Rosette-forming glioneuronal tumors (RGNTs) with FGFR1 tyrosine kinase domain internal tandem duplication (FGFR1 ITD) is exceedingly rare, with only a few cases reported in the literature. Hereby we present a case of a tumor with RGNT morphology occurring in area of septum pellucidum of 43-year-old male. The tumor showed FGFR1 ITD, no PIK3CA, PIK3R1 or NF1 alterations and inconclusive methylation profile with match for class of "low-grade glial/glioneuronal/neuroepithelial tumors". No areas characteristic of dysembryoplastic neuroepithelial tumor were identified. A brief review of literature on discrepancies between morphological diagnosis of RGNT and molecular profile of the entity is provided.

• MeSH
• Adult MeSH
• Humans MeSH
• Brain Neoplasms * pathology   genetics   MeSH
• Neoplasms, Neuroepithelial * pathology   genetics   MeSH
• Receptor, Fibroblast Growth Factor, Type 1 * genetics   MeSH
• Tandem Repeat Sequences MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

• MeSH
• Squamous Cell Carcinoma of Head and Neck virology   pathology   genetics   MeSH
• Adult MeSH
• Phenotype MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Papillomavirus Infections * pathology   complications   genetics   virology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Head and Neck Neoplasms * pathology   virology   genetics   MeSH
• Microtubule-Associated Proteins genetics   MeSH
• Receptor, Fibroblast Growth Factor, Type 3 * genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Carcinoma, Squamous Cell pathology   genetics   virology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues. In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.

• MeSH
• Cilia * metabolism   genetics   MeSH
• Epithelial Cells * metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Receptor, Fibroblast Growth Factor, Type 1 metabolism   genetics   MeSH
• Receptor, Fibroblast Growth Factor, Type 2 * metabolism   genetics   MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.

• MeSH
• Fibroblast Growth Factor 10 * metabolism   genetics   chemistry   MeSH
• Humans MeSH
• Mice MeSH
• Lung metabolism   embryology   MeSH
• Receptors, Fibroblast Growth Factor metabolism   MeSH
• Signal Transduction * MeSH
• Protein Stability MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Development of dentition is a commonly studied process as a representative of the development of ectodermal derivates. A key step is the formation of a signaling center called the enamel knot (EK), which organizes tooth crown formation. In the mouse lower jaw, the anterior part of the tooth-forming region undergoes a series of complex events before the first molar primary EK can form more posteriorly and the tooth can progress through the cap stage. Although much is known about the molecular factors involved in tooth development, disentangling their specific roles is difficult. In this study, we circumvented this problem by isolating the posterior part of the tooth-forming region at embryonic day 13.5 and cultivating it in vitro. By treating them with molecules activating or inhibiting Sonic hedgehog (Shh) and fibroblast growth factor (Fgf) pathways, we demonstrate that Shh plays the role of an inhibitor of EK formation, and we suggest that the FGF pathways may have both positive and negative roles, as seen in hair. By RNA-sequencing of the cultivated isolates after 0, 16, or 24 h in vitro, respectively, we screened for genes whose expression varies with EK and cap formation and pointed to Cdkn2b and Sema3b as 2 promising candidates in this process.

• MeSH
• Fibroblast Growth Factors physiology   MeSH
• Molar embryology   MeSH
• Mice MeSH
• Odontogenesis * physiology   genetics   MeSH
• Hedgehog Proteins physiology   metabolism   MeSH
• Signal Transduction MeSH
• Gene Expression Regulation, Developmental MeSH
• Tooth Crown * embryology   MeSH
• Dental Enamel * embryology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND & AIMS: Exogenous recombinant fibroblast growth factor 20 (FGF20) protein has been proved to treat ulcerative colitis; however, its mechanism of action remains unclear. This study aimed to explore the role and mechanism of action of FGF20 in ulcerative colitis. METHODS: Data from patients with ulcerative colitis were analyzed using the Gene Expression Omnibus dataset. A murine colitis model was established by administering 2% dextran sodium sulfate. FGF20 knockout mice and Adenoassociated viruses (AAV)-FGF20-treated mice were used to elucidate the specific mechanisms. Proteomic analysis was conducted to identify differentially expressed genes. RESULTS: FGF20 levels were significantly elevated in the colonic tissues of subjects and mice with colitis. FGF20 deficiency exacerbated dextran sodium sulfate-induced colitis; in contrast, FGF20 replenishment alleviated colitis through 2 principal mechanisms: restoration of impaired intestinal epithelial barrier integrity, and inhibition of M1 macrophage polarization. Notably, S100A9 was identified as a pivotal downstream target of FGF20, which was further demonstrated by pharmacologic inhibition and overexpression experiments of S100A9 using paquinimod (a specific inhibitor of S100A9) and AAV-S100A9 in FGF20 knockout and AAV-FGF20 mice with colitis, respectively. Additionally, the nuclear factor-κB pathway was found to be involved in the process by which FGF20 regulates S100A9 to counteract colitis. CONCLUSIONS: These results suggest that FGF20 acts as a negative regulator of S100A9 and nuclear factor-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with dextran sodium sulfate-induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis.

