Introduction: The t(12;21)(p13;q22) is the most common chromosomal translocation in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL), occurring in 5% of healthy newborns. This alteration generates the ETV6::RUNX1 (E::R) fusion gene, encoding an aberrant transcription factor that is insufficient to cause leukemia directly, but establishes a clinically silent pre-leukemic progenitor not yet fully characterized. We previously showed that E::R expression in the murine pro-B BaF3 cells caused the slowdown of cell cycle progression and increased phospho-histone H2AX levels, both features of Oncogene Induced Senescence (OIS).Methods. We explored whether E::R induces OIS in immature hematopoietic cells to uncover therapeutic targets for pre-leukemia. We used two E::R+ pre-leukemic models: an inducible BaF3 Pro-B cell system and Sca1-E::R transgenic mice, where E::R is expressed in immature Lin−Sca1+ cells.Results. We observed that E::R caused a senescence-like phenotype in BaF3 cells, characterized by altered morphology, increased β-galactosidase activity (% SA β-Gal positive cells: ctr = 8.05 ± 10,61; E::R = 50.02 ± 9.95, p<0.0001), elevated reactive oxygen species (ROS) (fold change of CM-H2DCFDA MFI, E::R versus ctr = 1.42 ± 0.41, p<0.001), and Senescence-Associated Secretory Phenotype (SASP) factor secretion. It dysregulated genes within the p53 pathway, including senescence-related genes, causing the accumulation of p53 protein and alteration in its post-translational modifications. In E::R positive cells, while p53-mediated cell cycle arrest occurred, apoptosis was impaired, providing a survival advantage under genotoxic stress mediated by etoposide (% annexin V+ ctr versus E::R cells: 0.5 μg/ml etoposide = 70 ± 6.6 versus 51 ± 6.7, p<0.01; 0.75 μg/ml etoposide = 76 ± 4.9 versus 64 ± 9.4, p=0.014). Multiple therapeutic approaches targeting these vulnerabilities were tested. Senolytics SSK1 and piperlongumine selectively eliminated E::R+ cells by exploiting elevated β-gal activity and ROS levels, respectively. TM5441 leveraged caspase-3 inhibitor PAI-1 upregulation to induce apoptosis. Furthermore, using Sca1-E::R transgenic mice, we validated E::R-induced OIS in the pre-leukemic Lin-Sca1+ immature population by observing an increased proportion of cells in G0 phase (% G0 cells: ctr = 59.34 ± 12.74; E::R = 73.19 ± 6.841, p = 0.0263), and enhanced SA β-Gal activity compared to WT mice (SA β-Gal MFI: ctr = 1941 ± 939.8; E::R = 2764 ± 1108, p = 0.03). We also observed reduced pre-B colony formation after SSK1 treatment (Ratio E::R pre-B colonies treated versus untreated: 1.6 pM SSK1 = 0.63 ± 0.11, p<0.01; 8 pM SSK1 = 0.61 ± 0.07, p < 0.01).Conclusions. These findings demonstrate E::R’s dual role in inducing OIS and conferring apoptosis resistance, highlighting the potential of senescence-targeted therapies to prevent leukemia progression and relapse in E::R carriers.

The snoRNA SNORA21 promotes gastric tumorigenesis by attenuating P53 activity through CHK1 phosphorylation inhibition and PERP-dependent feedback loops.

Identification and expression analysis of long noncoding RNAs in response to infection with VHSV in rainbow trout.

Early innate immune response to highly pathogenic avian influenza and functional characterisation of the chicken IRF1 promoter.

Colorectal liver metastases (CRLM) pose a significant clinical challenge due to their high recurrence rates, even after surgical resection. There is an urgent need for reliable prognostic biomarkers to improve risk stratification and guide treatment decisions for CRLM patients. In this study, we performed whole-exome sequencing (WES) on 57 CRLM patients and conducted a comparative genomic analysis of primary tumors and matched liver metastases in 8 patients. We systematically identified prognostic factors associated with overall survival (OS) and developed a predictive nomogram for CRLM patients. The most frequently mutated genes in our cohort were APC (64.91%) and TP53 (64.91%), followed by KRAS (50.88%), PIK3CA (24.56%), and SMAD4 (24.56%). Pathway analysis revealed significant enrichment in p53, IGF, and Ras signaling pathways. Notably, primary and metastatic lesions exhibited high mutational concordance. Multivariate analysis identified five independent prognostic factors for OS: number of metastasis-positive lymph node stations in primary resected tumor tissue, mutational status of ZNF717 and MUC2, APC mutation status, and chr9p13.3 amplification. The nomogram integrating these factors achieved a C index of 0.798 for OS prediction. Our findings suggest that integrating genomic profiling into clinical practice could enhance prognostic assessment and optimize treatment stratification for CRLM patients.

