GLI1 gene alterations including fusions and amplifications compromise a subset of malignant mesenchymal tumors exhibiting characteristic monomorphic nested morphology and frequent S100 positivity, which mimic glomus tumors or well differentiated neuroendocrine tumors. We report four high-grade uterine endometrial stromal sarcomas (ESS) harboring GLI1 and MDM2/CDK4 co-amplifications with a median age of 51.5 years (range 43 ~ 72 years). Histologically, tumors showed a heterogenous morphology, including ovoid to spindle cells, showing nested/nodular arrangement (4/4). Myxoid background was observed at least partially in 4 tumors with prominent capillary networks. Mitoses index was 2 to 20/10 HPF (median 9.5/10 HPF). Immunochemically, tumors showed diffuse staining of CD10 (3/4) with frequently positive CyclinD1(2/4 tested) and mostly negative S100 protein (3/4). Next-generationsequencing (NGS) studies revealed GLI1 and MDM2/CDK4 co-amplification in all cases (4/4) and GLI1 fusion in 1 case (1/4), which were validated by fluorescence in situ hybridization (FISH) analysis. BCOR fusions were firstly identified with GLI1 and MDM2/CDK4 co-amplification in 2 cases (2/4). Copy number (CN) segmentation data showed GLI1 co-amplified cases present generally a single peak at the 12q13.3-15 locus. Follow-up (range:3 to 112 months; median 37.5 months) showed recurrence and/or metastasis in all cases (4/4), in which 1 patient developed lungs and liver metastasis. Relapse-free survival (RFS) analysis showed similar median RFS between GLI1 co-amplified HGESS and GLI1 non-amplified HGESS groups, which were shorter than LGESS group. Unusual clinicopathologic features of these HGESS with GLI1 and MDM2/CDK4 co-amplification mimicked other neoplasms, which caused significant diagnostic challenge and pitfalls. However, identification of GLI1 alterations in these tumors is beneficial for diagnosis and potential use of targeted GLI1 inhibitors.

Long non-coding RNAs (lncRNA) H19 has drawn special attention because of its varied role in several malignancies, including OSCC. Therefore, this study was conducted to assess the association between H19-miR675-p53 by in-silico analysis, quantify the expression levels of H19, miRNA-675, and target oncogene p53 in cancerous versus normal individuals, and Correlate the Clinicopathological findings with their expression pattern.

Investigating the expression levels of immune checkpoint genes CD276, CD40, TNFSF14, and TNFSF9 in glioblastoma multiforme patients about copper death and patient prognosis.

Multiple myeloma (MM) is a major hematologic malignancy with limited therapeutic progress in radiotherapy. Although radiotherapy is widely used for palliation, its molecular effects in MM remain poorly defined. This study identifies RPL29 as a novel radiotherapy-responsive gene in MM and evaluates its prognostic and therapeutic relevance.

Spatial transcriptomics have emerged as a powerful tool in biomedical research because of its ability to capture both the spatial contexts and abundance of the complete RNA transcript profile in organs of interest. However, limitations of the technology such as the relatively low resolution and comparatively insufficient sequencing depth make it difficult to reliably extract real biological signals from these data. To alleviate this challenge, we propose a novel transfer learning framework, referred to as TransST, to adaptively leverage the cell-labeled information from external sources in inferring cell-level heterogeneity of a target spatial transcriptomics data.

Gefitinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in the treatment of non-small cell lung cancer (NSCLC). It is metabolized extensively in the liver by enzymes encoded by CYP3A4, CYP2D6, and CYP3A5 and is the substrate of membrane transporters including ABCB1 and ABCG2. Evidence shows that single-nucleotide polymorphisms (SNPs) in these metabolizing and transporting genes contribute to the inter-individual variability in gefitinib response and development of gefitinib-induced adverse drug reactions (ADRs). This narrative review identifies the existing literature exploring the impact of SNPs on plasma gefitinib concentration and ADRs in patients with NSCLC receiving gefitinib therapy. SNPs were identified in drug-metabolizing enzyme coding genes, including CYP3A4, CYP2D6, CYP3A5, and other CYP homologs, drug transporters including ABCB1, ABCG2, SLCO1B1 and other genes, including UGT1A7 and FOXO3. Current research has not identified any genetic association between specific SNPs in ABCB1, OATP1B1, and UGT1A7 and the pharmacokinetics of gefitinib. Additionally, most of these studies focused on individual SNP associations; however, it may be more important to consider them in combination to better understand their collective impact on gefitinib ADR. Hence, further comprehensive research is essential to examine these genetic variants across different ethnic groups, monitor the drug-drug interactions, and study the phenoconversion to draw definitive conclusions about the pharmacokinetics of gefitinib. This could lead to the development and implementation of a genotyping-based approach for gefitinib dosage optimization in clinical settings.

Metastatic melanoma, the most aggressive form of skin cancer, accounts for the majority of skin cancer-related deaths. While targeted kinase inhibitors have improved outcomes for patients with BRAF-mutated melanomas, their efficacy is often short-lived, and effective treatments for other mutations, such as NRAS, remain scarce. To address this clinical need, we investigated the combination of the novel panRAF inhibitor, brimarafenib, and the MEK inhibitor, mirdametinib, both of which target the MAPK pathway downstream of NRAS. This study demonstrates the efficacy of this combination in NRAS-mutated melanoma and is currently also investigated in a phase I/IIa clinical study. In vitro, the brimarafenib and mirdametinib combination exhibited synergistic effects, significantly inhibiting the growth of patient-derived NRAS-mutated melanoma cell lines. A colony formation assay showed that this combination prevented the emergence of drug-resistant clones, suggesting a strong potential to reduce disease relapse. Transcriptional and proteomic analyses revealed that the observed growth inhibition was due to modulation of MAPK signaling and induction of apoptosis. In vivo studies further validated these findings, showing that the combination treatment inhibited tumor growth and significantly prolonged survival in mouse models bearing patient-derived NRAS-mutated melanoma tumors. Given the tolerability of this combination in vivo, our results suggest that brimarafenib and mirdametinib represent a promising therapeutic strategy for patients with NRAS-mutated melanomas and potentially other RAS-mutated solid tumors.

The molecular and functional changes in endothelial cells during disease progression such as cancer have been noted but the mechanism of their activation is still under-studied. Previously we discovered that tumor-derived Oncostatin M induced tumor-associated vascular phenotypes, and the activated endothelial cells in turn promoted tumor progression and metastasis of clear-cell renal cell carcinoma (ccRCC). However, the mechanism of Oncostatin M action remains unknown. Here, we reveal that Oncostatin M signaling triggers specific epigenetic reprogramming of endothelial cells through upregulation of lysine acetyltransferase 6B, leading to increased histone 3 lysine 14 acetylation (H3K14ac) in vitro and in vivo. H3K14ac-modified chromatins upregulate specific gene sets associated with hypoxic response, hyper-angiogenesis, inflammation, and mesenchymal transition. Targeting H3K14ac in endothelial cells by interfering with acetyltransferase 6B function or neutralizing Oncostatin M ameliorates the premalignant hyperplastic phenotypes in the autochthonous ccRCC mouse model and diminishes tumor growth and metastasis in the ccRCC xenograft model.

The combination of lazertinib and amivantamab has shown superior efficacy over first line osimertinib in EGFR-mutated metastatic non-small cell lung cancer, but is associated with significant toxicity and high costs. Lazertinib exposure varies widely due to genetic polymorphisms of the encoding for GSTM1, with almost 50% of Caucasians having a non-functional enzyme resulting in an approximate twofold higher systemic drug exposure. Despite this, all patients receive a fixed 240 mg once-daily dose irrespective of GSTM1 status, leading to avoidable toxicity without additional clinical benefit. Our purpose was to develop alternative dosing regimens based on GSTM1 status.

Ovarian cancer represents one of the most prevalent gynecological malignancies with a poor prognosis. Targeting glycolytic pathways has emerged as a novel cancer therapeutic strategy. N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification plays a regulatory role in cancer glycolysis. Phosphoglycerate mutase 1 (PGAM1) functions as a critical glycolytic enzyme and potential therapeutic target in oncology. This study investigated the functional role and underlying mechanisms of NAT10 in ovarian cancer progression. Cellular glycolysis was assessed through glucose uptake measurements, lactate production quantification, and extracellular acidification rate analysis. Cell stemness characteristics were evaluated using sphere formation assays and western blot analysis. Molecular mechanisms were explored via quantitative real-time PCR, RNA immunoprecipitation (RIP), ac4C-specific RIP, dot blot analysis, and dual-luciferase reporter assays. Elevated NAT10 expression and ac4C modification levels were observed in ovarian cancer cells. NAT10 silencing significantly inhibited both cell stemness properties and glycolytic activity. Mechanistically, NAT10 enhanced PGAM1 mRNA stability through ac4C modification. Re-expression of PGAM1 reversed the functional effects induced by NAT10 depletion in ovarian cancer cells. Furthermore, in vivo tumor growth experiments demonstrated that NAT10 promotes tumorigenesis. Our findings demonstrate that NAT10 facilitates ovarian cancer progression by mediating ac4C modification of PGAM1. This study identifies a novel and potentially effective therapeutic target for ovarian cancer treatment.

