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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. 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. 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. 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. Show less

Fibroblast growth factor 21 (FGF21) analogs are in development for metabolic dysfunction-associated steatotic liver disease (MASLD), but their impact on problematic alcohol use (PAU), alcohol use disorder, binge drinking, and alcohol-related liver disease (ALD) is unknown. We leveraged genome-wide association study data from the UK Biobank, FinnGen, Million Veterans Program, and GenomALC for PAU, alcohol use disorder, binge drinking, weekly drinks, and ALD. Our four-tier evaluation included: (1) multivariable Mendelian randomization (MR) and mediation with circulating FGF21 levels; (2) comparative MR of MASLD and ALD targets (PNPLA3, TM6SF2, HSD17B13) using liver fat and expression instruments; (3) receptor-focused MR of β-Klotho (KLB) and FGFR1/2/3 incorporating brain-region expression; and (4) a phenome-wide MR across 1,022 traits to assess safety. Genetically higher FGF21 protein levels were associated with lower PAU (β = -0.097, 95% CI -0.135 to -0.059, p = 6.13 × 10 Human genetic evidence indicates that FGF21 analogs mitigate hazardous drinking and ALD via both behavioral and metabolic pathways. These findings distinguish FGF21 from other MASLD targets and highlight its potential for precision treatment of alcohol-related disorders. This study leverages human genetic evidence to validate FGF21 - a liver-derived hormone currently in clinical trials for fatty liver disease - as a dual-action therapeutic that both curbs harmful drinking behaviors and protects against alcohol-related liver injury, addressing a critical therapeutic gap with limited existing pharmacotherapies. The results are important for clinicians and researchers seeking precision medicine strategies for alcohol use disorder and liver disease, as well as for patients who currently face limited treatment options. By pinpointing FGF21's behavioral and metabolic pathways and demonstrating a favorable safety profile, our findings support the repurposing of FGF21 analogs in clinical trials of alcohol use disorder and alcohol-related liver disease and suggest that genetic stratification could optimize patient selection for therapy. While these conclusions rely on European-ancestry genetic data and Mendelian randomization assumptions, they help inform future clinical studies, biomarker development, and policy efforts aimed at expanding treatment options for alcohol-related conditions. Show less

Glioblastoma, isocitrate dehydrogenase wildtype (GBM, IDH-wt), is a highly aggressive brain tumor with a poor prognosis. Alterations in the fibroblast growth factor receptor (FGFR) gene family-such as FGFR::TACC fusions and FGFR1 mutations-have emerged as potential therapeutic targets; however, their clinical and genetic features in GBM, IDH-wt remain unclear. We analyzed 1076 GBM, IDH-wt cases using comprehensive genomic profiling data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. FGFR alterations were detected in 8.0% of patients, including FGFR::TACC fusions (3.3%) and FGFR1 mutations (2.9%). The FGFR::TACC fusion-positive group was older at diagnosis and showed higher frequencies of TERT promoter mutation and MDM2 amplification, and lower frequencies of EGFR amplification and TP53 mutation, compared with the fusion-negative group. The FGFR1 mutation-positive group was enriched for ATRX, NF1, and PIK3CA mutations and had significantly fewer TERT promoter and PTEN mutations, compared with the mutation-negative group. No significant differences in overall survival were observed, although both groups tended to have longer median overall survival compared with their respective negative groups. This study represents the largest genomic cohort to date of FGFR alterations in GBM, IDH-wt. FGFR::TACC fusion-positive and FGFR1 mutation-positive GBMs exhibited distinct genetic profiles, highlighting the clinical relevance of molecular subclassification and providing insight for future therapeutic strategies. Show less

Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the treatment of HS is of critical importance. Using summary statistics from the eQTLGen Consortium, Decode database, and FinnGen cohort, we conducted transcriptome-wide and proteome-wide Mendelian randomization (MR) to discover potential pharmacological targets against HS, with subsequent validation via RNA sequencing. Upstream regulators and downstream mechanisms were further investigated to better understand the roles of the pathogenic gene. Drug prediction, molecular docking, and molecular dynamics (MD) simulation were employed to estimate the value of potential drugs for HS. A high level of fibroblast growth factor receptor 1 (FGFR1) significantly increased the risk of HS according to transcriptome-wide (P = 0.011) and proteome-wide MR (P = 0.002) analyses. RNA-seq further validated the high expression of FGFR1 in HS. Gene-gene interaction network and enrichment analysis identified FGFR1 as the core gene driving the progression of HS, highlighting multiple biosynthetic processes. Pharmacological evaluation of candidate drugs predicted stable binding between Ro-4396686 and FGFR1. Our findings suggest that FGFR1 can serve as promising target for optimizing HS treatments, potentially reducing the costs of drug development. Show less