Therapeutic targeting of the HPV E7 oncoprotein: Current advances and emerging strategies.

BUB1 and CCNB2 mediate cell cycle and inflammation, influencing the progression of oral squamous cell carcinoma.

Mechanisms and targets of vascular natural aging from a systems biology perspective.

Endothelin-1/endothelin B receptor signalling mediates Prx1+ skeletal stem cells senescence: A driver of osteoporotic bone loss.

Precision oncology has been evolving rapidly, with increasing emphasis on early detection and personalized diagnostic approaches that translate into tailored treatment algorithms. The integration of molecular markers, quantitative imaging approaches and artificial intelligence (AI) in the diagnostic workflow of cutaneous squamous cell carcinoma (cSCC) has increased accuracy and has the potential to improve early detection rates in these cancers. Sun exposure is the primary etiologic factor in the development of cSCC. The primary objective of this review is to evaluate the current state and future directions of modalities and practices in diagnostic techniques for cSCC. Specifically, this review summarizes the key genetic alterations and potential molecular targets in cSCC. High-risk genetic mutations and pathways implicated in the pathogenesis of cSCC include p53, NOTCH, RAS/MAPK, cell-cycle, and adhesion pathways. This review further explores current and emerging modalities in optical imaging techniques and molecular-based diagnostic modalities in cSCC. Further, we discuss the role of radiomics and AI in the diagnostic work-up of cSCC. These techniques have the potential to enable more accurate risk models that refine conventional histopathology and guide personalized interventions. However, there are limitations to the clinical application of several of these modalities, with cost being an important driver. These challenges have been discussed in detail within this review. Nevertheless, ongoing research is focused on improving the workflow and initiating a shift in clinical practice with application of precision diagnostics as a standard of care.

Lactate accumulation is a hallmark and contributing factor of intervertebral disc degeneration (IVDD), while the role of protein lactylation caused by lactate accumulation in IVDD remains unclear. Via metabolomics, single-cell RNA-sequencing analysis, and lactylation proteomics, we reveal the lactylome landscape in IVDD and identified superoxide dismutase 1 (SOD1) lactylation at lysine 123 (SOD1K123la) as crucial for IVDD aggravation. Using in vitro site-directed mutagenesis, in vivo generation of SOD1K123R mutant male rats, and in silico molecular dynamics simulations, we find that SOD1K123la alters SOD1 conformation and impairs its enzymatic activity, and induces oxidative damage, and activates p53 pathway in nucleus pulposus cells (NPCs). Notably, we identify a small molecule ZL-01 that inhibits SOD1K123la. NPC-targeted delivery of ZL-01 via collagen type II-targeted peptide-modified extracellular vesicles alleviated IVDD in male rats. Together, these findings clarify the mechanism by which SOD1K123la promotes IVDD aggravation and provide a promising therapeutic strategy for IVDD.

Exposure to PFOA and GenX elicits cell typespecific impacts on p53 and TGF-β signaling pathways.

MDM4 HAPLOINSUFFICIENCY LEADS TO P53-MEDIATED BONE MARROW FAILURE.

Nitric oxide (NO) is a key signaling molecule that plays a vital role in maintaining homeostasis of physiological processes such as immune responses and neurotransmission. However, excessive NO production during inflammatory responses to infection can lead to cytotoxicity and tissue damage. The nasal epithelial barrier is a crucial first line of immunological defense against viral infections, and it is likely exposed to excessive NO levels during chronic inflammation. Therefore, clarifying the effects of NO on this barrier is thus critical. In this study, we investigated the biological effects of sustained NO exposure on RPMI2650 human nasal epithelial cells. Post-NO exposure transcriptomic analyses revealed significant upregulation of genes involved in the p53 signaling pathway. RT-qPCR analyses confirmed the temporal upregulation of p53 target genes associated with apoptosis and cell cycle regulation. These gene expression changes downregulated cell proliferation and induced cell death. Our findings suggest that excessive NO exposure induces nasal epithelial cell death via the p53 pathway, which over the long term can result in tissue damage and dysfunction under inflammatory conditions. These results provide new insights into how prolonged NO exposure affects the nasal epithelial cells and may contribute to the progression of chronic infectious diseases.