Pancreatitis, or inflammation of the pancreas, is a common gastrointestinal condition. While often acute and self-resolving, it can become chronic and promote pancreatic ductal adenocarcinoma (PDAC), the third deadliest cancer worldwide. Pancreatitis is accompanied by morphological and molecular changes, notably immune cell infiltration, fibrosis, and acinar-to-ductal metaplasia (ADM). ELP3, the catalytic subunit of the Elongator complex, modifies wobble uridine tRNAs to optimize codon translation rates. It is critical to inflammatory processes and cancer in multiple organ systems, yet its role in the pancreas has not been investigated. This study aimed to investigate the expression and implication of ELP3 during pancreatitis induced in mice via repetitive caerulein injections. Acute pancreatitis was accompanied by increased expression of ELP3, which was mainly detected in pancreatic epithelial cells. To assess its function, we genetically inactivated Elp3 in pancreatic epithelial cells. Elp3 deficiency had no detectable effects on pancreas homeostasis, on the initiation and resolution of acute pancreatitis, on the development of chronic pancreatitis, or on pancreatitis-induced PDAC initiation. Our findings indicate that ELP3 is dispensable in pancreatic formation, inflammation and PDAC initiation. Future studies should explore its role in non-epithelial cells and its potential involvement in other PDAC hallmarks, such as therapy resistance.

Bladder cancer (BLCA) exhibits considerable heterogeneity, and research into its tumor microenvironment and prognostic biomarkers remains insufficient. This study aims to identify key prognostic genes and immune microenvironment factors to enhance clinical assessment. Primary tumor (PT) and lymph node metastasis (LNM) samples were obtained from patients with BLCA, and single-cell RNA sequencing (scRNA-seq) was conducted to analyze cellular composition and functional variations. Prognostic genes were identified based on integrated bulk transcriptomic data, leading to the development of a risk model. Functional enrichment analyses further elucidated the molecular characteristics of high- and low-risk cohorts. The scRNA-seq analysis revealed significantly elevated metabolic activity in epithelial cells of LNM. A subpopulation of epithelial cells, defined by 133 characteristic genes, was identified as pivotal in the lymphatic metastasis of BLCA. The prognostic model, derived from nine key genes (APOL1, CAST, DSTN, SPINK1, JUN, S100A10, SPTBN1, HES1, and CD2AP), demonstrated robust predictive performance. Functional enrichment analysis indicated that the high-risk group predominantly activated extracellular matrix (ECM) receptor interactions and the complement pathway, while the low-risk group was primarily associated with carbohydrate metabolism pathways. This study provides insights into the tumor heterogeneity and immune microenvironment of BLCA, introduces a high-precision prognostic model, and establishes a novel theoretical basis for personalized BLCA treatment.

Triple-negative breast cancer (TNBC) is characterized by poor prognosis and limited targeted treatment options. Efferocytosis, an essential immune mechanism for the clearance of apoptotic cells, is increasingly recognized as a key contributor to tumor immune evasion. This study aimed to identify key efferocytosis-related genes in TNBC, investigate their impact on the tumor microenvironment and immunotherapy responses, and construct a prognostic model to inform and optimize treatment strategies. RNA sequencing data and clinical information for patients with TNBC were obtained from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Machine learning models were employed to derive efferocytosis-related signatures to predict clinical outcomes and immunotherapy responses. Eight efferocytosis-related genes were identified, considered efferocytosis-related gene signatures herein: P2RX1, IFNG, IL1A, CD93, XKR8, SIAH2, F2RL1, and TLR4. Using the individual risk scores derived from this model, patients were stratified into high- and low-risk groups, revealing significant differences in immune infiltration and immuno-therapy response. Our study highlights the predictive significance of efferocytosis in assessing chemotherapy sensitivity, emphasizing the pivotal role of the immune microenvironment in mediating drug resistance. Moreover, we identified potential targets for immunotherapeutic strategies in the treatment of TNBC.

