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Xenopus embryo serves as an ideal model for teratogenesis assays to observe the effects of any compounds on the cellular processes crucial for early development and adult tissue homeostasis. In our screening of a chemical library with frog embryo, caffeic acid phenethyl ester (CAPE) was found to upregulate the FGF/MAPK pathway, disrupting germ layer formation in early development. Exposure to CAPE interfered with the formation of anterior-posterior body axis and of ectodermal derivatives such as eyes, dorsal fin and pigment cells. These inhibitory effects were achieved by promoting paraxial mesodermal specification and neural differentiation concomitant with a repression of epidermal and neural crest cell fates. This compound also induced the caudalization of anterior neural fate, thereby recapitulating the activity of the FGF/MAPK signals in the anterior-posterior patterning of neural tissue. Consistently, phosphorylation of extracellular signal-regulated kinase (ERK) was elevated in CAPE-treated cells, which was mediated by the FGFR1 and FGFR4 pathway. Together, these results suggest that CAPE functions as an activator of the FGF/MAPK signaling pathway, generating severe teratogenic effects on germ layer specification in vertebrate early development. Show less

Pheochromocytoma and paraganglioma (together PPGL) are tumours with a high degree of heritability. Genetic landscape is divided into three clusters, cluster 1 (Krebs/pseudohypoxia signalling pathway), cluster 2 (kinase signalling pathway) and cluster 3 (Wnt signalling pathway). With increasing knowledge in the field of genetics, cluster-specific tumour characteristics, biochemical phenotype and imaging signatures are established in commonly found genes. The association of FGFR1 pathogenic mutations with PPGL have been recently described although its features are not yet well established. Here, we present four patients with PPGL who were found to have somatic FGFR1 pathogenic mutations. We discuss their clinical presentations, biochemical phenotypes, imaging signatures and treatment options that will be relevant for practicing physicians in managing these patients effectively. Show less

Sciatica, often resulting from lumbar disc herniation or nerve compression, disrupts electrical signal transmission, leading to muscle atrophy, mitochondrial dysfunction, and impaired energy metabolism. This study explored the therapeutic effects of Fu's subcutaneous needling (FSN) in a chronic constriction injury (CCI) rat model, assessing its impact on neuropathic pain, muscle mass, and structural integrity. Histological and ultrastructural analyses demonstrated that FSN alleviated hypersensitivity, reduced muscle atrophy, preserved mitochondrial density, and maintained glycogen storage. Gene expression and pathway enrichment analyses revealed FSN's involvement in PI3K-Akt, MAPK signaling, oxidative phosphorylation, and mitophagy, suggesting its role in modulating energy metabolism and cellular repair. FSN also normalized energy-related proteins FGFR1, FGFR3 and phosphorylated FOXO3, highlighting their significance in muscle repair and regeneration. These findings provide novel insights into FSN's potential for counteracting neuropathy-induced muscle damage and improving mitochondrial function, supporting its clinical application. Additionally, FSN's role in muscle repair suggests a connection between growth factor signaling and nerve regeneration, offering a foundation for future research on muscle-neural recovery mechanisms. Show less

Brain death induces systemic inflammation and hemodynamic changes that can lead to lung injury, impacting the quality of donor organs for transplantation. Extracellular vesicles (EVs) are cell-derived nanoparticles that carry functional biomolecules and reflect the physiological state of their cells of origin. We hypothesized that EVs from brain-dead donors may indicate lung injury and may be used to predict primary graft dysfunction (PGD) in lung transplant recipients. We performed transcriptomic profiling of plasma EVs from 44 brain-dead lung donors and 9 healthy controls using next-generation sequencing. Differential gene expression was assessed, followed by pathway enrichment analyses. The results were validated by quantitative polymerase chain reaction using the study cohort and an independent cohort. Variable importance of projection score analysis and regression models were used to identify EV transcripts associated with PGD in recipients. Transcriptomic analysis revealed that 13% of protein-coding genes were differentially expressed in lung donor EVs compared with controls, with 92% of these genes upregulated. Upregulated genes were enriched in pathways related to inflammation, coagulation, tissue remodeling, and metabolism. Seven key EV transcripts, RAD51D, ABL2, FGFR1, WDR82, PTBP3, OPRL1, and XG were identified as potential PGD indicator. These transcripts were associated with processes such as DNA damage repair, signal transduction, and inflammation, which may contribute to posttransplant lung injury. Donor plasma EVs carry distinct transcriptomic signatures associated with injury and inflammation. Specific EV transcripts, such as RAD51D and XG, hold promise as independent predictive biomarkers for PGD, possibly providing new tools for evaluating donor organ quality and improving lung transplant outcomes. Show less

Basal cell carcinoma (BCC) is the most common skin cancer, predominantly affecting sun-exposed areas. It typically grows slowly and rarely metastasizes, though untreated cases can cause significant tissue destruction and morbidity. Its pathogenesis primarily involves dysregulation of the Hedgehog (HH) signaling pathway, mainly through mutations in Show less

"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field. Show less

Aberrant activation of fibroblast growth factor receptors (FGFRs) plays a critical role in tumorigenesis across multiple cancer types, driving the development of various FGFR inhibitors. Despite clinical advances, therapeutic efficacy remains limited by the emergence of drug resistance, primarily mediated by gatekeeper mutations in FGFRs. To overcome this challenge, we designed and synthesized a novel series of 7-(1-methyl-1 Show less

Pilocytic astrocytoma (PA) is the most common pediatric tumor, typically located in the cerebellum, with spontaneous regression observed mainly in patients with neurofibromatosis type 1 (NF1). However, spontaneous regression of PA without NF1 is rarely reported. Here, we describe a case of spontaneous regression of PA without NF1, located in the left frontal lobe with FGFR1-TACC1 fusion, in a 14-year-old boy who presented with epilepsy. Initial MRI revealed a lesion in the left middle frontal gyrus, and subsequent follow-up MRI demonstrated spontaneous regression. Despite this regression, the patient's seizures persisted, leading to epileptic focus resection. Pathological examination confirmed PA with characteristic histological findings and FGFR1-TACC1 fusion. This case suggests that FGFR1-TACC1 fusion may be linked to spontaneous regression of PA, even in the absence of NF1. Surgical intervention may remain necessary in cases of epilepsy associated with PA, regardless of tumor regression. Show less

Osimertinib (OSI) therapy, a cornerstone in treating non-small cell lung cancer (NSCLC), has been severely limited by rapidly developing acquired resistance. Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance. Biguanides, with excellent anti-tumor effects, have recently attracted much attention for this potential. The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored. A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI. Proteomics, co-immunoprecipitation mass spectrometry, RNA sequencing, and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy. NSCLC tumor tissues, especially OSI-resistant tissues, obtained from our clinic were used to assess the correlations between key proteins and OSI resistance. SMK-010, a highly potent biguanide compound, effectively overcame OSI resistance These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide, SMK-010, in combination with OSI. Show less

Fibroblast growth factor receptor 1 (FGFR1) is recognized as an oncogene that fosters tumor development, playing a vital role in cancer progression. This has established it as a promising target for cancer drug development. However, existing FGFR1 inhibitors are often limited by drug resistance and lack of specificity, emphasizing the need for more selective and potent alternatives. To address this challenge, the present study employed an AI-driven virtual screening approach, integrating molecular docking (MD) and molecular dynamics simulations (MDS) to discover novel FGFR1 inhibitors. A voting classifier integrating three machine learning classifiers was utilized to screen 10 million compounds from the eMolecules database, leading to 44 promising candidates with a prediction probability exceeding 80%. MD identified compound with PubChem Compound Identifier (CID) 165426608 (-10.8 kcal/mol) as the highest-scoring ligand, while compounds with CID 145940129 (-9.8 kcal/mol), CID 131910163 (-9.4 kcal/mol), CID 155915988 (-9.2 kcal/mol), and CID 132423733 (-9.1 kcal/mol), exhibited binding affinities comparable to or slightly lower than that of the native ligand (-10.4 kcal/mol). MDS further revealed that all these compounds, except CID 131910163, maintained structural stability with time. Thermodynamic stability assessment confirmed the spontaneity and feasibility of their complex formation reactions with negative ΔGBFE values ranging from -21.87 to -12.76 kcal/mol. Decomposition of binding free energy change further provided key stabilizing residues. The heatmaps and histograms of the interaction over the full 200 ns simulation period highlighted the prominent interaction profiles. Structural similarity analysis of the four MDS-stable compounds displayed the dice similarity scores of 0.200000 to 0.452830 with known FGFR1 inhibitors. Additionally, the pIC50 prediction using a voting regressor indicated promising pIC50 values (7.07 to 7.47), highlighting their potential as hit candidates for further structural optimization and therapeutic development. Further, this study underscores the efficiency of machine learning-based virtual screening and in silico analysis as a cost-effective and reliable strategy for accelerating hit drug discovery from large datasets, even with limited resources and time. Show less

Cardiac fibrosis drives dysfunction in dilated cardiomyopathy (DCM); yet, effective therapies are limited. This study identifies FGFR1 as a critical target in cardiac fibrosis using transcriptomic and histological analyses of 58 human DCM biopsies. FGFR1 expression correlated with fibrosis severity, and inhibition by AZD4547 reduced fibrosis and improved cardiac function in organoid and murine models. These findings validate FGFR1 inhibition as a promising therapeutic strategy for mitigating fibrosis and improving outcomes in heart failure associated with DCM. Show less

Mind bomb 1 (MIB1) is an E3 ubiquitin ligase that promotes the polyubiquitination-mediated degradation of NOTCH ligands and plays an important role in various cancers by enhancing tumor cell proliferation. Also, MIB1 inhibited the cell cycle progression by transcriptional repression of P21 in HCT116 cells. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that plays a significant role in the progression of various cancers. However, the regulatory mechanisms underlying FGFR1-associated signaling in colon cancer remain unclear. We investigated whether MIB1 regulates protein stability of FGFR1 and impairs cell proliferation in HCT116 cells. We conducted immunoprecipitation assay to identify correlation of MIB1 and FGFR1. We also tested mRNA level of FGFR1 in MIB1-depleted HCT116 cells using reverse transcription-quantitative polymerase chain reaction. Furthermore, we transfected HA-MIB1 and FLAG-FGFR1 and analyzed the downstream signaling cascades by western blotting. Cell viability was assessed using colony formation assays and MTT assay. FGFR1 interacts with MIB1 and controls FGFR1 protein level in HCT116 cells. Transcriptome analysis revealed that the mRNA levels of FGFR1 increased when MIB1 was depleted in HCT116 cells. Moreover, histone deacetylase 3 (HDAC3) is involved in histone deacetylation and transcriptional repression, mediating the interaction between MIB1 and FGFR1. These findings suggest the importance of MIB1-mediated transcriptional repression of FGFR1 and its potential therapeutic target in colon cancer. Show less

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and is increasingly diagnosed in younger populations. Conventional biopsy techniques can be invasive and may not accurately capture tumor heterogeneity. Liquid biopsy, analyzing circulating tumor DNA (ctDNA), offers a minimally invasive and dynamic alternative for detecting genetic alterations critical to early diagnosis and personalized treatment strategies. We analyzed serum-derived ctDNA from 20 HCC patients to identify genetic variants using next-generation sequencing (NGS). Mutations in key oncogenes and tumor suppressor genes (eg, KIT, FGFR1, FGFR3, EGFR, BRAF, FBXW7) were evaluated for their association with clinical outcomes, including tumor size, metastasis, and overall survival. Statistical analyses were performed using SPSS (v.30), with survival curves assessed via the Kaplan-Meier method. Of the 20 patients (mean age 64.8±13.1 years), 35% had detectable ctDNA mutations. The most frequently observed alterations were in KIT (28.6% of ctDNA-positive patients), followed by FGFR1, FGFR3, EGFR, BRAF, and FBXW7. Patients harboring FGFR1 and FGFR3 mutations exhibited the poorest survival (3 and 7 months, respectively). Conversely, one patient with a BRAF mutation showed prolonged survival (60 months), and KIT mutations were linked to comparatively better outcomes. Overall, ctDNA-positive patients demonstrated shorter mean survival (22.5 months) than ctDNA-negative patients (35.7 months). Liquid biopsy-detected genetic alterations correlate with clinical outcomes in HCC, underscoring the prognostic value of ctDNA analysis. Mutations in FGFR1 and FGFR3 were associated with aggressive disease, suggesting these pathways as potential therapeutic targets. Integrating liquid biopsy with other diagnostic modalities may enhance personalized management and improve prognosis for patients with HCC. Show less

Colorectal cancer (CRC) is the second most common cancer in men and third in females, a heterogeneous disease involving multistep mechanisms that represents 10% of all cancers globally. This study investigates gene mutation profiling in CRC using Next-Generation sequencing machine. Formalin-fixed paraffin-embedded tissues of 30 CRC patients were retrieved and reviewed. DNA was isolated from selected tissues. Desirable quality check using Qubit and Nanoquant machine was done, and desirable libraries prepared were loaded into the sequencer for sequencing. Using Illumina BaseSpace and Illumina Variant interpreter, generated FastQ data were treated for annotation, alignment, and mapping with reference genome. Sequencing-runs with Phred-score ≥ 30 were selected as desirable runs. Finally, the variants were validated on NCBI-dsSNP and Ensembl databases for clinical consequence interpretations. Overall, patient distribution consists of 12(40%) females and 18 (60%) males with mean age (53.2 + 5.3). most patients were in TNM stage-3: 53.3% (15/30) and the least was Stage-4: 20%(6/30) respectively. Overall, 73.3%: (22/30) completed the sequencing, and 552 mutations involving 29 genes and 12 chromosomes were detected. The most upregulated variants are KIT:68(12.3%), FGFR4:61(11.1%), EGFR:60(10.9%), ALK:53(9.6%), DCUN1D1:41(7.4%), PDGFR:40(7.2%), KRAS:33(6.0%), CDK4:27(4.9%), FGFR3:26(4.7%), MTOR:14(2.6), while NRAS, CDK6, PIK3CA, and RET each has 13(2.4%) apiece. Chromosomes 4:134/55(24.2%), chr7:84/552(15.2%), chr12:71/552(12.9%), chr5:64/552(11.6%), chr2:61/552(11.1%), chr3:54/552(9.8%), and chr1:43/552(7.8%) are the most involved chromosomes. Nine genes (APC, NRAS, ALK, PIK3CA, KRAS, IDH1, FGFR1, ERBB2, and ESR1) are identified as pathogenic-causing variants in CRC. This is the first NGS-based molecular study on FFPE-CRC tissues in hospital-USM that showed the most upregulated variants in CRC and identified nine genes as crucial pathogenic variants. Show less

Our previous studies have identified phoenixin-14 (PNX-14) and its receptor GPR173 in the porcine corpus luteum (CL) during the estrous cycle and their role in the endocrine function. This study explored PNX-14's impact on luteal angiogenesis, proliferation, and apoptosis. Luteal cells were cultured with PNX-14 at doses 1-1000 nM for 24-72 h. Then, the transcript level and secretion of angiogenic factors (VEGFA, bFGF2, ANG-1) and protein expression of their receptors (VEGFR1, VEGFR2, FGFR1, FGFR2, TIE2) were analysed. Cell proliferation was assessed using the alamarBlue assay, whereas DNA fragmentation and caspase 3/7 activity through Cell Death Detection ELISA and CaspaseGlo 3/7 assay, respectively. We also examined mRNA and protein levels of proliferating cell nuclear antigen (PCNA), cyclins, and apoptotic factors. Using pharmacological inhibitors of extracellular signal-regulated kinases 1/2 (ERK1/2), protein kinase B (AKT), 5'AMP-activated protein kinase (AMPK), and silencing of GPR173 by siRNA we checked their involvement in PNX-14 action in CL. The results showed that PNX-14 increased levels of bFGF2 and ANG-1, and protein expression of VEGFR2, FGFR1, and TIE2, while it decreased FGFR2. It enhanced luteal cell proliferation and PCNA expression, with variable effects on transcript and protein levels of cyclins. Moreover, PNX-14 decreased DNA fragmentation and caspase 3/7 activity, expression of caspases 3, 8, 9, and BAX, and increased BCL2. Additionally, GPR173 receptor and ERK1/2, AKT, and AMPK are involved in PNX-14 action on luteal function. In conclusion, PNX-14 acts as a luteotropic factor in the porcine CL by promoting angiogenesis, proliferation, and protection against apoptosis. Show less

Merkel cell carcinomas (MCCs) exhibit diverse molecular profiles, often categorized by their association with Merkel cell polyoma virus (MCPyV). MCPyV-associated MCCs typically display a low tumor mutational burden (TMB), lacking both somatic mutations and ultraviolet signature. By contrast, MCPyV-negative MCCs commonly arise in sun-exposed skin and frequently exhibit a high TMB, along with TERT promoter mutation (TPM) and somatic mutations, particularly in TP53 and RB1 . Gene fusions are exceedingly rare in MCCs, and their specific frequency and fusion transcripts remain largely unexplored. Here, we present a unique case of MCPyV-associated MCC characterized by NSD3::FGFR1 fusion, representing a novel fusion transcript not previously reported in MCCs. A 72-year-old White man presented with a cyst-like nodule on the left elbow, which had progressively increased in size over a span of 6 months. Excisional biopsy specimen revealed a neuroendocrine carcinoma diffusely expressing CK20 (perinuclear dot-like), synaptophysin, CD56, NSE, and MCPyV, consistent with MCC. Next-generation sequencing identified a NSD3::FGFR1 fusion without any additional somatic mutations, including TP53 and RB1 mutations, or TPM. Although NSD3::FGFR1 fusion has been sporadically reported in other solid tumors, such as pulmonary squamous cell carcinoma, its identification in an MCC is unprecedented to our knowledge. This novel finding not only underscores the uniqueness of our case but also contributes to the evolving understanding of the molecular landscape of MCCs, particularly MCPyV-associated MCCs. Show less

Tumor-induced osteomalacia (TIO) is a rare disorder caused by a phosphaturic mesenchymal tumor (PMT) secreting fibroblast growth factor 23 (FGF23). The aim of this study was to analyze PMTs for their transcriptomic characteristics. We performed single-cell RNA (n = 3) alongside bulk RNA sequencing of PMTs (n = 5) and surrounding bone tissue (n = 4) obtained during tumor removal in 10 patients (age 44 (41;64), serum phosphate (Pi)- 0.54 (0.43; 0.59) mM/L, FGF23-113 (40; 205) pg/ml). We revealed a total of 22,449 cells divided into 13 different categories. We identified the heterogeneity of the PMT cell cluster and subsequently divided it into two tumor clusters 1 and 2 characterized by the deeper epithelial-mesenchymal phenotype transition, higher FGF23 expression as well as various SNP and CNV. We further identified tumor cell differentiation driving regulons ERG and EGR3, based on scoring by allele expression and velocity based pseudotime on a trajectory that may play a critical role in the tumorigenesis of PMTs. In both single-cell and bulk transcriptome analysis we found upregulation of vesicle-specific and exocytosis associated genes (SLC30A3, SYT1, STX1A and SNAP25) which most likely represent molecular mechanisms of active secretion in all PMT samples. We report transmembrane protein coding genes expressed in all PMTs specifically in tumor cell clusters (PHEX, ERBB4, PCDH7, LRRFIP2) which are suggested as potential diagnostic targets. We confirmed the presence of FN1-FGFR1 fusion genes and Klotho expression in most PMTs (6 out of 8). Conclusion: specific SNARE proteins gene upregulation along with transcriptional signatures of PMT offer new insights into its pathogenesis which may be further studied for diagnostic and therapeutic interventions. Show less

Ameloblastic fibro-odontoma (AFO) is a rare benign mixed odontogenic tumor that, after being classified for years as a distinct entity, was redefined as a "developing odontoma" in the 2017 World Health Organization classification. This article presents a unique case of an AFO with an FGFR1 mutation. We present a case of an 8-year-old child with a slowly progressive swelling in the lower left mandible. Next-generation sequencing (TSO500 panel) was performed. Panoramic radiography revealed an odontogenic tumor; therefore, a transoral enucleation was performed. Pathological microscopic examination confirmed the diagnosis of AFO, and next-generation sequencing detected an FGFR1 mutation. The presence of an FGFR1 mutation in an AFO may suggest a closer biological relationship between ameloblastic fibroma and AFO, potentially distinguishing it from odontomas. Further research, including genetic studies, is needed to enhance our understanding and refine the classification of these tumors. Show less

The intramuscular fat (IMF) content, as an important meat quality trait, can directly affect the tenderness, juiciness, and flavor of pork. Reasonably increasing the IMF content can improve the palatability of pork. Therefore, identification of important factors for the lipid accumulation among muscles is the breakthrough point for improving meat quality. FGF21, identified as a novel metabolic regulator, has been found to regulate glucose and lipid metabolism in 3T3-L1 adipocytes, but its function in porcine adipocytes remains unclear. In this study, we discovered that the administration of recombinant FGF21 protein promotes adipogenic differentiation and increases triglyceride accumulation in porcine adipocytes. While the expression of FGFR1 in adipocytes under muscle conditions is inhibited, affecting the signal transduction of FGF21. This inhibitory effect is accompanied by activation of the AhR signaling pathway. When treated with the AhR antagonist CH223191, there was a partial restoration of FGFR1 expression levels. This indicates that muscle cells suppress the expression of FGFR1 in adipocytes by activating the AhR signaling pathway, thereby affecting the signal transduction of FGF21. Our results reveal the regulatory role of FGF21 in pig adipocyte differentiation and the regulatory mechanism of muscle environment on FGFR1 expression, providing new theoretical basis for IMF content improvement from the perspective of FGF21-FGFR1 signaling transduction. Show less

H3 K27-altered diffuse midline gliomas (DMGs) are a rare form of primary CNS tumors. In this retrospective single-center case study, DMGs were reviewed for clinical and imaging findings, surgical approaches and challenges, and molecular diagnosis. Four cases of adult DMG, H3 K27-altered, located among midline structures of the thalamus, brainstem, and spinal cord are presented here. All tumors exhibited heterogeneous presentations on imaging. Symptoms ranged from unspecific back pain and vertigo to focal neurological deficits. Surgery was complicated by high vascularization, infiltrative growth, and proximity to eloquent areas. Diagnostic accuracy was increased by epigenetic DNA methylation-based classification. Three cases were rapidly progressive and resulted in death within 1 year of diagnosis. One case had an exceptionally long overall survival of > 5 years, which was associated with a FGFR1 p.N546K hotspot mutation. DMGs are rare but imitate other pathologies due to variable clinical and radiological characteristics. Surgery is complicated by location and high vascularization. Although DMGs are rare, they should be considered as a differential diagnosis in intracranial and spinal masses in adults. As the FGFR1 p.N546K hotspot mutation is associated with prolonged survival, it may justify more radical surgery in eloquent regions. https://thejns.org/doi/10.3171/CASE25357. Show less

Cardiac ischemia/reperfusion (I/R) induces systemic oxidative stress, which in turn gives rise to the development of multiple organ abnormalities, including brain injury. The paraventricular nucleus (PVN) of the hypothalamus is a cardiovascular regulatory center. Aerobic exercise is an effective intervention to protect the heart against I/R injury. However, the effect of aerobic exercise on cardiac I/R-induced neuronal injury in the PVN has not been fully elucidated. The aim of this study is to investigate whether aerobic exercise can up-regulate fibroblast growth factor 21 (FGF21) and alleviate neuronal oxidative stress and ferroptosis in the PVN caused by cardiac I/R. In vivo, after six weeks of aerobic exercise, the cardiac I/R model was established by ligating the left anterior descending (LAD) coronary artery for 30 min, followed by 2 h of reperfusion. Cardiac function and heart rate variability (HRV) were measured. Morphological changes, oxidative stress, expression of FGF21 and its downstream signaling molecules, as well as ferroptosis-related indicators in the PVN, were evaluated. In vitro, HT22 cells were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) and treated with recombinant human FGF21 (rhFGF21) and compound C to elucidate the potential mechanism. Cardiac I/R induced iron deposition, elevated expression of lipid peroxidation drivers, and impaired antioxidant capacity in the PVN, which collectively contributed to neuronal ferroptosis. Aerobic exercise up-regulated the expression of FGF21, FGFR1, and PGC-1α, maintained the phosphorylation of AMPKα, enhanced antioxidant capacity, reduced ROS and lipid peroxidation, regulated iron homeostasis, and effectively attenuated neuronal ferroptosis induced by cardiac I/R. In addition, rhFGF21 protected HT22 cells against OGD/R-induced oxidative stress and ferroptosis, which was blocked by AMPK inhibition. FGF21 plays a pivotal role in regulating neuronal oxidative stress and ferroptosis. Aerobic exercise could increase the expression of FGF21, FGFR1, and PGC-1α, maintain the phosphorylation of AMPKα, and alleviate cardiac I/R-induced neuronal oxidative stress and ferroptosis. These results confirm the protective effect of aerobic exercise against cardiac I/R-induced brain injury and provide an experimental basis for studying the relationship between exercise and the "heart-brain axis." Show less

Fibroblast Growth Factor (FGF) ligands and their receptor have been identified as the potent target in non-small cell lung cancer (NSCLC). However, the clinicopathological and microenvironmental characteristics of FGF/FGFR in NSCLC remain poorly elucidated. Here, we summarize 4656 NSCLCs and analyze clinicopathological features in 478 FGF/FGFR altered cases. AI analysis and multiplex immunofluorescence staining are used to reveal microenvironment features. First, around 10.27% NSCLC carry FGF/FGFR variant. Squamous cell carcinoma (41.95%) is much more than adenocarcinoma (8.32%). In 118 pathogenic variant (PV) cases, the most frequent variant is FGF/FGFR copy number increase (83.05%), the second is FGFR gene fusion (11.86%). Surprisingly, CCND1 always co-amplifies with FGF19 (100.00%). Furthermore, FGF PV is an independent risk factor for poor outcomes (overall survival: HR = 3.781, disease-free survival: HR = 3.340). And one-third of FGFR3-TACC3 fusion cases show clear cytoplasm in histology. Either CCND1/FGF19 co-amplification or KRAS co-mutation is closely related to cigarette exposure, and KRAS co-mutation acts as an independent factor of poor prognosis. Finally, the FGF/FGFR1/NOTCH1 within RB1 variant group has a remarkably high ratio of inner-tumor CD8+ T cell infiltration, non-exhausted T cells, exhausted T Show less

The vomeronasal organ (VNO) is a specialized chemosensory structure in the nasal cavity that detects pheromones and mediates social and reproductive behaviors. The VNO of rodents is populated by different types of vomeronasal sensory neurons (VSNs). Apical VSNs, located near the lumen, express the transcription factor (TF) Meis2, V1R family receptors, and the G protein subunit Gao; the VSNs distributed closer to the basal lamina express the TF Tfap2e/AP-2ε, V2R receptors, and the G protein subunit Gai2. In addition, sparse cells in the VNO express the Formyl Peptide Receptors (FPRs). Single-cell mRNA sequencing (scRNA Seq) identified over 980 differentially expressed genes between these cell types, with many linked to the endoplasmic reticulum (ER). Among these ER proteins, Canopy1 (Cnpy1), was found to be among the most enriched genes in V2R+ VSNs. Previously studied only in zebrafish, Cnpy1 was found to affect Fgfr1 signaling and is thus also known as "FGF signaling regulator-1". In a previous study, we discovered that AP-2e upregulates Cnpy1 expression. Although Cnpy1 knockout mice are viable and have normal VNO development at birth, they experience a progressive degeneration and loss of V2R-expressing VSNs. Prior to symptoms, the basal VSNs of KO mice display reduced V2R protein immunoreactivity in the soma and a complete absence of the protein at the lumen of the VNO, rendering the neurons non-functional. Cnpy1 KOs exhibit altered guidance cues and adhesion molecule expression, along with disrupted connectivity to the accessory olfactory bulb (AOB). Our study shows that distinct neuronal types depend on unique ER protein repertoires to maintain proper proteostasis. The loss of Cnpy1 highlights the importance of cell-type-specific ER factors in the differentiation and function of specific neurons, revealing mechanisms that drive neuronal diversity and vulnerability to ER gene disruption. Show less

Advanced/metastatic urothelial cancer (a/m UC) still has a poor prognosis despite the recent medical advances. Recent studies demonstrated that fibroblast growth factor receptor (FGFR) gene alterations (GAs) may be driver genes for UC; however, the proportion of UC genetic panel testing in Japan remains low. We clarified the proportion of patients with FGFR2/3 GAs, treatment patterns, and clinical outcomes in a/m UC patients in Japan. This study was a descriptive epidemiological study using the MONSTAR-SCREEN database, and 138 patients with a/m UC were evaluated. The primary endpoint was the proportion of patients with FGFR2/3 GAs. The secondary endpoints included treatment patterns, clinical outcomes, genomic status before and after treatment, etc. The proportion of FGFR GA-positive patients in a/m UC was 11.9%. The most common FGFR mutation variant and fusion gene were S249C (4.4%) and FGFR3-TACC3 fusion (3.7%), respectively. Fifty-one patients were tested two or more times; a few changes were observed in the FGFR GA status, regardless of the treatment regimen. Co-occurrence association was observed in FGFR1 with TET2, and in FGFR3 with CHEK2 or MLL2. During the first-, second-, and third-line treatment, median progression-free survival (PFS) of GA-positive patients was 7.3, 2.9, and 6.2 months, while for GA-negative patients, 6.9, 3.1, and 6.9 months, respectively. This study revealed that one in eight a/m UC patients had FGFR2/3 GAs, and a few changes were observed in FGFR GA status before and after treatment. Genetic testing will be beneficial for the selection of appropriate treatments after a diagnosis of a/m UC. Show less

The development of cerebral infarction is multifactorial, including both environmental and genetic factors. This study assessed the association between fibroblast growth factor (FGF)-related gene polymorphisms and the incidence of cerebral infarction among patients on direct oral anticoagulants (DOACs). Patients over 18 years old with atrial fibrillation who were receiving DOACs for cerebral infarction prevention at Ewha Womans University Mokdong Hospital and Ewha Womans University Seoul Hospital were enrolled in this analysis. Twenty-one single nucleotide polymorphisms (SNPs) from FGF1, FGF2, and FGFR1 were examined. In multivariable logistic regression analysis, three models (Model I: demographic factors only, Model II: demographic factors and genetic factors, and Model III: genetic factors and the CHA Among the 536 candidate patients, 21 (3.9 %) experienced cerebral infarction while taking DOACs. From Model I and Model II, age ≥ 75 years and previous thromboembolic event history increased the risk of cerebral infarction. For genetic factors in Model II and III, FGF1 rs1596776 GG, FGFR1 rs6996321 AA, and FGFR1 rs7012413 TT genotypes were associated with a higher risk of cerebral infarction. The area under the receiver operating curve increased from 0.747 (Model I) to 0.822 (Model II) by adding genetic factors, demonstrating better model performance. This study uncovered the association between FGF-related gene polymorphisms and cerebral infarction among patients with atrial fibrillation undergoing DOAC therapy. Show less