Phytochemical investigation of the aerial parts of Physalis angulata led to the isolation of 15 undescribed withanolides, including an unprecedented 2,3-seco-1,3-cyclo-physalin (1) and a C27-nor-physalin (12), along with two known analogues (16 and 17). Their planar structures and absolute configurations were established by comprehensive spectroscopic analysis, together with single crystal X-ray diffraction, ECD spectroscopy, and DFT NMR or TDDFT ECD calculations. All isolates were evaluated for their antimelanoma activity. In vitro, compounds 6 and 14 markedly inhibited the proliferation of B16F10 and A375 cells by inducing cell-cycle arrest and apoptosis via activation of the p53 signaling pathway, which was further confirmed by Trp53 knockout in B16F10 cells. In vivo, compound 6 significantly suppressed the growth of B16F10 and A375 subcutaneous xenografts in mice and concomitantly activated intratumoral p53 signaling pathway. These findings indicated withanolides isolated from P. angulata exert antimelanoma effects by activating the p53 signaling pathway.

Abstract Abemaciclib is an oral CDK 4/6 inhibitor approved by the FDA in October 2021 for adjuvant treatment of HR-positive, HER-2 negative early breast cancer in combination with endocrine therapy (1). In the monarchE trial, 2 years of abemaciclib with endocrine therapy improved 5-year absolute invasive disease-free survival by 7.6% and distant relapse-free survival by 6.7% in high-risk, node positive patients (1). Findings A 45-year-old female was diagnosed with bilateral locally advanced IDC. Right breast biopsy showed ER 70%, PR 90%, HER2 0, Ki-67 90% (hot spots), and left breast biopsy showed ER > 90%, PR 5-10%, HER2 0, Ki-67 > 20%, both with Nottingham grade 3 (3+3+2=8) histology and bilateral axillary lymph node biopsies positive for macrometastatic carcinoma. Staging scans at diagnosis, including CT CAP and bone scan, were negative for distant metastasis. Genetic testing was negative. She was treated with 4 cycles of neoadjuvant dose dense AC-Taxol, then bilateral mastectomies, radiation, oophorectomy for ovarian suppression and letrozole for endocrine therapy. Given prior nodal involvement she began adjuvant abemaciclib six months after mastectomy. 8 months into abemaciclib treatment new bony metastases were incidentally found during imaging for pancreatitis. Bone scan confirmed new foci of increased uptake in C2/C3, T11, L4 and the left acetabulum concerning for osseous metastasis. Left acetabular core needle biopsy revealed metastatic adenocarcinoma consistent with known breast primary, ER positive (5%), PR negative (0%) and HER2 negative (1+). Given strong discrepancies between original strongly ER positive breast cancers and the bone metastases with low ER positivity of 5%, she underwent an FES PET which confirmed her osseous metastasis did not demonstrate any ER expression, further confirming change in the tumor’s ER status. Tempus testing revealed multiple inactionable pathogenic mutations, including two TP53 mutations (c.783-2A>C Splice region variant - LOF VAF: 59.8% and p.R267_N268delinsPD - c.800_802delinsCGG Missense variant - LOF VAF: 55%). A study by Corti et al. (2025) evaluated changes in HR status and recurrence among high-risk, HR-positive, HER2-negative early breast cancer treated with adjuvant abemaciclib plus endocrine therapy. Of 163 patients, 15 (9.2%) had recurrence during or shortly after completing abemaciclib (2). The median time to recurrence was 8 months. While half the recurrent tumors had strong ER positivity at time of diagnosis, on recurrence the biomarkers showed statistically significant changes in HR status, with ER positivity ≤10% and PR positivity < 1% on first recurrence. Most common recurrence sites were liver (40%), bone (26.7%), and lung (13.3%). Interestingly, the tumors with recurrence showed alterations in the p53 pathway and of those that had next genomic sequencing completed (n=10), alterations in p53 were found in 90% of the subset. Our goal is to highlight the transition of HR status after adjuvant abemaciclib as our case illustrates a unique presentation of disease recurrence. Further study should evaluate the frequency of new p53 mutations in patients treated with abemaciclib and its role in the transition of HR status. Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes. J Clin Oncol 2024; 42:987-993 Corti C, Martin AR, Kurnia PT, et al. Clinicopathological features and genomics of ER-positive/HER2-negative breast cancer relapsing on adjuvant abemaciclib. ESMO Open. 2025 Jun 3;10(6):105126. doi: 10.1016/j.esmoop.2025.105126 Citation Format: A. Poles, S. Atluri, R. Rao. Transformation of ER/PR Positive Invasive Ductal Carcinoma to Triple-Negative Metastatic Breast Cancer Following Adjuvant Abemaciclib: A Case Report [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-13-14.