Tumor-associated macrophage (TAM) infiltration is associated with poor prognosis in human patients with melanoma. However, the mechanism by which TAMs infiltrate tumor tissues in dogs remains unclear. Therefore, the present study aimed to identify macrophage chemotactic factors involved in macrophage migration in canine oral malignant melanoma (OMM). We first analyzed RNA-seq data of canine OMM, then performed immunohistochemistry of OMM tissue, and finally performed a macrophage migration assay using factors secreted from a canine melanoma cell line. The RNA-seq and immunohistochemistry revealed high TAM infiltration in canine oral malignant melanoma. Migration assays were performed using macrophage cell lines and culture supernatants from seven canine melanoma cell lines to identify macrophage chemotactic factors. The analysis of chemokine expression in canine melanoma cell lines revealed a positive correlation between CXCL8 expression and macrophage migration. Furthermore, macrophage migration was significantly reduced by CXCL8 gene knockout and anti-CXCL8-neutralizing monoclonal antibody. Additionally, the addition of recombinant CXCL8 protein rescued the reduction in migratory macrophage cells caused by CXCL8 knockout. These findings indicate that CXCL8 plays a crucial role in macrophage migration and that targeting CXCL8 may be a novel therapeutic approach for canine melanoma.

The modulation of DNA replication dynamics has emerged as a key area of study in understanding genome stability and its perturbations in various physiological and pathological contexts. Replication fork rate is influenced by a variety of factors, including DNA repair pathways, origin firing, chromatin organization, transcription, and oncogenic signaling. This review highlights recent findings on the molecular mechanisms driving replication fork acceleration, focusing on scenarios such as PARP inhibition, oncogene activation, depletion of replication factors, and defects in Okazaki fragment processing. We discuss how reduced origin firing, R-loop resolution, and metabolic changes contribute to fork rate modulation, as well as the involvement of innate immune signaling, particularly through pathways such as cGAS-STING and ISG15. Special attention is given to consequences of accelerated replication forks for genome stability and their role in disease progression, particularly cancer. By unraveling the molecular mechanisms of fork acceleration, this Mini Review underscores its critical role in shaping genome integrity and cellular homeostasis, providing insights into future research directions and therapeutic strategies.

The Kruppel-like factor 15(KLF15) gene functions as a crucial transcriptional modulator involved in numerous cellular processes such as differentiation, proliferation, growth, and programmed cell death. The epithelial-to-mesenchymal transition (EMT) provides malignant cells with the adaptability and movement necessary for tumor advancement and spread, with zinc finger E-box binding homeobox 1(ZEB1) playing a pivotal role as a transcriptional factor in EMT. This investigation initially examined the association between the KLF15 protein and EMT associated transcription factors such as ZEB1, Slug, and Snail, along with marker proteins like E-cadherin and β-catenin in bladder cancer. Furthermore, we explored their connections with clinicopathological attributes and conducted prognostic analyses. Immunohistochemical techniques were utilized to ascertain the presence of KLF15 protein and EMT-associated transcription factor proteins, along with their marker proteins in 110 specimens of bladder cancer tissues. Concurrently, clinicopathological data and postoperative survival statistics were amassed. The rates of KLF15 and Slug protein expression were linked with pathological differentiation, lymphatic involvement, and pTNM staging. The protein expression rates of ZEB1, Slug, Snail, E-cadherin, and β-catenin also showed associations with lymphatic metastasis and pTNM stages. Notably, the expression of KLF15, the coexpression of KLF15 and ZEB1, and lymphatic metastasis emerged as independent prognostic indicators for the overall survival rates in bladder cancer cases. EMT enhances the risk of tumor recurrence and reduces overall survival durations in bladder cancer cases. Furthermore, KLF15 is a significant contributor to the EMT pathway in bladder cancer, primarily through its interaction with the transcription factor ZEB1. KLF15 and ZEB1 might serve as key biomarkers for metastasis and prognosis, offering potential new targets for therapeutic intervention in bladder cancer.

The mechanisms by which tumor-associated macrophages, key components of the glioblastoma (GBM) microenvironment, impair chemotherapy efficacy remain poorly understood. Resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, is associated with poor prognosis due to efficient DNA repair mechanisms. While low expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) has been linked to improved TMZ response, our previous findings suggest that N-methylpurine-DNA glycosylase (MPG) may also contribute to chemoresistance in GBM. Here, we report for the first time that conditioned medium from pro-inflammatory macrophages (CM-M1) enhances TMZ cytotoxicity by suppressing STAT3 phosphorylation, resulting in decreased MGMT and MPG expression in GBM cells. Proteomic profiling of CM-M1 revealed a unique, cytokine-rich secretome that may promote STAT1 activation, thereby inhibiting pSTAT3 and reducing DNA repair enzymes levels. Clinically, elevated MGMT and MPG protein levels were associated with increased pSTAT3 in our GBM patient cohort, and analysis of the TCGA database further showed that their combined overexpression correlates with significantly reduced progression-free survival. Gene silencing experiments confirmed the contribution of both enzymes to TMZ resistance, with dual knockdown producing a synergistic sensitizing effect. These findings uncover a novel mechanism of macrophage secretome-mediated chemoresistance and support the development of M1-based strategies to improve TMZ efficacy in GBM.

Trans-cinnamaldehyde (TCA), a natural compound isolated from the stem bark of Cinnamon cassia, has been recognized as a potential therapeutic agent for treating various diseases, including inflammatory conditions and diverse cancers. TNF-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis selectively in cancer cells while sparing normal cells. However, resistance to TRAIL-mediated apoptosis is a significant limitation in cancer therapy. This study aimed to investigate whether TCA could enhance the sensitivity of colorectal cancer cells to TRAIL induced apoptosis and to elucidate the underlying molecular mechanisms involved in this synergistic effect. The study was designed to evaluate the antitumor effects of TCA and TRAIL, both individually and in combination, using colorectal cancer cell lines and in vivo models. Various colorectal cancer cell lines and normal cells were treated with TCA, TRAIL, or their combination. Cell viability assays were conducted to determine the synergistic effects. Western blotting was performed to analyze the expression of ER stress-related proteins. Knockdown of DR5 or CHOP was achieved using siRNA to evaluate its role in the combined anticancer effect. in vivo experiments were conducted to confirm the antitumor effects of the TCA and TRAIL combination. We observed that the combination of TCA and TRAIL exhibits synergistic antitumor effects both in vitro and in vivo. The anticancer effect was notably enhanced when TCA and TRAIL were used to treat various colorectal cancer cell lines, but not normal cells. Additionally, the levels of endoplasmic reticulum (ER) stress-related proteins, such as phosphorylated protein kinase RNA-like ER kinase (PERK), phosphorylation of the eukaryotic initiation factor 2 (eIF2α), and C/EBP homologous protein (CHOP), increased in a dose-dependent manner when treated with TCA. Significantly, TCA elevated DR5 expression levels through ER stress. Knockdown of CHOP reduced the combined effect of TCA and TRAIL. TCA enhances TRAIL-induced apoptosis in colorectal cancer cells by inducing ER stress and upregulating DR5 expression. These findings suggest that TCA is a promising agent for overcoming TRAIL resistance and improving its therapeutic efficacy in colorectal cancer treatment.

This study aims to reveal the influence of SERPINA1 gene on the development, prognosis evaluation and immune environment changes of breast cancer. Cell lines with differential SERPINA1 expression were constructed. These models were used to explore its impact on the biological behavior of breast cancer cells. The expression of SERPINA1 in breast tumor tissues of patients undergoing surgery in our hospital was detected by immunohistochemistry to evaluate the regulatory effect of SERPINA1 gene on tumor microenvironment. The results found that the overexpression of SERPINA1 gene could significantly inhibit the proliferation and migration of breast cancer cells and promote apoptosis. Transcriptome sequencing analysis revealed that SERPINA1 may regulate the biological behavior of cells by affecting biological functional pathways such as adaptive immune response, natural killer cell-mediated cytotoxicity, and phosphatidylinositol signaling system1. Western blot analysis showed that SERPINA1 overexpression was accompanied by an increase in PTEN expression and a decrease in Akt and mTOR phosphorylation levels, suggesting a molecular mechanism by which SERPINA1 gene and PTEN cooperate to negatively regulate the passage of PI3K. In addition, the high expression of SERPINA1 is related to the recruitment of regulatory T cells (Treg) in breast cancer tissues, which may change the tumor microenvironment.

Identifying molecular signatures from complex disease patients with underlying symptomatic similarities is a significant challenge in the analysis of high-dimensional multi-omics data. Topological data analysis (TDA) provides a way of extracting such information from the geometric structure of the data and identifying multi-way higher-order relationships. Here, we propose an application of harmonic persistent homology, which overcomes the limitation of the ambiguity of the choice of a cycle representing a specific homology class. When applied to multi-omics data, this leads to the discovery of hidden patterns highlighting the relationships between different omic profiles, while allowing for common tasks in multi-omics analyses, such as disease subtyping, and most importantly biomarker identification for similar latent biological pathways that are associated with complex diseases. Our experiments on multiple cancer data show that harmonic persistent homology effectively dissects multi-omics data to identify biomarkers by detecting representative cycles predictive of disease subtypes.