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Age at first egg (AFE) has consistently garnered interest as a crucial reproductive indicator within poultry production. Previous studies have elucidated the involvement of the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-thyroid (HPT) axes in regulating poultry sexual maturity. Concurrently, there was evidence suggesting a potential co-regulatory relationship between these 2 axes. However, as of now, no comprehensive exploration of the key pathways and genes responsible for the crosstalk between the HPO and HPT axes in the regulation of AFE has been reported. In this study, we conducted a comparative analysis of morphological differences and performed transcriptomic analysis on the hypothalamus, pituitary, thyroid, and ovarian stroma between normal laying group (NG) and abnormal laying group (AG). Morphological results showed that the thyroid index difference (D-) value (thyroid index D-value=right thyroid index-left thyroid index) was significantly (P < 0.05) lower in the NG than in the AG, while the ovarian index was significantly (P < 0.01) higher in the NG than in the AG. Furthermore, between NG and AG, we identified 99, 415, 167, and 1182 differentially expressed genes (DEGs) in the hypothalamus, pituitary, thyroid, and ovarian stroma, respectively. Gene ontology (GO) analysis highlighted that DEGs from 4 tissues were predominantly enriched in the "biological processes" category. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that 16, 14, 3, and 26 KEGG pathways were significantly enriched (P < 0.05) in the hypothalamus, pituitary, thyroid, and ovarian stroma. The MAPK signaling pathway emerged as the sole enriched pathway across all 4 tissues. Employing an integrated analysis of the protein-protein interaction (PPI) network and correlation analysis, we found GREB1 emerged as a pivotal component within the HPO axis to regulate estrogen-related signaling in the HPT axis, meanwhile, the HPT axis influenced ovarian development by regulating thyroid hormone-related signaling mainly through OPN5. Then, 10 potential candidate genes were identified, namely IGF1, JUN, ERBB4, KDR, PGF, FGFR1, GREB1, OPN5, DIO3, and THRB. These findings establish a foundation for elucidating the physiological and genetic mechanisms by which the HPO and HPT axes co-regulate goose AFE. Show less

The fibroblast growth factor receptor (FGFR) signaling pathway plays important roles in cellular processes such as proliferation, differentiation, and migration. In this study, we highlighted the potential of FGFR inhibitors bearing the ( Show less

Breast cancer remains a significant global health challenge, necessitating the development of effective targeted therapies. This study aimed to create bispecific targeting molecules against HER2 and FGFR1, two receptors known to play crucial roles in breast cancer progression. By combining the high-affinity Affibody Z Show less

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a genetically and clinically diverse disorder encompassing Kallmann syndrome (KS) and normosmic CHH (nCHH). Although mutations in numerous genes account for nearly 50% of CHH cases, a significant portion remains genetically uncharacterized. While most mutations follow the traditional Mendelian inheritance patterns, evidence suggests oligogenic interactions between CHH genes, acting as modifier genes to explain variable expressivity and incomplete penetrance associated with certain mutations.In this study, the proband presented with nCHH, while his son exhibited KS. We employed whole-exome sequencing (WES) to investigate the genetic differences between the two, and Sanger sequencing was used to validate the results obtained from WES.Genetic analysis revealed that both the proband and his son harboured a mutation in Show less

Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction. Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification. Show less

Papillary thyroid carcinoma (PTC) is the most prevalent type of thyroid cancer and its incidence is rising globally. The molecular mechanisms of PTC progression remain unclear, hindering the development of effective treatments. This study focuses on hsa_circ₀₀₀₈₀₁₆ (circFGFR1), a circular RNA significantly up-regulated in PTC cells. Silencing circFGFR1 inhibited PTC cell proliferation and increased cell apoptosis, suggesting its role in PTC progression. The RNA-binding protein FUS was identified as a promoter of circFGFR1 formation. While circFGFR1 does not influence FGFR1 mRNA translation, it inhibits ubiquitination and degradation of FGFR1 protein, prolonging its half-life. CircFGFR1 also interacts with protein CBL, inhibiting CBL-mediated ubiquitination of FGFR1 proteins. Rescue assays confirmed circFGFR1 promotes PTC cell growth through mediating FGFR1. This study highlights the potential of circFGFR1 as a therapeutic target, offering insights into PTC's molecular mechanisms, and paving the way for novel treatment strategies. Show less