Aim. To identify mutational profile differences of non-muscle-invasive (NMIUC) and muscle-invasive urothelial carcinoma (MIUC) of the bladder, assessed through isolating alterations in deoxyribonucleic (DNA) and ribonucleic (RNA) acids by a next-generation sequencing (NGS) method using a panel of 523 genes. Materials and methods. Tumor tissue and medical data of 72 patients with histologically confirmed bladder UC were studied. NMIUC was diagnosed in 40 (55.6%) patients, and MIUC in 32 (44.4%) patients. In 25 (34.7%) samples the tumor grade was assessed as low: 24 (33.3%) with NMIUC and 1 (1.4%) with MIUC, and in 47 (65.3%) as high: 16 (22.2%) with NMIUC, 31 (43.1%) with MIUC. In isolated tumor cells DNA and RNA alterations were detected by NGS using a panel of 523 genes. Results. NMIUC, compared to MIUC, was characterized by a lower median mutational burden (9.9 mut/Mb vs. 11.8 mut/Mb, respectively; p=0.037) and was associated with a higher rate of mutations of the FGFR/FGF (p=0.059) and STAG2/IRF (p=0.055) signaling pathways genes, as well as the FGFR3 (p=0.001) and STAG2 (p=0.026) genes with a lower rate of aberrations of the p53 signaling pathway genes (p=0.005), TP53 (p=0.001) and FGF4 (p=0.057). The low grade NMIUC samples had a lower rate of high mutational burden (vs. high grade NMIUC, p=0.004; vs high grade MIUC, p=0.067) and were also associated with a higher rate of FGF/FGFR signaling pathway gene mutations (vs. high grade MIUC, p0.0001; vs. high grade NMIUC, p0.0001), mainly due to FGFR3 alterations (vs. high grade NMIUC; p0.0001; vs. high grade MIUC; p0.0001). Low grade NMIUC, compared to high grade MIUC, had a higher rate of PIK3CA (p=0.027) and KDM6A (p=0.001) mutations. The mutational profile of high grade NMIUC and high grade MIUC did not differ significantly. High grade MIUC, compared to low grade NMIUC had a higher rate of mutations of the p53 pathway genes (p=0.008), including TP53 (p=0.001), and a significantly lower rate of alterations of the FGF/FGFR signal pathway genes (p0.0001), including FGFR3 (p0.0001), as well as the STAG2/IRF pathway genes (p=0.035) and the PIK3CA gene (p=0.027). Conclusion. Differences of the histological structure and natural history of low grade NMIUC, high grade NMIUC, and high grade MIUC are due to significant differences in their mutational status. NMIUC has a high rate of mutations in genes of the FGF/FGFR signaling pathway and inactivating mutations in STAG2 and KDM6A genes. MIUC typically has driver mutations that inactivate the p53 signal pathway. High grade NMIUC has alterations typical for both NMIUC (FGF/FGFR pathway gene mutations) and MIUC (p53 pathway gene mutations).

