrative approach not only advances our understanding of epigenetic mechanisms in BC but also offers potential for developing innovative prognostic tools and therapeutic strategies tailored to personalized medicine.

The increasing percentage of follicular neoplasms among thyroid nodules submitted to fine-needle aspiration (FNA) cytology raises concerns regarding diagnostic uncertainty and clinical management. This study aims to investigate the factors contributing to this phenomenon, including the influence of the implementation of ultrasound (US) risk stratification systems and of the third edition of the Bethesda system for reporting thyroid cytopathology.

A retrospective cohort of 1255 patients (1470 nodules) diagnosed during the first 9 months of 2023, in a single institution, was analysed.

US classifications are used in 77.8% of the reported nodules, predominantly EU-TIRADS (44.4%) and ACR-TIRADS (32.2%). Bethesda category IV (follicular neoplasm) diagnoses increased from 7.7% to 11.8% after adopting the third edition, although without statistical significance. Notably, 39% of nodules were submitted to FNA without US indication, emphasising the need for improved adherence to guidelines.

The study highlighted the significant increase in follicular neoplasms among nodules with US indication for FNA. The transition from the 2nd to the 3rd edition of the Bethesda system increases the probability of indication for surgery by 1.5-fold, while the US indication for FNA increases the probability of indication for surgery by 1.6-fold, and demonstrated that the nodules with surgical indications (Bethesda categories IV, V, VI) increased from 5.3% in 2021 to 11.4% in 2023. Despite limitations, this work underscores the importance of aligning FNA practices with evidence-based recommendations to optimise patient care and minimise overdiagnosis.

Proteasome inhibitors (PIs) such as Bortezomib, Carfilzomib, and Ixazomib have significantly improved outcomes in multiple myeloma (MM), but their real-world safety profiles require further exploration.

To assess adverse drug events (ADEs) associated with Bortezomib, Carfilzomib, and Ixazomib in MM patients using the FDA Adverse Event Reporting System (FAERS), and to identify new ADE signals not listed in product labels.

A total of 47,310 ADE reports (Bortezomib: 23,843; Carfilzomib: 9,835; Ixazomib: 13,632) were analyzed from FAERS (2004 - Q4 2024). Signal detection was conducted using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Onset time was evaluated using Weibull survival analysis.

All three PIs were associated with significant ADE signals across multiple system organ classes, notably in the hematologic, nervous, cardiovascular, hepatobiliary, and gastrointestinal systems. Newly identified ADEs included muscular weakness (Bortezomib), pancytopenia (Carfilzomib), and cognitive disorder (Ixazomib). Onset time analysis showed that most ADEs occurred within the first 30 days of treatment.

This study highlights both known and newly detected ADEs linked to PIs, emphasizing the importance of early-phase monitoring and ongoing pharmacovigilance. The findings provide crucial real-world evidence for clinical risk management and future label updates.

Objectives: To investigate the expression of signal-induced proliferation-associated 1 (SIPA1) in colorectal cancer tissues and its relationship with patient prognosis. To explore the effects of SIPA1 on proliferation and migration abilities, as well as the possible molecular mechanisms. Methods: Using The Cancer Genome Atlas (TCGA) database to analyze the differential expression of SIPA1 and conduct survival analysis. Then, plotting receiver operating characteristic curve (ROC) and prognosis calibration curve analysis to assess the predictive capability and accuracy of SIPA1 for patient prognosis. Subsequently, verifying the expression levels of SIPA1 in tumor tissues and adjacent normal tissues using immunohistochemistry (IHC) and western blot (WB) assays(from March 1, 2023, to May 1, 2024, pathological specimens of five colorectal cancer patients were selected from the tissue bank of affiliated hospital of Nantong University. tissue microarrays were constructed using both cancerous tissues and adjacent normal tissues), and exploring the correlation between SIPA1 and clinical pathological parameters. Next, establishing SIPA1 stable knockdown cell lines in colorectal cancer cell lines DLD1 and HCT116, and assessing the biological behavior changes of tumor cells after SIPA1 knockdown through cell proliferation, invasion, and migration experiments. Validating the impact of SIPA1 on colorectal cancer cell proliferation in vivo through subcutaneous xenograft experiments in nude mice. Exploring the potential pro-tumor mechanisms of SIPA1 through pathway enrichment analysis, and confirming these using WB experiments. The proliferation, invasion and migration of tumor cells were detected after adding PI3K activator. Lastly, conducting correlation analysis between SIPA1 and immune checkpoint, as well as the association with immune cells in the tumor microenvironment. Results: Differential analysis showed that mRNA expression of SIPA1 in colorectal cancer tissues was significantly higher than that in adjacent normal tissues (P＜0.05). Prognostic analysis indicated that patients with high expression of SIPA1 had poor overall survival (P＜0.001), and the expression level of SIPA1was correlated with lymph node invasion (P＜0.001) and N stage (P＜0.05). ROC curve and prognosis calibration curve suggest that SIPA1 can effectively predict five-year survival rate of patients (AUC=0.7), and the predictive performance of the model is relatively accurate (P＜0.001). WB experiments showed a significant increase in the expression level of SIPA1 protein in colorectal cancer specimens (P＜0.001). Immunohistochemistry results indicated higher staining scores of SIPA1 in tumor tissues. In vitro experiments demonstrated that SIPA1 knockdown significantly inhibited the proliferation, invasion, and migration capabilities of colorectal cancer cells. In DLD1 and HCT116 cells, the SIPA1-knockdown group exhibited significantly lower absorbance compared to the control group (0.89±0.01 vs. 1.57±0.02 and 0.72±0.01 vs. 1.31±0.03, respectively, both P＜0.001). The SIPA1-knockdown group also demonstrated a reduced number of migrated cells relative to the control group (197.93±16.64 vs. 518.48±29.15 and 171.83±12.49 vs. 446.00±21.81, respectively, both P＜0.001). Furthermore, the cell wound-healing rate was significantly lower in the SIPA1-knockdown group than that in the control group [(0.32±0.01)% vs. (0.61±0.01)% and (0.28±0.01)% vs. (0.75±0.01)%, respectively, both P＜0.001]. In vivo animal experiments suggested that SIPA1 knockdown could inhibit tumor growth [(460.35±57.47) mm³ vs (1 177.55±208.24)mm³, (0.76±0.11)g vs (1.43±0.08)g, P＜0.05]. Pathway enrichment analysis revealed significant enrichment of the receptor tyrosine kinase signaling pathway, and SIPA1 knockdown could inhibit the activation of the phosphatidylinositide 3-kinases (PI3K)/protein kinase B (PKB)/glycogen synthase kinase-3β (GSK3β) signaling pathway. The PI3K activator reversed the inhibitory effect of SIPA1 silencing on tumor cell proliferation, invasion and migration. Correlation analysis indicated that high expression of SIPA1 was associated with immune checkpoints and various immunosuppressive cells (all P＜0.05). Conclusions: SIPA1 is highly expressed in colorectal cancer and associated with poor prognosis. SIPA1 may affect the proliferation and migration abilities of tumor cells by regulating the PI3K/AKT/GSK3β signaling pathway.

Understanding the role of cancer hotspot mutations is essential for unraveling mechanisms of tumorigenesis and identifying therapeutic vulnerabilities. Correcting cancer mutations with base editing is a novel, yet promising approach for investigating the biology of driver mutations.

Here, we present a versatile platform to investigate the functional impact of cancer hotspot mutations through adenine base editing in combination with transcriptomic profiling. Using this approach, we correct TP53 hotspot mutations in cancer cell lines derived from diverse tissues, followed by mRNA sequencing to evaluate transcriptional changes. Remarkably, correcting these mutations not only reveals the dependency on mutant allele expression but also restores highly conserved tumor-suppressive transcriptional programs, irrespective of tissue origin or co-occurring mutations, highlighting a shared p53-dependent regulatory network. Our findings demonstrate the utility of this base editing platform to systematically interrogate the functional consequences of cancer-associated mutations and their downstream effects on gene expression.

This work establishes a robust framework for studying the transcriptional dynamics of cancer hotspot mutations and sheds light on the conserved biological processes reinstated by p53 correction, offering potential avenues for future targeted therapies.

Cancer cells orchestrate the surrounding tumor microenvironment (TME) to strike a fine balance between tissue regeneration providing them with nutrients, and tissue destruction triggered by immunogenic alarm signals. At steady state, the tenuous balance favors cancer growth. Therapies aimed at enhancing the immunogenic properties of cancer cells or the reacting immune responses can, however, revert the equilibrium to clear the host of cancer. The understanding of factors that affect this balance is progressing rapidly due to advances in high throughput technologies disclosing from previously uncharted territories new biologies referred to as "dark matter". These advances are critical for the understanding of the true mechanisms leading to immune-mediated cancer rejection.This review focuses on cancer genetic, epigenetic and metabolic derangements that approximate those caused by intra-cellular pathogen infection, a phenomenon referred to as "viral mimicry" (VM) and other aspects of cancer/host cells interactions unexplored in the past that enhance the VM effects. On the cancer side, VM prompts alterations of cancer cell metabolism leading to the generation of aberrant cellular products recognized as foreign by the host's immune system. The latter are defined as "dark matter" to emphasize the powerful effects exerted by these obscure bioproducts on the TME as the mass of invisible particles can dictate the rotational period of galaxies. On the other side, a myriad of previously unappreciated factors can influence the host responses. Thus, here we propose an extended definition of dark matter beyond the limits of cancer cell-intrinsic biology, to a broader interpretation encompassing elements that influence the cellular networks within the TME.

Immune expression profiling in colorectal lesions may provide insights into the origins of antitumor immunity and senescence. Optimal approaches for analyzing samples with lower quality RNA from molecularly diverse lesions are lacking. Therefore, we developed a NanoString nCounter-based approach for quality control (QC), normalization, and differential expression (DE) analysis, optimized for FFPE samples in contexts of high biologic heterogeneity.

The approach incorporates a colon specific positive control gene set (11 genes) to minimize sample exclusions. We evaluated three normalization methods Removal of Unwanted Variation (RUVg), NanoStringDiff (NSDiff), and nSolver using a 277 gene immune panel to compare 100 samples, including sessile serrated lesions (SSLs) (n = 25), tubulovillous and villous adenomas (TVs) (n = 27), and tubular adenomas (TAs) (n = 48) We assessed Type I error rates, computational efficiency, and gene significance via FDR-corrected q-values.

Incorporating the colon-specific QC set reduced sample exclusions by 63% compared to standard methods (13 vs. 35 sample exclusions). All three normalization approaches identified DE genes between SSLs and TAs (e.g., TFF1, MUC5AC, MUC6). For TVs vs. TAs, only RUVg and NSDiff detected significant DE genes, revealing wide-spread under-expression of innate and adaptive genes. While NSDiff labeled twice as many significant genes as RUVg, suggesting greater sensitivity, it also exhibited higher Type I error rates and increased computational demand.

RUVg achieved a balance between computational efficiency and low Type I error, while NSDiff was more sensitive but computationally demanding and exhibited higher Type I error. Our approach provides a robust framework for profiling immune genes in heterogeneous lesions.

Ferroptosis, marked by iron-dependent lipid peroxidation, emerges as a promising approach for osteosarcoma (OS) intervention due to its tumor susceptibility. Ubiquitination is a key post-translational modification involved in regulating cell ferroptosis and is closely linked to cancer development. Ubiquitin protein ligase E3C (UBE3C), an E3 ubiquitin ligase plays a carcinogenic role in several cancers. However, the roles and molecular mechanisms of UBE3C in OS cell ferroptosis remain unclear. UBE3C level was enhanced in OS tissues and cells, and UBE3C depletion impeded OS cell proliferation, migration, and invasion and accelerated ferroptosis. Moreover, Fer-1 administration counteracted the inhibitory impact of UBE3C silencing on the malignant behavior of U2OS and 143B cells. Mechanistically, UBE3C promoted the ubiquitination and degradation of AHNAK in U2OS and 143B cells. AHNAK counteracted the effect of UBE3C on promoting cell proliferation, migration, and invasion and inhibiting cell ferroptosis. Further, METTL5-mediated m6A modification enhanced UBE3C mRNA stability by enabling YTHDF1 to bind and protect the modified mRNA from degradation. METTL5 addition inhibited AHNAK level which was abolished by UBE3C silencing. Our work uncovered a new METTL5-YTHDF1-UBE3C-AHNAK signaling axis regulating ferroptosis and driving OS progression. Targeting this axis offers a promising approach to enhance ferroptosis sensitivity against OS.

Breast cancer is a leading cause of cancer mortality in women with triple-negative breast cancer (TNBC) presenting greater treatment challenges due to its aggressive disease progression. Understanding TNBC's unique cell signaling and gene expression profiles will reveal novel therapeutic strategies. Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as key regulators of gene expression and potential therapeutic targets. This study focuses on a TNBC-enriched lncRNA, non-coding RNA in the aldehyde dehydrogenase 1A pathway (NRAD1, previously LINC00284), which promotes progression in multiple cancers. Our analysis reveals that NRAD1 is central to miRNA-mRNA networks in TNBC cells, mediating cancer-promoting gene expression changes. Fractionation studies showed that NRAD1 is primarily located in the nucleus and mitochondria, with some cytoplasmic presence allowing for transcript-specific competitive endogenous RNA (ceRNA) interactions with miRNAs. However, NRAD1 primarily effects miRNAs independently of ceRNA activity, instead upregulating DICER (a miRNA biogenesis protein), altering sub-cellular distribution, and reducing biogenesis of mitochondria-localized miRNA (i.e., miR-4485-3p). These findings demonstrate novel regulatory interactions between the cancer-promoting lncRNA NRAD1 and miRNAs that alter gene expression in TNBC, expanding our understanding of regulatory lncRNA-miRNA effects, TNBC biology, and highlighting future therapeutic strategies for targeting non-coding RNAs.

Previous studies majorly focused on the role of driver gene variation in the occurrence, development and treatment of glioma. Here, we revealed the effect of signaling pathway abnormality by accumulated genetic mutations on patient survival and explored potential mechanism in glioma. We found that abnormalities of three signaling pathways, including autophagy-animal, focal adhesion and neuroactive ligand-receptor interaction, were associated with progression-free survival (PFS) in glioma. Based on the three pathways, we constructed and validated a biological pathway score (BPS) model to predict patient prognosis. Both PFS and overall survival (OS) were poorer in glioma patients with high BPS. In the glioma patients with high BPS, mutation frequencies of PTEN, TTN and EGFR were significantly increased. Immune checkpoints (PD-1, PD-L1 and TIM-3) were strikingly expressed in the high BPS patients with glioma, despite observed high levels of infiltrating immune cells. Differential expression genes in the high BPS patients were enriched in proliferation-related pathways. These results revealed potential reasons of poor prognosis in the high BPS patients with glioma. In addition, we found that low BPS patients with glioma might benefit from sevoflurane during surgery anesthesia. Overall, this study exhibited that the abnormalities of PFS-related signaling pathways by genetic mutations impacted survival of patients and revealed potential mechanism of poor PFS in glioma.