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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

Orthodontic treatment enables tooth movement through bone remodeling. The effects of fibroblast growth factor 2 (FGF2) on human periodontal ligament fibroblasts (HPdLFs) in response to mechanical stimulation that occurs during orthodontic treatment remain unexplained. We investigated the effects of FGF2 and mechanical stress on HPdLF differentiation, focusing on cementoblast differentiation. The effects of FGF2 and mechanical stress (applied for 24 hours using a centrifuge) on HPdLFs were evaluated. Changes in marker levels were assessed using real-time reverse transcriptase-polymerase chain reaction and western blotting. Furthermore, the effect of FGF2 treatment on HPdLF mineralization was assessed after 3 and 5 weeks using Alizarin red S staining (BMK-R009: Bio Future Technologies, Tokyo, Japan). Treatment of HPdLFs with 20 ng/mL FGF2 increased the expression of CEMP1 and RUNX2 but did not significantly alter the expression of FGF2, FGFR1, and FGFR2. In HPdLFs exposed to mechanical stress, expression of FGFR1 and OCN was increased, whereas that of FGF2, CEMP1, CAP, GLUT1, ALP, and OPN was reduced considerably. Treatment of mechanically-stressed HPdLFs with FGF2 did not change FGF2 expression, but expression of FGFR1, CEMP1, CAP, and GLUT1 increased significantly. In addition, FGFR1 was significantly upregulated at the protein level, whereas cementoblast differentiation markers showed an upward trend. Mineralization showed no changes at 3 weeks. However, at 5 weeks, considerable mineralization was observed in mechanically-stressed cells continuously exposed to FGF2. Mechanical stress increases FGFR1 expression in HPdLFs. FGF2 promotes the differentiation of mechanical-stressed HPdLFs into cementoblasts and their mineralization. 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

Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known to be involved in the disease pathomechanism. On the other hand, cleft lip/palate (CL/P) usually results from polygenic and environmental factors, with the complex interplay of both leading to this malformation. Pathogenic variants in We conducted targeted next-generation sequencing (NGS) in the proband with SHFM, followed by segregation analysis in the family members. In this study, we report an index patient presenting with isolated SHFM and his brother with CL and facial dysmorphism, as well as their father with isolated hyposmia. Targeted next-generation sequencing revealed a previously reported heterozygous missense pathogenic variant in This study expands the phenotypic spectrum associated with Show less

Parkinson's disease (PD), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca Show less

SH003, a novel herbal mixture consisting of NSCLC cell lines (A549, H460, HCC827) were treated with SH003 to evaluate cell viability (MTT assay), colony formation, apoptosis (Annexin V/7-AAD staining, western blot), and cell cycle distribution (PI staining). Phosphorylation of RTKs and related signaling molecules was analyzed using a phospho-RTK array and western blot. NSCLC cell lines A549, H460, and HCC827 treated with SH003 showed significant, dose-dependent cell viability and colony formation reductions. SH003 induced apoptosis, evidenced by increased cleaved PARP and caspase-8 levels, and caused G SH003 is a promising multi-target therapeutic agent for NSCLC, offering a novel strategy to improve patient 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

Hemangioblastoma is a highly vascularized, benign tumor in the central nervous system, frequently associated with von Hippel-Lindau (VHL) disease. Hemangioblastoma may cause tumor-associated hemorrhage or exert pressure on nearby structures, leading to life-threatening complications. Although surgical resection is the primary treatment, complete removal is not always feasible. Accordingly, there is a need to explore targeted or anti-angiogenic therapies. The fibroblast growth factor receptor (FGFR) family has roles in tumorigenesis and angiogenesis, making it a potential target in personalized therapy. The distribution and significance of FGFRs in hemangioblastoma have yet to be investigated. We examined 139 formalin-fixed, paraffin-embedded hemangioblastoma samples from 111 patients, including sporadic cases and those associated with VHL disease. Immunohistochemistry revealed positive staining for FGFR2 (95%) and FGFR4 (61%), while FGFR1 (0%) and FGFR3 (12%) were mainly negative. FGFR2 expression was significantly increased in VHL-mutated tumors (75%, p = 0.034) and in male patients (68%, p = 0.020). Tumors located in the cerebrum (n = 6, 5%) had a higher likelihood of positive FGFR4 staining (100%, p = 0.009). Additionally, a larger tumor diameter was associated with a higher likelihood of FGFR4 expression (median 12.0 mm vs 17.5 mm, p = 0.018), suggesting its contribution in tumor growth. Our study revealed the expression of FGFR2 and FGFR4 in a significant number of hemangioblastomas. This finding demonstrates the potential of FGFRs as promising therapeutic targets for patients with hemangioblastoma. 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

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

Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. 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

Pancreatic cancer is characterized by a poor prognosis and limited responsiveness to conventional therapies, presenting a substantial therapeutic challenge. Although chemotherapy remains the cornerstone of systemic treatment, options become scarce once frontline therapies fail. While targeted therapies and immunotherapies have emerged as potential alternatives, their efficacy in pancreatic cancer is not well established. As research advances, exploring the tumor immune microenvironment (TiME) of pancreatic cancer is crucial and holds significant potential for developing novel treatment strategies.We report a case of a pancreatic cancer patient who, after the failure of frontline and second-line treatments, was treated with a pioneering combination of targeted therapy and immunotherapy to modulate the unique TiME. The targeted agent, surufatinib, is a tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor 1 receptor (CSF-1R). The immunotherapy agent, toripalimab, is an immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1). Remarkably, the patient benefitted from this regimen, exhibiting stable disease, improved clinical symptoms, and prolonged progression-free survival. This case highlights the potential of personalized therapy in treating pancreatic cancer, particularly in patients with distinctive features of the TiME that may predict favorable responses to immunotherapy. Personalized strategies that consider the spatial structure and composition of the TiME may offer a promising avenue for achieving long-term progression-free survival in patients with pancreatic cancer. 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

Clinical trials have demonstrated Sodium-glucose cotransporter 2 inhibitors (SGLT2i) antihypertensive effects, yet their underlying mechanisms remain to be fully elucidated. Fibroblast growth factor 21 (FGF21) circulating levels are associated with hypertension in humans. This study aims to investigate the roles of SGLT2i and FGF21 in improving hypertension and their potential mechanisms. A mouse model of Ang II-induced hypertension was established. Wild-type (WT) C57BL/6 mice and FGF21 knockout (FGF21 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

Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its antibacterial properties remain unknown. Here, we demonstrated that DZB displays broad-spectrum activity against 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

Surufatinib is a novel, China-developed small-molecule tyrosine kinase inhibitor that demonstrates high selectivity for VEGFR, FGFR1, and CSF1R. Surufatinib has been approved for the treatment of neuroendcrine tumors, including pancreatic neuroendocrine tumors (PNEN) and non-pancreatic neuroendocrine tumors (N-pNEN). The purpose of this retrospective study is to assess Surufatinib's safety and effectiveness in patients with various advanced solid malignancies. The general clinical statistics and follow-up data of patients treated with Surufatinib for advanced solid tumors at Zhejiang Provincial People's Hospital between January 2021 and April 2024 were gathered. Enhanced CT was used to assess the effectiveness during that time, and cases side effects were gathered. Survival rates of different diseases were analyzed using the Kaplan-Meier method. A total of 28 eligible patients were enrolled in this study. At the end of follow-up, treatment with Surufatinib resulted in the following outcomes: Complete response (CR) in 0 cases (0.0%), Partial response (PR) in 5 cases (17.9%), Stable disease (SD) in 7 cases (25.0%), and Progressive disease (PD) in 16 cases (57.1%). Objective response rate (ORR) and Disease control rate (DCR) were 17.9% and 42.9%, respectively. In the PNEN group, ORR was 33.3%, DCR was 66.7%, median progression-free survival (mPFS) was 11 months, while median overall survival (mOS) was 17 months. In the N-pNEN group, ORR was 14.3%, DCR was 42.3%, mPFS was 6 months and mOS was 7 months. ORR was 8.3%, DCR was 25%, mPFS was 2 months, and mOS was 2 months. The most common adverse reactions included hypoproteinemia, proteinuria, bone marrow suppression and gastrointestinal toxicity, and which of them were grade 1 to grade 2. In advanced solid tumors beyond PNEN, Surufatinib demonstrates clinically meaningful survival benefits for patients refractory to standard therapies, with a generally manageable safety profile. 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

This study investigated the impact of alterations in six key genes ( Genomic data from five datasets were merged to identify 437 ESCC patients, categorized into altered ( The altered group exhibited a significantly higher tumor mutational burden (TMB) and mutation count than the unaltered group ( This study highlights that genomic alterations in these six genes are associated with poorer OS in ESCC, despite higher TMB potentially increasing tumor neo-antigens. These findings underscore the need for further research to explore their prognostic and therapeutic potential. Show less

Gastrointestinal malignancies account for 25% of all cancer cases and 35% of cancer-related mortality. Next-generation sequencing (NGS) can elucidate the genomic landscape of gastrointestinal cancers; tissue-based genotyping has traditionally been used, but liquid biopsy-based genotyping is a noninvasive alternative. Moreover, geographical variations in the genomic landscape of gastrointestinal cancers have not been fully elucidated. This retrospective study aimed to gain insight into the genomic landscape of patients with gastrointestinal cancers from the Asia and Middle East (AME) region using plasma-derived circulating tumor DNA (ctDNA). From routine clinical practice, 2,601 plasma samples were collected from 2,062 patients with gastrointestinal cancers in the AME region. NGS profiling was conducted using the Guardant360® assay. The frequency of biomarkers that can aid decision-making in cancer patients was investigated. Single-nucleotide variants affected most commonly TP53 (70.4%), KRAS (44.0%), APC (25.7%), ATM (15.1%), and PIK3CA (12.3%). Copy number alterations were most often observed in EGFR (13.7%), CCNE1 (5.9%), PIK3CA (5.0%), MYC (4.7%), and FGFR1 (4.6%); fusions were detected in 1.6% of patients and most frequently affected FGFR2, RET, ALK, FGFR3, and NTRK1/3. In patients with pancreatic adenocarcinoma, the most frequently observed clinically informative genomic biomarkers occurred in KRAS (G12C, 1.6%; all others, 67.1%), BRCA1/2 (4.1%), BRAF (V600X, 1.5%), and microsatellite instability-high (MSI-H) (1.0%). In patients with colorectal cancer, the most common clinically relevant alterations were KRAS (49.0%), BRAF (V600E, 7.6%), and NRAS (5.7%) mutations; ERBB2 amplifications (2.5%); and MSI-H (1.8%). In patients with biliary tract cancers, actionable alterations included IDH1 mutations (11.1%), ERBB2 amplifications (4.6%), FGFR2 fusions (2.0%), MSI-H (2.0%), and BRAF V600E (1.5%). In patients with gastric or gastroesophageal junction adenocarcinomas, actionable alterations included ERBB2 amplifications (10.1%) and MSI-H (3.6%). Our data provide insight into the genomic landscape of patients with gastrointestinal cancers from the AME region using ctDNA analysis. These findings highlight the potential utility of liquid biopsy as a noninvasive tool for characterizing tumor genomic profiles and support its role in clinical practice. 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

Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment. 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

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence and limited treatment options. To identify actionable therapeutic targets, we developed a patient-derived xenograft (PDX) model using a metastatic ASCC sample and performed single-cell RNA sequencing. Our analysis confirmed previously reported genetic mutations highly expressed in the sample, along with copy number alterations, and revealed epithelial cancer cell heterogeneity. Notably, epithelial cells exhibited a low hybrid epithelial-mesenchymal transition (hEMT) signature compared to stromal cells. Among epithelial subpopulations, the most abundant cluster displayed high expression of FGFR1-2 and FGF ligands. Treatment with AZD4547, an FGFR1-3 inhibitor, resulted in a significant reduction in tumor volume over time (p = 0.0036). Immunohistochemistry staining for proliferative Ki67 and cleaved caspase 3 suggested ongoing proliferation in residual cells. Fourier-transform infrared (FTIR) spectroscopy of post-treatment residual tumors revealed significant differences in the Amide I and Amide II regions between AZD4547-treated and control groups. These findings demonstrate that FGFR inhibition effectively attenuates ASCC tumor growth and highlights the promise of precision medicine in managing this rare cancer. Show less

Cholangiocarcinoma (CCA) is a diverse group of aggressive liver tumors with up to 20% being intrahepatic CCA (iCCA). Up to 15% of patients with iCCA have fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. Here we evaluated iCCA treatment with pemigatinib, a selective inhibitor of FGFR1-3, in two patients from Denmark and Finland. We identified a total of two Nordic patients with iCCA in our clinics, who received first-line cisplatin/gemcitabine before initiating pemigatinib. Case 1 was a 34-year-old woman with aggressive, metastatic iCCA upon presentation, who progressed on cisplatin/gemcitabine. Pemigatinib was initiated after FGFR2 fusion detection by genomic testing. She had a partial response after three cycles (9 weeks) of pemigatinib but experienced disease progression after three more pemigatinib cycles. Adverse events were primarily managed by supportive care and dose reduction, except hyperphosphatemia, which was complicated by food allergies and required medication. She received subsequent chemotherapy but deteriorated rapidly and died 1 month later. Case 2 was an 81-year-old man with unresectable iCCA who achieved stable disease with first-line chemotherapy. He switched to pemigatinib after FGFR2 fusion detection by next-generation sequencing. The tumor shrank by 20% after three pemigatinib cycles and completely calcified with continued treatment. Adverse events were managed by two dose adjustments. Treatment has continued for 57 months and is ongoing. CCA is an aggressive disease that requires early molecular testing of abundant biopsy tissue so not to delay second-line therapies, such as pemigatinib. Variability in treatment outcomes is expected. Show less