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Drug resistance severely hinders the clinical application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC). Notably, resistance caused by rare target mutations (with a mutation incidence rate below 5 %) accounts for approximately 15 % of total resistance cases in NSCLC. Due to the diversity and complexity of these mutations, targeted therapies against them are currently very limited. To address the challenge of multi-driver resistance in NSCLC, this study aimed to explore a novel therapeutic strategy that can simultaneously inhibit multiple resistance drivers and enhance drug resensitization to EGFR-TKIs, overcoming the limitations of conventional single-protein inhibitors. Established gefitinib-resistant HCC827 cell models driven by rare co-activation of two EGFR-independent membrane proteins. Developed a strategy targeting lipid raft cholesterol to destabilize raft integrity, leveraging the cholesterol-modulating properties of ginsenosides. Evaluated the synergistic effect of co-administering ginsenoside Rg3 with gefitinib in both in vitro and in vivo models. Explored the mechanism of Rg3 action, including its binding to lipid raft cholesterol, disruption of membrane anchoring of resistance-associated receptor tyrosine kinases, and acceleration of their endocytic degradation. Co-administration of ginsenoside Rg3 with gefitinib synergistically restored antitumor efficacy in both in vitro and in vivo models, outperforming conventional single-protein inhibitors. Mechanistically, Rg3 specifically binds to lipid raft cholesterol, disrupting the membrane anchoring of resistance-associated receptor tyrosine kinases (e.g., FGFR1 and VEGFR2) and accelerating their endocytic degradation. Structural-activity relationship analyses revealed that the cholesterol-binding capacity of ginsenosides-critical for resistance reversal-is modulated by the stereochemical configuration of sugar moieties at C3, C6, and C20 positions. This study elucidates a novel membrane-centric paradigm for overcoming multi-driver resistance in NSCLC, where pharmacological perturbation of cholesterol-lipid raft interactions by natural compounds like Rg3 enables broad-spectrum suppression of coexisting resistance mechanisms. It not only provides novel insights into the mechanisms underlying resistance in NSCLC but also presents a promising clinical strategy that could significantly improve treatment outcomes for patients. Show less

Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. 359 tumor samples from 346 patients with angiosarcoma were identified from the AACR Project GENIE v18.0-public database using cBioPortal. Somatic mutations and copy number alterations were assessed. Statistical significance was assessed by Recurrent mutations included In one of the largest genomic analyses of angiosarcoma to date, we identified recurrent alterations, suggesting potential future therapeutic targets. Show less

During the formation of hypertrophic scars (HS), there is often a notable abnormal proliferation and differentiation of cells, especially fibroblasts, but it remains ambiguous whether a causal relationship exists between fibroblast growth factor receptors (FGFRs) and hypertrophic scar. This study explored the causal impact of FGFR1, FGFR2, FGFR3, and FGFR4 on HS utilizing a two-sample Mendelian randomization (MR) analyses. The elevated expression of FGFR1 and FGFR 4 emerged as two potential risk factors against HS in the inverse-variance weighted analysis. Conversely, FGFR2 and FGFR3 exhibited no significant causal relationship with hypertrophic scars. Rigorous analyses including assessments of heterogeneity, genetic horizontal pleiotropy, and leave-one-out sensitivity collectively affirmed the stability and reliability of the findings in this study. Taken together, the elevated expression of FGFR1 and FGFR 4 act as two key regulatory factors in preventing the formation of HS and serves as a crucial modulator in impeding scar formation. Show less

The mitogen-activated protein kinase (MAPK) signaling pathway plays roles in cell proliferation, differentiation, and apoptosis, all crucial for cellular transformation. It's no surprise that MAPK alterations are prevalent in numerous tumors. Several critical genes in the MAPK signaling pathway, including Show less

Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Bronchial biopsy specimens were obtained from healthy subjects and patients with severe asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). A selective CDH11 antagonist SD133 (100 mg/kg) was given to allergen-exposed mice after airway challenge. The effects of recombinant CDH11 were also tested in vivo, and FGFR1 inhibition was used to explore a possible mechanism for CDH11-induced inflammatory responses in the lung. We detected upregulated expression of CDH11 in the airway mucosa of severe asthma patients when compared with the healthy control. In the OVA/CFA-induced model, though CDH11 expression in the lung remained unchanged, pharmacological antagonism of CDH11 with SD133 dramatically decreased airway neutrophil accumulation, as well as IL-6 production, but had no effect on eosinophilic infiltration, type 2 inflammation (IL-4 and IL-5) nor airway hyperresponsiveness. In the TDI model, pulmonary CDH11 expression was upregulated. Treatment with SD133 inhibited TDI-induced airway hyperresponsiveness and neutrophilic inflammation, decreased IL-6 and TNF-α production, with no effect on airway eosinophil counts and type 2 inflammatory cytokines. In addition, intratracheal instillation of recombinant CDH11 led to neutrophil recruitment in the lungs of mice, which could be attenuated by inhibition of FGFR1 signaling. CDH11 contributes to airway neutrophilic inflammation in severe asthma through the FGFR1 pathway. Show less

Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital neurocutaneous disorder characterized by ocular, skin, and central nervous system manifestations. Despite its recognizable clinical features, such as nevus psiloliparus, histopathologic characterization of ECCL remains limited in the dermatopathology literature, and diagnosis is often clinical. This scarcity of published histopathological descriptions makes diagnostic confirmation challenging and underscores the value of synthesizing the available evidence. This comprehensive review synthesizes reported histopathological findings across cutaneous manifestations highlighting key tissue-level features that may aid diagnostic confirmation. Additionally, we review the emerging role of molecular diagnostics, particularly the identification of mosaic activating mutations in Show less

8p11 myeloproliferative syndrome (EMS) is a rare aggressive hematologic malignancy with a poor prognosis that can rapidly develop into acute leukemia. It is characterized by the translocation of fibroblast growth factor receptor-1 (FGFR1), and there is still a lack of effective and reliable treatment methods at present. This report provides a new therapeutic strategy for EMS patients diagnosed with BCR-FGFR1 fusion. This report describes a case of EMS patient with a positive BCR-FGFR1 fusion gene, whose manifestations are similar to those of chronic myeloid leukemia (CML). After diagnosis by fluorescence in situ hybridization (FISH) and RNA sequencing (RNA-seq), olverembatinib, the third-generation tyrosinase inhibitor (TKI) developed in China, was used for treatment. After monotherapy and follow-up for more than one year, partial molecular response (PR) was achieved. During this period, hematologic remission and cytogenetic remission were achieved. The treatment safety of the entire process was excellent. In summary, olverembatinib provides more treatment options for rare diseases such as 8p11 myeloproliferative syndrome. Show less

Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2-) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT). Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the Kaplan‒Meier method. Differences were tested by the log-rank test. We identified 58 patients (including 16 with de novo stage IV disease). The median OS, PFS, and ToT in the total cohort were 26 (16, 37), 7 (5, 10), and 7 (5, 10) months (mos), respectively. No differences were observed between pre-menopausal patients and postmenopausal patients. The OS, PFS, and ToT rates at the initial diagnosis of Stage III later developing metastatic breast cancer (MBC, N = 42) and de novo IV (N = 16) patients were 19 (15, 34) vs 34 (21, NR), 7 (5, 14) vs 9 (6, NR), and 6 (5, 10) vs 9 (4, NR) mos, respectively (ns). OS, PFS, and ToT in patients receiving CDKI in the first-line vs second-line metastatic setting were 27 (19, 44) vs 17 (12, 39), 7 (5, 15) vs 6 (3, NR), and 7 (5, 15) vs 6 (3, 20) mos, respectively (ns). Among the patients initially diagnosed with stage III disease later progressing to MBC, brain metastases were observed in 12/42 patients. Thirty-eight patients underwent genomic testing either before CDKI treatment (N = 21) or at progression (N = 17). Among the 38 patients who underwent genomic testing, 34 had mutations, most commonly in TP53, PIK3CA, FGFR1, CCND1, and ARID1A. ESR1 mutations were present in 0% of the samples tested prior to CDKI treatment, and 29% of the samples tested at progression. Patients with metastatic HR+HER2- IBC demonstrated a shorter time on treatment suggesting shorter duration of response on CDKI + HT, which is markedly inferior to reported data for non-IBC patients from phase III trials. Show less