Invasive lobular carcinoma (ILC) comprises ∼10%-15% of breast cancers and is characterized by loss of the cell-adhesion molecule E-cadherin (encoded by CDH1), discohesive growth, predominant estrogen receptor (ER) positivity, low-to-intermediate proliferation, and atypical metastatic spread to bone and gastrointestinal/peritoneal sites. Diagnostic assessment is often challenging owing to diffuse infiltration, frequently yielding non-measurable disease per response evaluation criteria in solid tumors (RECIST). Molecularly, ILC is enriched for phosphoinositide 3-kinase (PI3K) activation and harbors emerging vulnerabilities-such as ROS1 synthetic lethality in CDH1-deficient tumors and fibroblast growth factor receptor 1 (FGFR1)/bromodomain and extra-terminal (BET) dependencies-now under study. Because metastatic ILC remains underrepresented in trials, systemic therapy often mirrors invasive ductal carcinoma (IDC). This short communication synthesizes current evidence to distinguish shared from plausibly lobular-specific signals; highlights near-term opportunities-including antibody-drug conjugates (ADCs), oral selective ER degraders (SERDs), and selective use of immunotherapy in an immune-enriched subset with higher tumor-infiltrating lymphocytes (TILs) and PD-L1; and outlines trial-design adaptations-such as incorporating 18F-fluoroestradiol PET (FES-PET)-to improve representation and interpretability in metastatic ILC research. Show less

Fibroblast growth factor (FGF) signaling plays an important role in the pathogenesis of various respiratory diseases, including idiopathic pulmonary fibrosis (IPF). FGF ligands can exert both pro- and anti-fibrotic effects, depending on the responding cell, the expression levels of FGF receptors (FGFR1-4) and the context of other signaling molecules such as Transforming growth factor β (TGF-β). We evaluated here the effect of a modified version of a soluble FGFR3 decoy receptor (designated as "sFGFR3-Fc"), that specifically sequesters pro-fibrotic FGFR3 ligands, FGF1, FGF2 and FGF9 as a potential anti-fibrotic drug. We showed that FGF2 stimulated proliferation and expression of various fibrotic markers in human pulmonary fibroblasts from healthy donors and IPF patients. The sFGFR3-Fc was able to reduce these FGF2-mediated responses and also partially attenuate the pro-fibrotic phenotype induced by TGF-β, including gel contraction. Furthermore, single cell transcriptomic analyses revealed heterogeneity of IPF-derived fibroblasts for FGF2 response and confirmed the potential efficacy of sFGFR3-Fc in decreasing the expression of a subset of TGF-β1 pathway genes. Finally, sFGFR3-Fc was shown to improve the progression of pulmonary fibrosis using both a preventive and therapeutic strategy, evaluated in the standard single bleomycin (BLM) instillation mouse model as well as in a more severe model of repeated BLM instillations, as evidenced by the reduction in ECM deposits, the recovery of body weight and the restoration of lung function. Our data highlight the interplay between the TGF-β and the FGF signaling pathways and demonstrate the potential of targeting pro-fibrotic FGFR3 ligands as therapeutic strategy for IPF. Show less

Myelin debris accumulation after spinal cord injury (SCI) drives persistent neuroinflammation, lysosomal dysfunction, and lipid overload in macrophages, ultimately impairing tissue repair. Here, we identify fibroblast growth factor 4 (FGF4) as a previously unrecognized regulator of macrophage-mediated myelin debris clearance. Endogenous FGF4 transiently increased in the early phase of SCI but rapidly declined. Using in vitro models, we demonstrate that exogenous FGF4 markedly enhances myelin debris phagocytosis through activation of the FGFR1-PI3K/AKT signaling pathway, leading to upregulation of Clec10a, a C-type lectin receptor not previously linked to myelin debris processing. Silencing Clec10a significantly mitigated the phagocytic and neuroprotective benefits of FGF4, supporting Clec10a as an important mediator of this response. D-GalNAc competitive inhibition assays showed that Clec10a does not rely on the conserved carbohydrate-recognition domain to bind to myelin debris. FGF4 enhanced the maturation and degradative efficiency of the endolysosomal system, driving internalized myelin debris through Rab5 The online version contains supplementary material available at 10.1186/s12974-026-03743-0. Show less