• MeSH
• Fibroblast Growth Factors * metabolism   genetics   pharmacology   MeSH
• Calgranulin B * metabolism   genetics   MeSH
• Colitis * chemically induced   MeSH
• Humans MeSH
• Macrophages * immunology   metabolism   drug effects   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• NF-kappa B * metabolism   MeSH
• Signal Transduction MeSH
• Dextran Sulfate toxicity   MeSH
• Intestinal Mucosa * pathology   metabolism   immunology   drug effects   MeSH
• Colitis, Ulcerative * pathology   chemically induced   immunology   metabolism   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The neuropeptide B/W signalling system (NPB/W) has been identified in multiple body regions and is integral to several physiological processes, including the regulation of food intake and energy homeostasis. Recently, it has also been detected in human skin; however, its specific functions in this context remain to be thoroughly investigated. This study aims to identify the expression of neuropeptides B/W receptor 1 (NPBWR1) and neuropeptides B/W receptor 2 (NPBWR2) in human dermal fibroblasts of mesenchymal origin using genomic and proteomic techniques. We will also investigate the role of these receptors in cell proliferation and calcium signalling. METHODS: The mRNAs for NPBWR1 and NPBWR2 were detected using quantitative PCR (qPCR) analysis and further validated by western blot and immunofluorescence analyses. Additionally, we synthesised ligands for these receptors, specifically hNPB (25-53) and hNPW (33-62), to investigate their effects on cell proliferation and intracellular calcium levels in human fibroblasts. RESULTS: Our results demonstrated that hNPW (33-62) has anti-proliferative effect on human dermal fibroblasts and concentration of 0.1-μmol/L can significantly decrease intracellular calcium levels (p < 0.05). CONCLUSION: This finding suggests a potential role for the NPB/W signalling system in pathologies associated with impaired calcium handling, such as fibrosis. Furthermore, we observed that the proliferation of human fibroblasts was not affected by hNPB (25-53). Our findings could lead to the development of new therapeutic strategies for various skin conditions and improved wound healing.

• MeSH
• Fibroblasts * metabolism   MeSH
• Cells, Cultured MeSH
• Skin * metabolism   cytology   MeSH
• Humans MeSH
• Neuropeptides metabolism   genetics   MeSH
• Cell Proliferation * MeSH
• Receptors, Neuropeptide metabolism   genetics   MeSH
• Signal Transduction MeSH
• Calcium * metabolism   MeSH
• Calcium Signaling MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

PURPOSE: Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) protein overexpression is an emerging biomarker in gastric cancer and gastroesophageal junction cancer (GC). We assessed FGFR2b protein overexpression prevalence in nearly 3,800 tumor samples as part of the prescreening process for a global phase III study in patients with newly diagnosed advanced or metastatic GC. METHODS: As of June 28, 2024, 3,782 tumor samples from prescreened patients from 37 countries for the phase III FORTITUDE-101 trial (ClinicalTrials.gov identifier: NCT05052801) were centrally tested for FGFR2b protein overexpression by immunohistochemistry (IHC) and had evaluable results. FGFR2b positivity was defined as both any % tumor cells (TC) and ≥10% TC exhibiting moderate-to-strong (2+/3+) membranous FGFR2b staining. Prevalence was analyzed across patient and sample characteristics. RESULTS: FGFR2b protein overexpression at any % and ≥10%, 2+/3+ TC positivity was 37.8% (1,428/3,782 [95% CI, 36.2 to 39.3]) and 16.2% (612/3,782 [95% CI, 15 to 17.4]), respectively. Of any %, 2+/3+ TC-positive tumors, 42.9% (612/1,428 [95% CI, 40.3 to 45.4]) were FGFR2b ≥10%, 2+/3+ TC positive. FGFR2b prevalence was not notably different within multiple patient and sample characteristics examined (age, sex, collection method [biopsy v resection], collection site, location of primary tumor, and geographic region). CONCLUSION: As of the data cutoff date, we report the largest prevalence assessment of FGFR2b protein overexpression in GC with more than one third (37.8%) of patients with GC exhibiting FGFR2b protein overexpression (any % TC, 2+/3+) by a validated IHC assay. Approximately 16% of patients had FGFR2b protein overexpression in ≥10% of TC. FGFR2b prevalence was similar across geographic regions and within defined patient and sample variables regardless of the level of expression.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Stomach Neoplasms * pathology   metabolism   MeSH
• Prevalence MeSH
• Receptor, Fibroblast Growth Factor, Type 2 * metabolism   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH

Pulmonary hypertension is a complex and heterogeneous condition with five main subtypes (groups). This review focuses on pulmonary hypertension caused by chronic hypoxia (hypoxic pulmonary hypertension, HPH, group 3). It is based mainly on our own experimental work, especially our collaboration with the group of Professor Herget, whose fifth anniversary of death we commemorate. We have found that oxidation and degradation of the extracellular matrix (ECM) in vitro, in either the presence or the absence of pro-inflammatory cells, activate vascular smooth muscle cell (VSMC) proliferation. Significant changes in the ECM of pulmonary arteries also occurred in vivo in hypoxic rats, namely a decrease in collagen VI and an increase in matrix metalloproteinase 9 (MMP-9) in the tunica media, which may also contribute to the growth activation of VSMCs. The proliferation of VSMCs was also enhanced in their co-culture with macrophages, most likely due to the paracrine production of growth factors in these cells. However, hypoxia itself has a dual effect: on the one hand, it can activate VSMC proliferation and hyperplasia, but on the other hand, it can also induce VSMC hypertrophy and increased expression of contractile markers in these cells. The influence of hypoxia-inducible factors, microRNAs and galectin-3 in the initiation and development of HPH, and the role of cell types other than VSMCs (endothelial cells, adventitial fibroblasts) are also discussed. Keywords: Vasoconstriction, Remodeling, Oxidation, Degradation, Extracellular matrix, Collagen, Proteolytic enzymes, Metalloproteinases, Macrophages, Mast cells, Smooth muscle cells, Endothelial cells, Fibroblasts, Mesenchymal stem cells, Hypoxia-inducible factor, microRNA, Galectins, Hyperplasia, Hypertrophy, Therapy of hypoxic pulmonary hypertension.

• MeSH
• Hypoxia * metabolism   MeSH
• Humans MeSH
• Myocytes, Smooth Muscle * metabolism   pathology   MeSH
• Hypertension, Pulmonary * metabolism   pathology   MeSH
• Cell Proliferation MeSH
• Muscle, Smooth, Vascular * metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Wound healing represents a complex and evolutionarily conserved process across vertebrates, encompassing a series of life-rescuing events. The healing process runs in three main phases: inflammation, proliferation, and maturation/remodelling. While acute inflammation is indispensable for cleansing the wound, removing infection, and eliminating dead tissue characterised by the prevalence of neutrophils, the proliferation phase is characterised by transition into the inflammatory cell profile, shifting towards the prevalence of macrophages. The proliferation phase involves development of granulation tissue, comprising fibroblasts, activated myofibroblasts, and inflammatory and endothelial cells. Communication among these cellular components occurs through intercellular contacts, extracellular matrix secretion, as well as paracrine production of bioactive factors and proteolytic enzymes. The proliferation phase of healing is intricately regulated by inflammation, particularly interleukin-6. Prolonged inflammation results in dysregulations during the granulation tissue formation and may lead to the development of chronic wounds or hypertrophic/keloid scars. Notably, pathological processes such as autoimmune chronic inflammation, organ fibrosis, the tumour microenvironment, and impaired repair following viral infections notably share morphological and functional similarities with granulation tissue. Consequently, wound healing emerges as a prototype for understanding these diverse pathological processes. The prospect of gaining a comprehensive understanding of wound healing holds the potential to furnish fundamental insights into modulation of the intricate dialogue between cancer cells and non-cancer cells within the cancer ecosystem. This knowledge may pave the way for innovative approaches to cancer diagnostics, disease monitoring, and anticancer therapy.

• MeSH
• Autoimmunity * MeSH
• Wound Healing * immunology   MeSH
• Interleukin-6 * metabolism   immunology   MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   MeSH
• Neoplasms * immunology   metabolism   pathology   MeSH
• Aging * immunology   MeSH
• Inflammation * immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH