Search Results (801)

From an epidemiological perspective, polymorphous low-grade neuroepithelial tumor (PLNTY) represents a small proportion of brain tumors encountered in epilepsy surgery series. Their rarity and relatively recent recognition likely contribute to underdiagnosis and poor prognosis. In terms of histopathological features, they are similar to oligodendrogliomas. Molecular analyses can be used to show the fusion between fibroblast growth factor receptor (FGFR3) and transforming acidic coiled coil (TACC) proteins, which most commonly results in progression towards glioblastoma (GBM). We report a case of a 62-year-old man who underwent left frontal craniotomy to remove a frontal mass. Histologically, the glial lesion consisted of elements associated with oligodendroglia-like features. Immunohistochemistry was positive for glial fibrillary acidic protein (GFAP), oligodendrocyte transcription factor 2 (OLIG2), and α-thalassemia X-linked mental retardation syndrome (ATRX) nuclear expression, but negative for isocitrate dehydrogenase 1 (IDH1) and BRAF-V600E. Next-generation sequencing showed the FGFR-TACC3 fusion, and taken together, these findings supported the final diagnosis of PLNTY. During follow-up, the patient underwent a second neurosurgery, where histological evaluation indicated a GMB. This article presents clinical and radiological data, morphology, immunohistochemistry, molecular features, and treatment to enhance the clinical and pathological understanding of PLNTY with FGFR3-TACC3 fusion for all professionals involved in medical decisions. Full article

Deuterium abundance has been proposed as a modulator of cellular metabolism; however, its influence on cancer-associated gene expression networks remains incompletely characterized. We analyzed A549 lung adenocarcinoma cells cultured across four deuterium concentrations (40, 80, 150, and 300 ppm) using NanoString nCounter profiling. Expression data were processed through multistep filtering, symbolic trajectory encoding, and density-based spatial clustering (DBSCAN) to identify extreme expression responders, and Gaussian mixture modeling (GMM-6) to resolve coordinated gene-expression modules. DBSCAN identified 11 outlier genes under deuterium depletion, including reduced expression of multidrug-resistance–associated ABCB1 (−42% at 80 ppm), proliferative signaling component FGFR4 (−19%), and transcriptional amplifier MYCN (−24%). In contrast, enrichment at 300 ppm produced a broad increase in oncogenic expression (mean +44%), with marked elevation of inflammation-related (IL6, TGFBR2) and invasion-associated (MMP9) genes. GMM-6 clustering of the remaining core network resolved six functional modules, indicating that depletion preferentially reduces expression of genes associated with plasticity-related programs (Cluster 5: TGFB1, S100A4), while basal survival-associated genes (Cluster 6: BIRC5, RET) remain comparatively stable. Together, these results indicate that deuterium concentration acts as a bidirectional modulator of gene expression programs in the A549 model, with enrichment broadly elevating oncogenic expression and moderate depletion associated with selective downregulation of genes linked to resistance, signaling, and invasive behavior. Significance: Deuterium depletion is associated with reduced expression of genes involved in multidrug resistance, growth-factor signaling, and transcriptional amplification, revealing deuterium-responsive transcriptional vulnerabilities within the A549 lung adenocarcinoma model. Full article

Endometriosis is a heterogeneous chronic inflammatory disorder associated with substantial diagnostic delay and limited therapeutic options, highlighting the need of robust non-invasive biomarkers and actionable molecular targets to complement existing low-sensitivity tests. To identify conserved pathogenic mechanisms with translational potential, here, we uniformly reprocessed three independent the Gene Expression Omnibus (GEO) microarray cohorts (GSE7305, GSE25628, and GSE11691) and applied a strict, directionally consistent intersection strategy to identify conserved transcriptional signals. We identified 262 consensus differentially expressed genes enriched for immunity/inflammation, cell adhesion and migration, and angiogenesis, consistent with key biological hallmarks of lesion establishment and persistence. Protein–protein interaction topology prioritized 11 highly connected hub genes (VCAM1, CCL2, MCAM, CD14, CD24, FGFR1, SIRPA, CSF1R, S100A9, S100A8, and LY96) that likely act as an integrated immune-adhesion-angiogenesis axis. Notably, 63/262 (24%) of the consensus genes were annotated to the extracellular exosome compartment, supporting their translational relevance as liquid-biopsy candidates. Finally, connectivity mapping using the LINCS L1000 framework nominated small-molecule perturbagens predicted to reverse the endometriosis-associated signature, providing a rational starting point for drug-repurposing experiments. In conclusion, this study elucidates a conserved immune–adhesion–angiogenesis axis driven by an 11-gene hub network in endometriosis. These core regulators represent promising candidates for the development of non-invasive liquid biopsies and precision, non-hormonal therapeutics. Full article

Chemotherapy has significantly improved survival in breast cancer and, in the neoadjuvant setting, contributes to tumor downstaging and increased rates of breast-conserving surgery while enabling in vivo assessment of tumor biology and chemosensitivity. Pathological complete response (pCR) is a key endpoint associated with favorable outcomes; however, tumor heterogeneity highlights the need for reliable predictive biomarkers. This study evaluated the mRNA expression of 13 candidate genes in relation to molecular subtypes and pathological response to neoadjuvant chemotherapy (NAC) to identify potential predictive and prognostic markers. Pretreatment core biopsies from 92 patients receiving NAC were analyzed by quantitative RT-PCR. Molecular subtypes were determined by immunohistochemistry (ER, PR, HER2, Ki67), and pathological response was classified using the Miller–Payne scale as good (MP 4/5) or poor (MP 1–3). Multivariate logistic regression assessed associations between gene expression, subtype, and pCR. Hormone receptor-positive tumors showed significantly higher expression of AXL, FGFR1, RAP80, GAS6, BTRCP, and ZNF217. Significant associations with pCR were observed for AXL, FGFR1, YAP, and BRCA1. Low AXL and BRCA1 expression levels were independently associated with pCR. In addition, their combined low expression was associated most strongly with breast pCR in this cohort. These findings should be interpreted as exploratory and require validation in independent cohorts. Full article

Background: Therapeutic resistance to CDK4/6 inhibitors (CDK4/6i) remains a critical barrier in HR⁺ breast cancer. While network-based approaches offer a route to identify salvage therapies, existing methods often rely on inconsistent centrality metrics or retrospective public transcriptomes, lacking a unified framework to translate topology into pharmacological actionability. Methods: We developed the Topology-Integrated Hubness Score (TIHS), a quantitative framework that integrates five orthogonal network metrics into a unified hubness vector. To rigorously validate this framework and overcome the limitations of public bulk datasets, we combined cross-cohort statistical benchmarking with original RNA-sequencing data generated from a laboratory-derived palbociclib-resistant model (MCF7-PR). TIHS was applied to prioritize repurposing candidates by overlaying network hubness with drug–target affinity profiles. Results: Methodologically, TIHS demonstrated robust cross-dataset stability (cosine similarity ≥ 0.98) and statistically outperformed single-metric approaches in predicting drug sensitivity. In application, the framework identified sorafenib as a top-ranked candidate for reversing CDK4/6i resistance. Experimental validation confirmed these predictions: sorafenib significantly resensitized resistant cells (IC₅₀ reduction from 6.57 μM to 1.15 μM), and molecular dynamics simulations supported stable binding to the TIHS-prioritized hub, FGFR3. Furthermore, functional assays involving siRNA-mediated knockdown validated that FGFR3 is mechanistically required for the sorafenib resensitization phenotype. Conclusions: This study presents TIHS as a mechanism-agnostic, experimentally validated bridge between resistance-state transcriptomes and clinical decision-making. By coupling computational prioritization with in vitro functional verification, we demonstrate that targeting topology-defined hubs is a viable strategy for overcoming therapy resistance. Full article

Background/Objectives: Head and neck cancer (HNC) represents the seventh most common cancer diagnosis globally, yet current treatments, including surgery, radiation, and immunotherapy, have shown limited improvement in outcomes. Drug repurposing offers a cost-effective strategy to identify new therapeutic options by leveraging existing medications with known safety profiles. Within this study, we developed the GARD pipeline (Genomic Alteration-based Repurposing for Drugs), designed to uncover repurposing candidates for HNC using genomic and network-based approaches. Methods: GARD integrates multi-omics data from The Cancer Genome Atlas (TCGA), including copy number variation (CNV) and somatic mutations (SOM). The cohort was stratified by human papillomavirus (HPV) status. Risk-associated genes were identified and then expanded via high-confidence protein–protein interaction (PPI) networks. Top candidate genes were filtered through comprehensive analysis of publicly available literature data in PubMed using LLMs to validate the relationship between the identified genes and HNC. The top risk genes and their network-expanded neighbors were mapped against DrugBank, and through statistical significance testing and literature validation, established significant drug–gene associations. Results: Significant genes associated with HNC, inferred by genomics alteration, were identified across HPV-positive and HPV-negative subgroups, such as PIK3CA, SOX2, TP53, EIF4G1, TLR7, CLDN1, PRKCI, and EPHA2. Further expansion through the PPI network identified other targetable genes such as EGFR, ERBB2, and the FGFRs. Literature-based validation efforts ensured confidence in the gene–disease association. Drug–gene mapping revealed candidates spanning those already in clinical trials for HNC (e.g., Afatinib, Cabozantinib, Dasatinib, Brigatinib, Lenvatinib, Capivasertib, and Erdafitinib) and emerging or repurposing candidates (Amuvatinib, XL765 (Voxtalisib), Golotimod, Artenimol, Quercetin, and Acetylsalicylic Acid), offering opportunities for precision repurposing. Conclusions: The GARD pipeline demonstrates a genomics-driven, network-informed framework for systematic drug repurposing in HNC. HPV stratification enhances precision, literature-based validation strengthens confidence, and integrated drug mapping enables refinement of existing therapies and discovery of novel candidates for personalized treatment strategies. Code Availability: The full implementation of the GARD pipeline, including preprocessing scripts, statistical analysis modules, and visualization tools, is publicly available on GitHub. Full article

Background/Objectives: There is a lack of cohesion in integrating current knowledge on the genetic and environmental etiology of dental impaction. The primary aim of this article is to review the current literature to identify candidate genes involved in the pathogenesis of dental impaction. Methods: A scoping review was conducted following PRISMA-ScR guidelines to identify and organize the available body of evidence. Relevant literature was searched in MEDLINE (via PubMed), Scopus, and Web of Science, with the final search conducted on 03 January 2026. Eligibility criteria included case–control, cohort, cross-sectional observational, and case report studies in humans. Selected studies focused on syndromic and non-syndromic variants, inheritance patterns, and genetic analyses. Risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists and AMSTAR 2. Results: Only 18 studies met the eligibility criteria. Most articles were case reports and retrospective observational studies, revealing a multifaceted genetic landscape underlying dental impaction, with mutations affecting transcription factors and signaling pathways critical for odontogenesis, particularly RUNX2, FGFR1, MSX1, PAX9, and AXIN2. Overall, the included studies showed moderate methodological quality. Conclusions: Current evidence does not clearly support specific genes as causal factors in dental impaction, but instead suggests a complex, likely polygenic susceptibility that modulates the anatomical threshold for tooth eruption. This review highlights RUNX2, FGFR1, MSX1, PAX9, and AXIN2, as well as emerging candidates involved in eruption and bone remodeling pathways. Future progress depends on standardized phenotyping, large replicated cohorts, and functional studies linking genetic variation to dental follicle-mediated eruptive remodeling. Full article

Several receptors have received considerable attention as therapeutic targets in gastric cancer (GC), and numerous receptor inhibitors have been developed. However, the development of novel gastric cancer therapeutics is time-consuming. Therefore, this study aimed to identify drugs effective against gastric cancer from existing anticancer agents originally developed for other malignancies. In this study, the cancer-related genomic profiles of 286 genes were analyzed in 14 gastric cancer cell lines using targeted DNA sequencing, and these cell lines were utilized as models to evaluate the efficacy of 35 anticancer drugs. The 14 cell lines were assessed for 286 gene alterations, copy number variations, amplification of 14 gastric cancer-related therapeutic targets, and sensitivity to 35 drugs. p-MET and MET were overexpressed in the SNU5, SNU620, MKN45, and Hs746T cell lines, while p-EGFR was overexpressed in the NCI-N87 cell line. FGFR2 overexpression was observed in the Kato III and SNU16 cell lines. TGFβR1 was overexpressed in the MKN7 cell line. HER2 and CDK12 were overexpressed in the NCI-N87 and MKN7 cell lines. PD-L1 overexpression was detected in the Hs746T and MKN7 cell lines. CD44 was overexpressed in the SNU5 and Hs746T cell lines and CLDN18 overexpression was observed in the MKN7 cell line. Well-characterized gastric cancer cell lines are essential for drug development research. This study provides a framework for selecting cell lines that are responsive to each of the 35 anticancer drugs and elucidating their underlying therapeutic mechanisms through follow-up studies. Ultimately, clinical studies are required to confirm the therapeutic efficacy of the selected drugs. Full article

Mutations in the fibroblast growth factor 10 (FGF10) gene in humans cause aplasia of the lacrimal and salivary glands (ALSG). In patients with ALSG, heterozygous loss-of-function mutations are found, and FGF10 haploinsufficiency results in the absence of these secretory organs. Lacrimal glands (LGs) are formed through epithelial thickening, budding, and branching morphogenesis. To compare the variable phenotypes of the Fgf10^+/− Harderian glands (HGs) previously reported, we examined the development of LGs in wild-type (WT), Fgf10^+/−, and Fgf10-null mice. Pax6 immunostaining was performed to visualize the LG primordia from embryonic day 15.5 (E15.5) onwards. In situ hybridization of the genes encoding the epithelial receptor of FGF10, FGFR2b, and its other ligands was performed to determine their potential involvement in LG development. LG primordia were not observed in Fgf10^+/− mice bilaterally at E16.5 or later stages. At E15.5, budding from the developing conjunctival epithelium (CE) was observed in a small fraction of the Fgf10^+/− LG primordia. In contrast, the Fgf10-null CE failed to promote budding. Among Fgf1, Fgf3, Fgf7, Fgf10, and Fgf22, Fgf10 was expressed in the mesenchyme surrounding developing LG epithelial cells, whereas Fgf1 was expressed in the LG epithelium of WT mice. Fgf7 was initially expressed in the mesenchyme surrounding the nascent LG epithelium, but its expression subsequently became diffused. Thus, we conclude that among the FGFR2b ligands, initial LG formation is dependent on the mesenchymal factors FGF10 and FGF7, and FGF1 is likely to function as an epithelial factor in the LG primordia. A single allele of Fgf10 was found to be insufficient to support the budding process during LG morphogenesis. Full article

Rhabdomyosarcoma is a small round-cell soft tissue tumor that occurs mainly in pediatric and adolescent/young adult (AYA) patients but also rarely in adults. Multidisciplinary treatments including multidrug therapy and local therapy (surgery and/or radiation) are the current standard of care, and treatment strategies are determined according to the estimated risk based on the patient’s age, site of onset, and histologic type, as well as the disease stage. New treatment developments in recent years have been based on risk; lower cumulative doses of alkylating agents to reduce late toxicity for low-risk patients are being studied, and long-term maintenance therapy or the addition of new drugs inhibitors to standard multidisciplinary therapy for intermediate- to high-risk patients have been investigated. For high-risk and metastatic patients, novel molecular targeted drug candidates are being evaluated. The target candidates for rhabdomyosarcoma have included the RAS-signaling pathway, ALK, NTRK, FGFR, and MSI-High. In addition, fusion genes (e.g., PAX3/7-FOXO1), which play an important role in diagnostic and prognostic factors, are also being investigated as potential therapeutic targets as their underlying backgrounds are gradually becoming clear. This review summarizes the overall picture of the development of novel therapies for rhabdomyosarcoma and discusses the direction that should be taken in the future. Full article

Gastric cancer remains a leading cause of cancer-related mortality worldwide and is marked by pronounced molecular heterogeneity. Advances in genomic profiling have identified key genetic alterations, including oncogenes (HER2, PIK3CA, and MYC), tumor suppressor genes (TP53, CDH1, and ARID1A), and regulators of genome stability and cell architecture (MLH1, RHOA, and CLDN18), which have driven the development of targeted therapeutic strategies. Although genetically engineered mouse models and xenograft systems have been indispensable for functional validation and preclinical drug testing, many approaches that showed promising efficacy in animal models—such as inhibition of EGFR, MET, FGFR2, and the PI3K pathway—failed to translate into overall survival benefits in clinical trials, highlighting major translational limitations. In contrast, HER2- and CLDN18.2-targeted therapies represent rare but notable clinical successes, underscoring the importance of true oncogenic dependency, precise biomarker-driven patient selection, and robust preclinical validation. In this review, we systematically categorize gastric cancer-associated genes according to their biological functions, summarize representative animal models, and critically examine key successes and failures in clinical translation, emphasizing the need for biologically faithful models and precision-driven translational strategies. Full article

Background: Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and hepatocyte-derived host factors play important roles in HBV-associated tumor progression. Alpha-1B glycoprotein (A1BG) is a plasma glycoprotein reported to be dysregulated in multiple cancers. In this study, we investigated the functional role of A1BG in HBV-associated HCC progression. Methods: Both the HepG2 and HBV-transfected HepG2 cell lines were used to examine the biological effects of A1BG. A1BG expression was modulated using siRNA and a plasmid vector. A series of functional assays were conducted to assess cell proliferation, apoptosis, stemness, migration, and invasion. RNA microarray analysis and gene set enrichment analysis (GSEA) were performed to identify A1BG-regulated pathways. Results: Functionally, A1BG overexpression suppressed cell proliferation, stemness, migration, invasion, and HBV products while promoting apoptosis in both HepG2 and HBV-transfected HepG2 cells. In contrast, opposite effects were shown in the event of A1BG knockdown. Moreover, A1BG expression was reduced in HBV-associated HCC tissues and correlated with advanced pathological stage and poor prognosis. RNA microarray analysis and GSEA revealed the activation of anti-HBV-related genes and suppression of FGFR1 signaling and the matrix metalloproteinase pathway in A1BG-overexpressing cells. Conclusions: This study provides evidence that A1BG may be a novel host factor associated with the in vitro suppression of HBV replication and HCC progression by modulating pathways related to enhanced antiviral effects, reduced proliferative capacity and stemness, and suppression of EMT. These findings suggest that A1BG is a potential therapeutic target in HBV-related HCC. Full article

Background/Objective: Breast cancer (BC) management has traditionally relied on static clinicopathologic and immunohistochemical biomarkers (hormone receptor status, HER2 expression, and proliferative activity assessed at diagnosis). However, these biomarkers are typically evaluated at a single time point and may not reflect therapy-induced molecular evolution. This study evaluates whether longitudinal molecular profiling before and after treatment better characterizes tumor dynamics and provides clinically actionable insights into treatment response, resistance, and prognosis. Methods: Thirty-two patients with invasive breast carcinoma were analyzed using histopathology, immunohistochemistry, tissue-based next-generation sequencing, and plasma circulating tumor DNA (ctDNA) analysis. Paired tumor tissue and plasma samples were collected before and after treatment when available. Changes in biomarker expression, molecular subtype, and genomic alterations were assessed to characterize molecular plasticity under therapeutic pressure. Results: The cohort had a median age of 54 years (range 29–86), predominantly invasive ductal carcinoma (>85%), and high-grade disease. Hormone receptor-positive tumors accounted for 78.1%. Molecular subtypes were Luminal A (34.4%), Luminal B HER2− (40.6%), Luminal B HER2+ (6.3%), HER2-enriched (6.3%), and triple-negative breast cancer (12.5%). Initial tissue sequencing identified PI3K/AKT pathway alterations in 28.1% of cases. Post-treatment analyses revealed substantial molecular discordance, including progesterone receptor loss (33.3%), HER2 status changes (33.3%), and Ki67 variability (77.8%). Plasma ctDNA analysis was informative in 53.1% of patients and identified additional clinically relevant alterations, including FGFR1 amplification and BRCA1/2 variants not detected in tissue. Conclusions: BC molecular profiles are dynamic and frequently altered by therapy. Longitudinal molecular assessment reveals clinically actionable changes overlooked by static subtyping, supporting a dynamic model of molecular classification, highlighting the potential value of adaptive molecular subtyping to improve treatment stratification and resistance monitoring. Full article

Background: Fibroblast growth factor receptors (FGFRs) play a crucial role in tissue homeostasis and organ development by regulating cellular processes, including proliferation, differentiation, and survival. Dysregulation of FGFRs contributes to developmental disorders and carcinogenesis. As membrane-bound receptors, they represent promising targets for therapeutic intervention and drug development. Methods: This study employed a systematic in silico analysis of publicly available phosphoproteomics datasets to provide a comprehensive overview of the phosphorylation regulatory network of the FGFR family. Results: We identified predominant phosphosites in FGFR1-4 that exhibited differential abundance across diverse experimental conditions, specifically, Y653 in FGFR1; S453, Y586, Y656, and Y657 in FGFR2; S444 and S445 in FGFR3; and S573 in FGFR4. Our analysis identified 32 and 89 significantly co-modulated phosphosites on other proteins with FGFR3 and FGFR4, respectively. Beyond the upstream kinases from the FGFR family, we also identified MAPK1 as a potential upstream kinase of FGFR4. Furthermore, disease enrichment analysis revealed that proteins co-modulated with FGFR3 were primarily involved in skeletal developmental disorders, such as brachydactyly, short toe, and syndactyly of fingers, whereas those associated with FGFR4 were linked to various cancers. Conclusions: Our findings highlight key disease-associated phosphosites within the FGFRs and offer a foundation for advancing phosphosite-focused therapeutic research. Full article

Small bowel obstruction (SBO) in dogs is most commonly caused by foreign bodies or neoplasia; however, SBO secondary to transmural fibroplasia remains a rare clinical complication of canine chronic enteropathy. This report describes the complex case of mechanical SBO caused by transmural ileal fibroplasia and inflammation at the ileocolic junction in a 9-year-old mixed-breed dog with concomitant hyperadrenocorticism (HAC). The primary presentation involved chronic severe weight loss and intermittent anorexia, contrasting with the acute presentation typical of most SBO cases. Imaging studies revealed severe, circumferential thickening up to 10 mm of the small intestine wall at the ileocolic junction (ICJ), resulting in complete luminal stricture and marked proximal dilation. Surgical intestinal resection and anastomosis were performed for alleviation of the obstruction, and histopathology confirmed severe mural and serosal enteritis with extensive fibroplasia extending into the adjacent mesentery, thereby excluding neoplastic processes. Quantitative PCR analysis demonstrated a significant upregulation of mRNA expression for PDGFRB and FGFR compared to normal tissue. Postoperative recovery was rapid; although soft feces persisted for one month, normal stool consistency was subsequently restored, and the patient achieved significant weight gain. This case underscores the diagnostic and therapeutic challenges associated with non-neoplastic, inflammation-driven SBO and suggests that activation of the PDGFR-β/FGFR pathways may play a key role in fibroplasia-related intestinal strictures, offering a novel molecular perspective beyond conventional SBO etiologies. Full article