In the present study, a systematic revision in the Medline was conducted to determine the somatic mutation in gangliogliomas. A Medline search for relevant publications up to October 2024 using the key phrase "ganglioglioma mutation" led to the retrieval of 297 studies. This corpus provided the basis for the present review. The records without abstract or descriptions of somatic mutations were excluded. Only records in the English language were considered. A total of 43 papers were evaluated, reporting a total of 1360 cases of ganglioglioma. Among them, 528 cases presented mutations in 6 genes: BRAF BRAF Show less

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. 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. 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. Our findings highlight key disease-associated phosphosites within the FGFRs and offer a foundation for advancing phosphosite-focused therapeutic research. Show less

FGFR1 overexpression is strongly correlated with tumorigenesis, malignant progression, and poor clinical outcomes of nonsmall cell lung cancer (NSCLC). The development of PET radiotracers specifically targeting FGFR1 holds significant clinical value for guiding FGFR1-targeted therapy, evaluating treatment efficacy, and monitoring drug resistance. In this study, we used computational simulation approaches to develop linear peptide RY9 along with cyclic peptides cRY9 and cRY9M, derived from FGF2, a particular ligand of FGFR1, and designed FGFR1-targeting radiotracers [ Show less

FGFRs genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in cancers, leading to the initiation and progression of tumors by enhancing FGFR signaling. The substantial problems arising from the lack of decisive clinical evidence have resulted in the cessation of some inhibitor applications, and identifying effective small molecule inhibitors that selectively target FGFRs can advance the therapy of cancers driven by FGFRs abnormalities. The three-dimensional structure of the FGFR1/2/3/4 protein and the amino acid positions within the tyrosine kinase domain were downloaded from the PDB database, and small molecule data were extracted from the ZINC15 database. Then, we used molecular docking and dynamics simulations to assess compounds interacting with FGFR proteins, and screening potential small molecules targeting FGFR. Finally, we evaluated its effects by two CRC cell line HCT116 and NCI-H716. In the study, by docking with 2.8 million small molecules, we identified three promising FGFR small molecule inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of the three compounds, we found that ZINC000101867325 could form the stable binding interactions with FGFR1/2/3. And, ZINC000101867325 inhibited the activity of FGFR signaling, and resulted in cell apoptosis and decrease in cell proliferation and migration in colorectal cancer cell lines. In addition, ZINC000101867325 is also predicted to target FGFR2 mutations in colorectal cancer patients. We predicted three small molecules targeting FGFRs, and ZINC000101867325 shows superior chemical bond types and stability with FGFR1/2/3, and inhibits FGFR signaling in CRC cell lines. This study provides novel FGFRs inhibitors, which enrich treatment strategies for cancers. Show less

Nivolumab and nintedanib are both established agents for pre-treated NSCLC of adenocarcinoma histology. Hypothesizing that the combination of immune checkpoint inhibition (nivolumab) and anti-angiogenesis (nintedanib) increases efficacy, we intended to determine a safe and efficacious dose for the combination. Our multi-center, open-label, single arm, phase Ib/II study enrolled patients with histologically confirmed stage IIIB/IV adenocarcinoma NSCLC and one or two previous lines of systemic treatment with platinum-based chemotherapy +/- checkpoint inhibitors (CPI). A traditional 3 + 3 design was used to determine a recommended phase II dose (RP2D) for nintedanib combined with nivolumab. Primary endpoints were safety and tolerability together with 6- and 9-month rates of progression-free survival (PFS). The RP2D was determined as 200 mg nintedanib twice daily (bid) with 240 mg nivolumab biweekly (Q2W). No new safety signals were detected. PFS milestone rates at 6 and 9 months for the 52 patients who received this dose were 25% [95% CI 14.3-37.3%] and 11.5% [4.7-21.8%], respectively. Median overall survival (mOS) was 12.2 months [95% CI: 8.13-18.37]. Central biomarker analysis based on combined positive score (CPS) revealed that high PD-L1 and low PD-L1/low FGFR1 identified patients with prolonged OS at 36 months (70% and 40%, respectively), while low PD-L1/high FGFR1 was associated with shorter OS (p = 0.0195). CPI-rechallenged patients had better OS outcomes than those who were CPI-naïve (mOS 8.13 months [95% CI 2.03-15.2] vs. 14.7 months [95% CI 8.2-NR]; logrank p = 0.0493). Combination of nivolumab and nintedanib was shown to be safe and feasible. Despite missing synergistic effects on efficacy for the overall population, promising OS was observed for patients with high PD-L1 expression and for patients with previous immunotherapy. Therefore, CPI responsiveness may have been restored in some cases. Inhibition of FGFR-mediated tumor progression seems relevant in tumors with lower levels of both PD-L1 and FGFR1 expression and might be effectively inhibited by nintedanib. The combination nivolumab/nintedanib might warrant further exploration in selected patients. Show less

Coronary artery disease (CAD) remains a leading cause of mortality worldwide, with substantial unmet therapeutic needs. This study aimed to identify and prioritize genetically supported therapeutic targets for CAD using Mendelian randomization (MR). We implemented a two-sample MR framework to infer the causal effects of blood druggable cis-expression quantitative trait loci (cis-eQTLs) on CAD. To consolidate MR findings, we applied Steiger filtering, Bayesian colocalization, and multiple sensitivity analyses. Mediation and phenomewide MR analyses were employed to investigate potential mechanisms and on-target effects of prioritized druggable genes. We identified 66 causal druggable genes associated with CAD in European populations (false discovery rate < 0.001). Among these, ERP29 (odds ratio [OR] = 1.311; 95% confidence interval [CI]: 1.176-1.460), MCL1 (OR = 0.877; 95% CI: 0.840-0.915), TNXB (OR = 1.183; 95% CI: 1.102-1.269), DAGLB, FES, and TRPM4 colocalized with CAD (posterior probability for colocalization > 0.8). The associations for ERP29, MCL1, and TNXB were replicated in an East Asian cohort. Protein-protein interaction network analysis highlighted MAPK3 and TNF as prioritized druggable targets at the protein level. Mediation analysis indicated that body mass index, triglycerides, blood pressure, and atrial fibrillation partially mediate the association between MAPK3 and CAD. Phenome-wide MR analysis further suggested additional beneficial effects of targeting MAPK3 and TNF on diabetes mellitus, obesity, hypertension, unstable angina, myocardial infarction, angina pectoris, coronary atherosclerosis, ischemic heart disease, and disorders of lipoid metabolism. This druggable genome-wide MR study not only corroborated the targets of FDA-approved CAD medications (e.g., FGFR1, MAPK3, NEU1) but also uncovered several novel genes, such as ERP29, MCL1, TNXB, DAGLB, FES, and TRPM4, implicating mechanisms related to blood pressure, lipid metabolism, and additional beneficial effects on endocrine/cardiometabolic traits and circulatory system disorders. Further exploration is imperative to explore their feasibility and generalizability. We identified circulating ERP29, MCL1, TNXB, DAGLB, FES, TRPM4, MAPK3, and TNF as promising, genetically supported druggable targets for CAD treatment. Notably, MAPK3 and TNF demonstrated strong protein-level interactions and close associations with cardiometabolic disorders. Show less

Distant metastasis of colorectal cancer (CRC) is strongly driven by metabolic reprogramming and epithelial-mesenchymal transition (EMT). Increasing evidence suggests that these two processes form a reinforcing positive feedback loop; however, the integrated regulatory mechanism and its potential for pharmacological intervention remain insufficiently understood. This study aimed to elucidate the mechanistic coupling between autophagy, metabolic reprogramming, and EMT, and to develop a targeted pharmacological strategy capable of disrupting this positive feedback loop. We systematically constructed and validated an autophagy-metabolism-phenotypic transformation regulatory axis centered on ATG4B and PKM2, and evaluated the therapeutic efficacy of Curcumol as a pathway-specific natural compound intervention. Biochemical assays, protein-protein interaction analyses, and functional experiments were performed to determine how ATG4B regulates PKM2 Tyr105 phosphorylation, nuclear translocation, and glycolytic activity. Curcumol was applied to assess its ability to activate ATG4B-dependent autophagy and inhibit PKM2 activation. Anti-tumor efficacy was validated using colorectal cancer organoids, orthotopic implantation, and liver metastasis mouse models. ATG4B was identified as a core autophagy enzyme that directly binds to and shields the PKM2 Tyr105 site, preventing FGFR1-mediated phosphorylation and nuclear translocation. This blockade suppressed the Warburg effect, reduced lactate production, and synergistically inhibited EMT progression. Curcumol activated ATG4B-dependent autophagy, inhibited PKM2 activation, and effectively disrupted the metabolism-EMT positive feedback loop. In multiple CRC models, Curcumol markedly suppressed tumor growth and metastasis, supporting its therapeutic potential. This study reveals the ATG4B-PKM2 axis as a critical regulatory node linking autophagy, metabolic reprogramming, and EMT. Targeting this axis with Curcumol provides a precise strategy to interrupt metabolism-phenotype coupling, offering a mechanistically grounded and translationally promising approach for inhibiting CRC progression and metastasis. Show less