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH) Show less

Aging is an inevitable process integrating chronological alterations of multiple organs. A growing aging population necessitates feasible anti-aging strategies to deal with age-associated health problems. We previously performed a proteomics analysis in a healthy-aging cohort, and revealed an age-related downregulation of ARMH4. Here we generate a whole-body Armh4-knockout mouse line, and investigate its impact on systemic aging. Under normal feeding conditions, Armh4 deficiency significantly lowers spontaneous mortality and extends maximum lifespan. In the female mice, Armh4 deficiency postpones sexual maturity for one week. At the organ level, the age-related pathologies of the heart, liver, kidney, and spleen are substantially alleviated by Armh4 deletion. Mechanistically, ARMH4 interacts with IGF1R/FGFR1 to sensitize the activation of PI3K-Akt-mTORC1 and Ras-MEK-ERK pathways, consequently promoting protein synthesis and inhibiting autophagy. Moreover, ARMH4 is required for the maintenance of IGF1R/FGFR1 expressions through regulating the transcription factor c-Myc. Therefore, ARMH4 maintains a positive-feedback growth signaling to promote aging. Show less

The global obesity epidemic necessitates the identification of novel therapeutic targets. Although central administration of α-Klotho improves metabolic function in rodents, its precise mechanisms of action remain unclear. Since α-Klotho signals through fibroblast growth factor receptors (FGFRs), we hypothesized that FGFR1 within specific hypothalamic neuronal populations is critical for maintaining metabolic homeostasis. We investigated the metabolic role of FGFR1 in the arcuate nucleus of adult mice using an adeno-associated virus (AAV)-mediated CRISPR/Cas9 system, in conjunction with transgenic models, to achieve cell-type-specific knockout of FGFR1 in mature glutamatergic, gamma-aminobutyric acid (GABA)ergic, and agouti-related peptide (AgRP) neurons. We found that FGFR1 governs distinct metabolic functions in different neuronal populations. Conditional deletion of FGFR1 in glutamatergic neurons impaired glucose tolerance. In contrast, its ablation in GABAergic neurons induced a severe energy imbalance, resulting in obesity characterized by significant weight gain and adiposity. Notably, AgRP neuron-specific deletion of FGFR1 recapitulated this obese phenotype. Furthermore, the loss of FGFR1 in AgRP neurons disrupted α-Klotho signaling, preventing its ability to modulate AgRP neuron activity and abolishing its beneficial effects on glucose and energy metabolism. Our results establish FGFR1 in hypothalamic neurons as an essential component of the pathway through which α-Klotho regulates systemic energy balance. These findings identify hypothalamic FGFR1 as a critical molecular target for developing anti-obesity therapies. Show less

For decades, platinum chemotherapy was the mainstay of treating metastatic urothelial carcinoma (mUC). More recently, checkpoint inhibitors (CPI) were an important addition to the armamentarium capable of inducing durable responses for a minority of patients. Management of mUC has changed significantly with the advent of antibody-drug conjugate (ADC) therapies and fibroblast growth factor receptor inhibitors (FGFRi). Enfortumab vedotin, a Nectin-4 targeting ADC, is now the first line therapy of choice in combination with pembrolizumab. Erdafitinib, a pan FGFR1-4 inhibitor, is approved for patients with susceptible FGFR3 alterations. There are multiple other agents in development within both therapeutic classes that hold promise. But most patients will still succumb to their disease, either via primary or secondary resistance. This review looks critically at the approved and pipeline ADC and FGFR-targeting agents of interest in mUC as well as known mechanisms of resistance by which their efficacy is dampened. We propose strategies for overcoming resistance including combination strategies, tumor microenvironment modification, and drug structure modification to maximize efficacy. The progress to date in mUC has been remarkable, but there is still significant work to do in this deadly disease and this review highlights the gap between current available therapeutics and cure that so desperately needs to be closed. Show less