Nanocatalytic therapy is an emerging strategy that leverages in situ catalytic reactions within the tumor microenvironment to convert endogenous substrates into cytotoxic species, achieving spatially confined cancer cell killing with reduced systemic toxicity. However, the lack of durable, DNA-focused cytotoxic mechanisms hampers the translational efficacy of nanocatalytic therapy. Herein, we proposed a cascade nanocatalysis-mediated strategy for endogenous amplification of apoptosis, achieved by an engineered metal organic framework nanomedicine (MOF-Au-L-Arginine, abbreviated as MAL). The MOF serves both as a nanocatalyst and as a carrier for L-Arginine (L-Arg), while embedded Au nanoparticles enhance nanocatalyst reactivity. Subsequently, MOF catalyzes the generation of hydroxyl radicals (•OH) and superoxide anions (O2 •-), and then the O2 •- undergo a cascade reaction with NO released from L-Arg, generating highly cytotoxic peroxynitrite (ONOO-), which has greater cytotoxicity to tumor cells, can induce extensive DNA damage, and simultaneously impair DNA repair and disrupt the cell cycle. Genome-wide RNA sequencing reveals MAL can activate the p53 pathway, thereby regulating apoptosis related proteins. In addition, MAL reduces mitochondrial membrane potential and promotes mitochondrial-mediated apoptosis through the BAX/Bcl-2/caspase-3 axis, further amplifying endogenous apoptosis in tumor cells. In vivo, MAL effectively inhibits tumor growth with favorable biocompatibility.

We recently identified variants in 10 genes that are members of either the p53 pathway or Fanconi Anemia Complex (FAC), regulators of the DNA repair (DNA damage response; DDR) in 17 cases with Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) or regression in autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD). We aimed to identify additional cases with genetic vulnerabilities in DDR and related pathways. Whole exome sequencing (WES) and whole genome sequencing (WGS) data from 32 individuals were filtered and analyzed to identify ultrarare pathogenic or likely pathogenic variants. Variants affecting DDR were found in 14 cases diagnosed with PANS or regression (CUX1, USP45, PARP14, UVSSA, EP300, TREX1, SAMHD1, STK19, MYTl1, TEP1, PIDD1, ADNP, FANCD2, and RAD54L). The CUX1 variant is de novo, as are two cases who had mutations in genes that affect mitochondrial functions that are connected directly or indirectly to mitophagy (PRKN and POLG), which can trigger the same innate immune pathways when disrupted as abnormal DDR. We also found pathogenic or likely pathogenic secondary mutations in several genes that are primarily expressed in the gut that have been implicated in gut microbiome homeostasis (e.g., LGALS4, DUOX2, CCR9). These findings align with previous genetic findings and strengthen the hypothesis that abnormal DDR and mitochondrial dysfunction underly pathogenic processes in neuropsychiatric decompensation. The potential involvement of genetic variants in gut microbiome homeostasis is a novel aspect of our study. Functional characterization of the downstream impact of DDR deficits may point to novel treatment strategies.

Background/Objectives: To mine single-cell sequencing data for colorectal cancer (CRC), identify CRC epithelial cell subtypes, and explore the heterogeneity of epithelial cells and their impact on the tumor microenvironment (TME). Methods: The GSE201348 dataset, including normal, colorectal adenoma, high-grade colorectal intraepithelial neoplasia, and CRC tumor tissue samples, was downloaded from the Gene Expression Omnibus. The Seurat package of R software was used for data quality control, data integration, normalization, and clustering. The Feature Plot and the Recode function were executed to annotate and group the epithelial cells. Finally, genetic differences, copy number variant heterogeneity, pseudotime, cell-cell communication, and Gene Set Variation Analysis (GSVA) were further conducted. Results: In total, 26,335 gene matrices from 263,872 cells were obtained for subsequent analyses. Four cell clusters, including immune cells, fibroblasts, endothelial cells, and epithelial cells, were identified. Epithelial cells were further divided into 11 subgroups characterized by MKI67, SLC27A6, PLCE1, NKD1, KCNMA1, GDA, CLCA4, BEST4, LRMP, ACTG2, and ASPM. GSVA enrichment analysis suggested a role of the "P53 pathway," "Wnt-β-catenin signaling," and "MYC targets V1" pathways in epithelial cells during the malignant progression of tumors. Survival analysis indicated that downregulation of KCNMA1 and upregulation of MKI67 were associated with poor prognosis. Cell-cell communication analysis suggested a bidirectional regulatory role between epithelial and fibroblast subsets. Conclusions: This study analyzed the gene expression characteristics of 11 types of epithelial cells during the malignant progression of CRC. KCNMA1+ and MKI67+ epithelial subpopulations are important indicators for the malignant progression of CRC.