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis. Show less

The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined. To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models. Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 loss increased the intrinsic firing rate of AgRP neurons and abolished the suppressive effect of α-Klotho on their activity. At the molecular level, FGFR1 knockdown decreased phosphorylation of the transcription factor FOXO1 and elevated AgRP mRNA expression. Our results define a crucial FGFR1 signaling axis in AgRP neurons that coordinately regulates their electrical activity and peptide expression, thereby establishing FGFR1 as an essential regulator of energy homeostasis. Show less

Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We examined whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome for these patients. Ectopic expression of FGFR1N546K induced constitutive downstream signaling and IL-3-independent growth in Ba/F3 cells, indicating oncogene-addicted proliferation. In FGFR1N546K;MYCN transgenic mice, neuroblastoma developed within the first days of life, with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1-mutant, high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K-mutant neuroblastoma cells and inhibited tumor growth in FGFR1N546K;MYCN transgenic mice and in a chemotherapy-resistant, patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K-mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma associated with failure of current standard chemotherapy and suggest potential clinical benefit of FGFR-directed therapies in patients with high-risk mutant FGFR1. Show less

In the phase 3 CLEAR study, lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with clear cell renal cell carcinoma (ccRCC). Previous preclinical studies demonstrated that lenvatinib attenuated tumor-associated macrophage (TAM) infiltration into tumor tissues by inhibiting fibroblast growth factor receptor (FGFR). However, the role of the FGFR pathway in ccRCC remains underexplored. This study aims to evaluate FGFR1-4 expression in ccRCC and investigate its relationship with the tumor microenvironment, particularly TAM. We primarily analyzed FGFR1-4 expression and CD163 positive cell count as estimation of TAM infiltration in 57 ccRCC specimens from patients undergoing nephrectomy using immunohistochemistry. Transcriptomic analysis was performed to assess immune-related gene signature and gene expressions. FGFR1 expression was elevated in over 80% of ccRCC samples and was significantly associated with increased CD163-positive TAM infiltration. FGFR1 expression was also negatively correlated with the IMmotion150 Teff gene signature and the expression of interferon-γ signaling targeted genes such as IFNG, GZMB, and CD274, suggesting an immunosuppressive phenotype. In contrast, FGFR2 and FGFR4 expression were less prevalent, and FGFR3 expression was not detected. This study provides the first comprehensive evaluation of FGFR1-4 expression in ccRCC and suggests that FGFR1 expression may contribute to the immunosuppressive tumor microenvironment by recruiting TAM. These findings indicate that FGFR1 could serve as a potential biomarker for therapeutic strategies and highlight the need for further research to explore FGFR-targeted therapies in ccRCC. Show less

Uveal melanoma (UM), a rare yet aggressive ocular malignancy in adults, highlights the critical need for targeted therapies to improve clinical outcomes. Elevated FGFR1 expression in UM correlates with aggressive disease progression and poor survival outcomes, underscoring its therapeutic value. This study reports the development of [ Show less

Approximately 10% of breast cancer cases are hereditary and associated with germline BRCA1/2 mutations. To characterize the somatic alteration landscape and HRD-related genomic features, we analyzed next-generation sequencing and clinical data from 1,243 breast cancer patients treated at Tianjin Cancer Hospital Airport Hospital between October 2021 and November 2024. We compared mutation patterns and clinicopathological features between patients with and without germline BRCA (gBRCA) mutations and further assessed somatic alterations and homologous recombination deficiency (HRD) in those carrying pathogenic variants. PIK3CA mutations were significantly more frequent in the Non-Germline and non-gBRCA groups than in the Germline and gBRCA groups (49% vs. 6%; 47% vs. 0%; both P < 0.001), indicating mutual exclusivity with gBRCA mutations. Conversely, PTEN alterations co-occurred in 30% of gBRCA cases, while TP53 mutations were mutually exclusive with MDM2 and FGFR1. HER2 amplification was identified in 10% of gBRCA-mutated tumors, and somatic alterations in non-gBRCA tumors were enriched in endocrine-resistance pathways. HRD scores were markedly higher in gBRCA patients than in non-gBRCA patients (median 59 vs. 24.5, P = 0.015), driven by significant increases in large-scale state transitions (LST) and telomeric allelic imbalance (TAI). The overall gBRCA1/2 mutation frequency was 15.61%, and two previously unreported variants, BRCA1 NM₀₀₇₂₉₄.3:c.4185G>A and BRCA2 NM₀₀₀₀₅₉.3:c.439C>A, were identified in the Chinese population. These findings provide a biological rationale to explore AKT1/HER2-targeted combinations with PARP inhibition in future studies for gBRCA-mutated breast cancer and provide the first evidence of PIK3CA-gBRCA mutual exclusivity in Chinese patients. The elevated HRD scores further underscore the presence of homologous recombination deficiency in the gBRCA group. Show less

Microtia is a common feature of several human syndromes affecting the external ear (pinna), yet the cellular and molecular mechanisms remain poorly understood. Using human embryos and mouse models of branchio-oto-renal (BOR) and 22q11.2 deletion syndromes, we show that the syndromic genes Eya1 and Tbx1 are expressed in mesoderm-derived auricular muscle. In Eya1 mutant mice, auricular muscles failed to form and pinna morphogenesis was disrupted, with comparable defects observed in mesoderm-specific Tbx1 mutants. Both mutant pinnae exhibited impaired cartilage differentiation, suggesting that auricular muscle provides signals to the neural crest-derived mesenchyme to regulate cartilage differentiation. In contrast, defects in cartilage development alone or loss of muscle contraction did not affect early pinna morphogenesis. Auricular myocytes expressed Fgfs, while the surrounding mesenchyme expressed Fgfr1, Fgfr2 and ERM proteins. Disrupted Fgf signalling was observed in mutant cartilage and muscle. In ex vivo cultures, inhibition of Fgf or Bmp signalling recapitulated cartilage defects, whereas BMP4 restored Sox9 expression. These findings identify the mesoderm as essential for pinna initiation and morphogenesis, and reveal signalling mechanisms underlying microtia in BOR and 22q11.2 deletion syndromes. Show less

Aberrant fibroblast growth factor receptor 3 (FGFR3) activation drives bladder carcinogenesis in humans, but currently approved pan-FGFR inhibitors lack FGFR3 isoform selectivity and fail to counter clinically acquired resistance mutations (e.g., FGFR3 V555M/L). Herein, we report the structure-based drug design of 4-(1-methyl-1 Show less

To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline Show less

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and most often presents with an increase in the number of blasts in the peripheral blood and bone marrow. Although ALL typically presents with circulating blasts, atypical findings such as hypereosinophilia may obscure diagnosis and delay appropriate management. Severe eosinophilia in patients with ALL is a very rare phenomenon and is usually associated with specific genetic abnormalities or myeloid malignancies. The combination of severe eosinophilia, bicytopenia, and cardiac mass is unusual and challenging in diagnosis and treatment. A 4-year-old male patient, with no significant past or family history, presented to the emergency department with persistent fever. On initial examination, hepatosplenomegaly was evident. Blood tests showed WBC = 125,000cell per microliter, Hb = 8.7 g/dL, Plt = 77,000 per microliter, and severe eosinophilia (73.4%) absolute eosinophil count 91,250. A peripheral blood smear showed abundant mature eosinophils without blasts. Chest imaging showed bilateral pulmonary involvement, and ultrasonography showed bilateral pleural effusion. Echocardiography revealed a mass in the right ventricle suggestive of thrombus formation or infiltration, along with some degree of heart failure. Molecular tests for BCR-ABL, PDGFRα, PDGFRβ, FGFR1, and t (5:14) were negative, and bone marrow flow cytometry was also negative. Bone marrow biopsy with immunohistochemistry confirmed the diagnosis of Pre-B acute lymphoblastic leukemia with positive CD20 and TdT. The patient underwent protocol treatment and the MRD at the end of induction was reported to be 0.0011% and the biopsy was negative. The cardiac mass was also resolved during chemotherapy treatment. This case emphasizes the importance of noting unusual eosinophilia with bicytopenia, even in the absence of peripheral blasts, and the need for bone marrow biopsy and immunohistochemical examination for accurate diagnosis. Show less