Undifferentiated pleomorphic sarcoma (UPS) is a diagnosis of exclusion; given limited effective treatments and marked heterogeneity, there is a need to identify therapeutic targets, a task facilitated by next-generation sequencing (NGS) in clinical practice. We report 2 STS pts with the diagnosis of UPS, G3 - each treated in a clinical trial (NCT03651374) with UNRESARC protocol consisting of neoadjuvant chemotherapy (CHT), radiotherapy, and surgical resection. Biopsy samples from each patient were subjected to NGS with the TruSight™ Oncology 500 assay (Illumina) and analysed in PierianDX (commercial software). 5 pathogenic alterations were identified: Case A: CCNE1 (6 copies) and MYC (3 copies) amplifications; Case B: CCND1 (3 copies), EGFR (3 copies) and FGFR1 (4 copies) amplifications. Amplifications of cell-cycle associated (CCNE1, CCND1) and apoptosis-related (MYC) genes contribute to uncontrolled proliferation and resistance to apoptosis, while amplifications in receptor tyrosine kinases (EGFR and FGFR1) activate pathways (RAS/MAPK and PI3K/AKT), involved in tumour growth and metastasis. In both patients, a poor pathological response, early local recurrence (LRFS of 9 months in both patients) and progressive disease (PD) when treated with first-line palliative CHT (PFS of 5 months in A and 4 months in B) were noted. All tumours demonstrated a low tumour mutation burden (TMB) (1.6-3.9 mut/Mb) and no microsatellite instability (MSI), explaining no sensitivity to immune checkpoint inhibitors. NGS assays may enable accurate diagnosis and identify predictive biomarkers and novel therapeutic targets - of particular importance in poor-prognosis entities such as UPS. Our report is consistent with the literature classifying UPS as malignancy with a high frequency of CNAs and low TBM. Show less

Recombinant growth factors, particularly fibroblast growth factor 2 (FGF2), are major cost drivers in the production of cultured meat. In this study, we investigated the potential of polyphenol salts to reduce reliance on FGF2 in media supporting the proliferation and mesodermal differentiation of bovine embryonic stem cell (bESC) aggregates. The activation potential of these salts was first verified using a luciferase reporter assay in COS-7 cells expressing human FGFR1. Several compounds, particularly Na-Quercetin, induced strong, dose-dependent FGFR1 activation with sub-nanomolar EC₅₀ values, comparable to FGF2. We then evaluated the use of three of the salts Sodium-Curcumin (NaCur), Potassium-Naringenin (K-Ng) and Sodium-Quercetin (Na-Q) on bESC aggregates. NaCur significantly enhanced aggregate growth under reduced FGF2 conditions, restoring proliferation to levels exceeding those observed with 20 ng/mL FGF2 alone. Additionally, NaCur supported mesodermal differentiation, as indicated by Brachyury expression, when combined with low-dose FGF2. K-Ng and Na-Q improved aggregate growth in the absence of FGF2 serum-free conditions but were insufficient to support mesodermal differentiation. These findings suggest that NaCur can reduce the required concentration of recombinant FGF2 while supporting both proliferation and differentiation, whereas K-Ng and Na-Q may be better suited for the early expansion phase. Our results highlight the potential of using polyphenol supplementation as a strategy to lower medium costs in cultured meat production systems. Show less

Fibroblast growth factor receptor 1 (FGFR1) is crucial in the progression of various cancers, participating in the processes of cell proliferation, survival, and differentiation. FGFR1 plays a role in the resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Therefore, using monoclonal antibodies and tyrosine kinase inhibitors to target FGFR1 and enhancing ICIs by modifying the tumor microenvironment and combating immune suppression represents a potential therapeutic strategy. Based on the FGFR1-related research and the active targeting strategy, we believe that modifying the surface of nanomedicines with anti-FGFR1 antibodies (such as OM-RCA-01) is an effective targeted treatment method for tumors with high expression of FGFR1. Although there have been relevant studies confirming the feasibility of this approach, there are challenges in clinical application, especially in terms of maintaining uniform quality during large-scale production. Therefore, we suggest conducting further optimization studies in the future to accelerate the clinical application of such drug delivery systems and provide more efficient and cost-effective options for tumor treatment. Show less

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Show less

Podocyte injury is central to diabetic kidney disease (DKD) pathogenesis, however, the mechanisms underlying podocyte loss remain unclear. Emerging evidence underscores the involvement of fibroblast growth factors (FGFs) in renal pathophysiology. Here we reveal a previously unappreciated role of podocyte-secreted FGF4 in safeguarding renal function. FGF4 expression is downregulated in renal tissues from DKD patients and animal models, correlating with disease severity. Podocyte-specific deletion of Fgf4 exacerbated podocyte loss and accelerated DKD progression in mice. Conversely, treatment with recombinant FGF4 (rFGF4) improved glomerular filtration and reduced renal injury and fibrosis in diabetic male mice. These effects are primary mediated by activating the FGFR1-AMPK-FOXO1 signaling cascade in podocytes, which mitigates oxidative stress, suppresses apoptosis, and fosters podocyte survival. Notably, rFGF4 also restores the morphology and function of human podocytes exposed to high glucose. Our findings establish FGF4 as a critical regulator of podocyte homeostasis and a potential therapeutic target for DKD. Show less

Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer with poor prognosis and limited response to conventional therapies. The fibroblast growth factor receptor 1 (FGFR1) has emerged as a pivotal molecular target among the oncogenic drivers of OSCC because of its critical role in tumor cell proliferation, migration, and chemoresistance. This research employed a comprehensive multi-tiered computational drug-discovery approach, integrating multi-class QSAR modeling, virtual screening, and molecular dynamics simulations, to identify novel small-molecule FGFR1 inhibitors with therapeutic potential for OSCC. The ChEMBL database was utilized to create a dataset of 3,222 distinct inhibitors, subsequently categorized into four bioactivity classes. Exploratory data analysis revealed that more potent compounds had a higher average molecular weight, an increased number of hydrogen bond acceptors, a higher count of rotatable bonds, and a higher. The ROS technique was employed on the training set to address the issue of dataset imbalance. We employed 10 distinct machine learning techniques to develop and assess multi-class QSAR models. These models explain how the chemical structures of substances connect to their biological functions mathematically. The Extra Trees (ET) classifier had the best performance, achieving a test set accuracy of 0.926 and MCC of 0.902. This made it the optimal model for our upcoming virtual screening. We employed the validated ET model to examine a repository of FDA-approved drugs and identified high-priority potential drugs. Molecular docking studies in the FGFR1 active site (PDB ID: 6MZW) followed by 200 ns molecular dynamics simulations demonstrated the stability of the top candidates. The study identified two significant lead compounds, CHEMBL155526361 and CHEMBL155529723, exhibiting robust binding affinities and strong interactions. This study provides a robust computational framework and remarkable molecular scaffolds for further preclinical investigation. This will expedite the search for innovative therapeutics for OSCC. The online version contains supplementary material available at 10.1186/s12885-025-15471-4. Show less

Methylation of CpG islands plays a crucial role in the regulation of gene expression. The study of DNA methylation profiles offers deep insights into key oncogenic processes and facilitates the differentiation of tumor entities at the epigenetic level. Methylation profiling was performed on 8 CNS tumors (6 children, 1 adolescent, 1 young adult) with inconclusive diagnoses, available frozen tissue, and surgeries dating back over 5 years. Our goal was to correlate the resulting methylation classes with the clinical-radiological data and to evaluate the diagnostic and prognostic power of this analysis. The resulting molecularly defined diagnoses were: pilocytic astrocytoma (3 cases), pilocytic astrocytoma subclass Show less

Based on the "gut-brain" axis, this study investigated the molecular mechanism of the antidepressant effect of Bupleuri Radix. The effect of Bupleuri Radix on human intestinal flora cultured in vitro was analyzed by 16S rRNA sequencing. Differential bacteria were identified by real-time quantitative PCR(qPCR). Short-chain fatty acid(SCFA) content was determined by the GC-FID method. A depression-like mouse model was established using the "triple-one" compound stress method. Mice were administered the aqueous extract of Bupleuri Radix by gavage, transplanted with Bacteroides acidifaciens or spore-forming bacteria, or gavaged with SCFAs. Behavioral changes were assessed. SCFA content in feces was measured by GC-FID. Hippocampal(fibroblast growth factor 21, FGF21) protein expression was detected by Western blot. The formation of fibroblast growth factor receptor 1-5-hydroxytryptamine receptor 1A(FGFR1-5-HT₍₁A)R) heterodimers was examined using the Duolink PLA method. The results showed that Bupleuri Radix significantly increased the abundance of the three spore-forming bacterial genera Ruminococcus, Dorea, and Blautia(P<0.05), as well as B. acidifaciens(P<0.001). Administration of Bupleuri Radix(P<0.001 or P<0.05) and transplantation of B. acidifaciens(P<0.01) both increased the levels of SCFAs such as acetic acid and butyric acid in bacterial metabolites. Treatment with Bupleuri Radix, transplantation of B. acidifaciens, or high doses of SCFAs significantly improved depression-like behaviors in mice, increased hippocampal FGF21 expression(P<0.05, P<0.01, or P<0.001), and promoted FGFR1-5-HT₍₁A)R heterodimer formation(P<0.05 or P<0.01), whereas transplantation of spore-forming bacteria showed no obvious antidepressant effect. In conclusion, the antidepressant effect of Bupleuri Radix is mediated by intestinal bacteria such as B. acidifaciens, which regulate the synthesis and metabolism of SCFAs, thereby modulating hippocampal FGF21 expression and activating FGFR1-5-HT₍₁A)R heterodimers. Show less

Phosphaturic mesenchymal tumor (PMT) is a rare bone or soft tissue tumor. It exhibits distinctive morphologic features, including bland spindled cells, highly vascularized stroma, "smudgy or grungy" calcified matrix, and osteoclast-like giant cells. It is characterized by paraneoplastic tumor-induced osteomalacia through producing phosphatonins, especially FGF23. Recent findings suggest that its tumorigenesis and FGF23 overproduction depend on the FGFR1 pathways, which may be activated via FN1::FGFR1 or FN1::FGF1 fusion, as well as by α-Klotho overexpression in the majority of fusion-negative PMTs. This review discusses the clinical, histologic, immunohistochemical, and molecular genetic features, along with potential therapies and differentiation from potential mimics. Show less

Molecular analysis of Each participating institution was requested to apply its own diagnostic testing strategy on 8 sections obtained from artificial reference specimens built to harbor Overall, cell resuspension yielded higher amounts of DNA and RNA (SNU16 61.5 ng/µl, 38100.0 pg/µl; RT112 118.0/µl, 2140.0 pg/µl, respectively) in comparison with SNU16+ RT112 mixing cell block (0.7 ng/µl DNA and 412.0 pg/µl RNA). Moreover, FFPE samples showed a higher fragmentation index (DIN 1.2 and RIN not calculated) compared with cell line resuspension (DIN 2.2 and 9.5 for SNU16 and RT112; RIN 3.9 and 6.8 for SNU16 and RT112). All participating institutions identified NGS represents the most suitable approach in molecular profiling of Show less

The molecular pathogenesis of hepatocellular carcinoma (HCC) exhibits striking etiological heterogeneity, with non-HCV-associated cases representing an increasingly prominent clinical challenge in regions like Egypt, where environmental carcinogens significantly contribute to the disease burden. Through integrated analysis of genomic data Egyptian cohort comprising 48 HCC cases (23 non-HCV, 25 HCV-positive) was examined and validated against TCGA/ICGC datasets using cBioPortal and Cytoscape. This study identifies a distinct oncogenic program in non-viral HCC characterized by recurrent alterations in receptor tyrosine kinases (RTKs) FGFR1, MET, ERBB2 and FLT3. These mutations were found to be 4.3-fold more prevalent in non-HCV HCC compared to viral counterparts (26.1% vs. 6.0%, p=0.008), demonstrating strong etiological specificity. Functional characterization revealed these alterations converge on MAPK and PI3K-AKT-mTOR signaling cascades through shared adaptor proteins, creating an interconnected signaling network that drives tumor progression. Clinically, FGFR1/MET co-alterations predicted significantly worse outcomes (HR=2.3 for recurrence, 95% CI 1.1-4.8), while maintaining 92% specificity for non-viral HCC diagnosis. These findings establish the FGFR1-MET-ERBB2 axis as both a molecular classifier and therapeutic target, providing a rationale for etiology-specific management strategies in HCC precision oncology. Show less

Osteoglophonic Dysplasia (OGD) is an autosomal dominant skeletal dysplasia characterized by impaired bone growth resulting in short stature, severe craniofacial abnormalities, and in some patients FGF23-mediated hypophosphatemia. It is caused by gain-of-function variants in FGFR1, particularly in or near the transmembrane domain of the receptor. We used CRISPR in mice to knock-in the FGFR1 p.N330I variant, chosen based on its association with FGF23 excess. Skeletal phenotyping of this Show less