Esophageal squamous cell carcinoma (ESCC) remains a major health burden, particularly in Asia, with poor patient prognosis despite advancements in radiotherapy, chemotherapy, and immunotherapy. The marked inter-patient and intra-tumor heterogeneity of ESCC underscores the need for molecularly informed diagnostic and therapeutic strategies. Recent high-throughput omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have substantially advanced our understanding of ESCC biology. Genomic profiling has revealed recurrent alterations such as TP53 and NOTCH1 mutations, as well as actionable targets including PIK3CA, FGFR1, and SOX2 amplifications, which provide new opportunities for precision therapy. Epigenomic and transcriptomic analyses have identified methylation-based early detection markers (e.g., PAX9, SIM2) and immune-related transcriptomic subtypes associated with prognosis and immunotherapy responsiveness. Proteomic and metabolomic studies have further uncovered cell cycle and spliceosome pathway activation and altered lactate metabolism, offering additional biomarker and therapeutic insights. In this review, we synthesize these multi-omics advances and highlight how they collectively inform improved diagnostic, prognostic, and therapeutic strategies for ESCC. Despite these developments, the clinical translation of multi-omics findings remains limited due to the lack of standardized analytical pipelines, insufficient multi-center validation, and the high cost and technical complexity of integrating multi-omics data into routine clinical workflows. Future research integrating artificial intelligence with multi-omics data holds promise for enhancing diagnostic accuracy and enabling more precise therapeutic decision-making in ESCC. Show less

ObjectiveColorectal cancer (CRC) patients with high microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) had heterogeneous pathology and distinct prognoses. This study aimed to examine the difference in the gene expression profile of dMMR/MSI-H CRC patients with different disease stages and explore the different molecular mechanisms of disease progression.MethodsA total of 47 patients with dMMR/MSI-H CRC were enrolled and retrospectively studied, including 27 stage II and 20 stage IV patients. Each patient had paired tumor tissue and white blood cell samples, which were analyzed by next-generation sequencing (NGS) of 416 cancer-relevant genes. Pathway enrichment analysis was then performed to analyze the disease stage-specific signaling pathways.ResultsA total of 2878 mutation sites, spanning 378 mutated genes, were detected from the 47 dMMR/MSI-H CRC patients. The mutation frequencies of SMARCA4, EPHA3, MTHFR, RAD50, and PDGFRB were significantly higher in stage II patients than in stage IV patients ( Show less

Sickle cell disease (SCD) is characterized by osteopenia and impaired bone mineralization, but the underlying mechanisms remain unclear. Fibroblast growth factor 23 (FGF23), elevated in SCD, regulates phosphate metabolism through FGFRs/klotho and contributes to bone loss. Although FGF23's systemic effects are known, its local actions in SCD bone remain poorly defined. Using bone marrow stromal cells (BMSCs) derived from SCD mice, we previously reported that enhanced local FGF23/FGFR1 signaling and increased osteopontin impair osteoblast mineralization, which is rescued by an FGF23-neutralizing antibody (FGF23Ab). Here, we further investigated downstream signaling and pyrophosphate/phosphate (PPi/Pi)-regulatory mechanisms contributing to mineralization defects. FGF23Ab reduced phospho-FGFR1, restored phospho-FGFR2 and phospho-AKT, and decreased pSTAT3 activation. SCD-BMSCs exhibited increased matrix inhibitors, matrix Gla protein (MGP) and matrix extracellular phosphoglycoprotein (MEPE), and reduced mineralization promoters PHEX and DMP1, which were partially normalized by FGF23Ab. FGF23Ab also corrected elevated PPi-generating enzymes ENPP1 and ANK and restored tissue-nonspecific alkaline phosphatase (TNAP). In contrast, the phosphate importer PiT2 was significantly reduced in SCD BMSCs and was further suppressed with FGF23Ab. These findings indicate that excessive local FGF23 signaling disrupts mineralization by upregulating matrix inhibitors and altering PPi/Pi-regulatory pathways. FGF23 neutralization partially restores mineralization capacity. Show less