Anterior disc displacement (ADD) is a common clinical issue and may cause osteoarthritis (OA). However, the research of protein changes in synovial fluid as disease development marker and potential treatment clue is still insufficient. We conducted the high-resolution mass spectrometry (MS) of synovial fluid collected from 60 patients with normal disk position to ADD and ADD with osteoarthritis (OA). The proteins with significant changes among the 3 groups were analyzed by biological information and further validated by in primary rat condyle chondrocytes and OA animal model. FGL2, THBS4, TNC, FN1, OMD etc. were significantly increased in ADD without OA (p < 0.05), which reflected the active extracellular matrix and collagen metabolism. FGFR1, FBLN2, GRB2 etc. were significantly increased in ADD with OA group (p < 0.05), which revealed an association with apoptosis and ferroptosis. Proteins such as P4HB, CBLN4, FHL1, VIM continuously increase in the whole disease progress (p < 0.05). Both the in vitro and in vivo results are consistent with protein changes detected in MS profile. This study firstly provides the expression changes of proteins from normal disc condyle relationship toward ADD with OA, which can be selected and studied further as disease progress marker and potential treatment targets. Show less

Previously characterized as an oncogenic player in breast cancer, the function of circular RNA NINL (circNINL) in lung cancer (LC) remained elusive. This study aimed to delineate the biological role of circNINL in LC and to unveil its potential molecular mechanisms. We discovered elevated expression levels of circNINL and Fibroblast Growth Factor Receptor 1 (FGFR1) concomitant with diminished expression of microRNA-3918 (miR-3918) in LC specimens. Knockdown of circNINL led to a marked decrease in cell proliferation, migration, invasion, and aerobic glycolysis, alongside an upsurge in apoptosis in LC cells. Either downregulation of miR-3918 or overexpression of FGFR1 mitigated the suppressive impact of circNINL knockdown on LC pathogenesis. Mechanistic studies validated that circNINL served as a competitive endogenous RNA for miR-3918, thus influencing FGFR1 expression. Further, in vivo experiments using nude mouse xenograft models underscored that silencing circNINL substantially curtailed tumor growth in LC. Collectively, these findings illuminate that circNINL exacerbates LC malignancy via the miR-3918/FGFR1 axis, a process integrally linked with the activation of aerobic glycolysis. Show less

Fibroblast growth factor receptor 1 ( FGFR1 ) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l -1 , follicle-stimulating hormone (FSH) levels were 1.0 IU l -1 , and testosterone levels were 1.3 nmol l -1 . In contrast, the de novo group had LH levels of 0.2 IU l -1 , FSH levels of 0.5 IU l -1 , and testosterone levels of 0.9 nmol l -1 , indicating milder hypothalamus-pituitary-gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations. Show less

KDM6A (Lysine-Specific Demethylase 6A) is a specific demethylase for histone 3 lysine (K) 27 trimethylation (H3K27me3). The purpose of this study is to investigate whether KDM6A in renal tubule cells plays a role in the regulation of kidney function and blood pressure. We first crossed Notably, conditional knockout of This study provides the first evidence that KDM6A plays an essential role in maintaining normal tubular function and blood pressure. Renal tubule cell specific KDM6A deficiency causes hypertension due to increased H3K27me3 levels and the resultant downregulation of Show less

Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials. Show less

The association between obesity and some cardiovascular complications such as heart failure (HF) is well established, and drugs affecting adiposity are supposed to be promising treatments for these conditions. The sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antidiabetic drugs showing benefits in patients with HF, despite the underlying mechanisms have not been completely understood yet. SGLT2i are supposed to promote systemic effects, such as triglycerides mobilization, through the enhancement of fibroblast growth factor-21 (FGF-21) activity. So, in this study, we evaluated the effects of dapagliflozin treatment on FGF-21 and related receptors (FGF-Rs) gene expression and on lipid content in myocardial tissue in an animal model of genetically induced obesity to unravel possible metabolic mechanisms accounting for the cardioprotection of SGLT2i. Six-week-old C57BL/6J wild-type mice and B6.V-LEP (ob/ob) mice were randomly assigned to the control or treatment group (14 animals/group). Treatment was based on the administration of dapagliflozin 0.15 mg/kg/day for 4 weeks. The gene expression of FGF-21 and related receptors (FGF-R1, FGF-R3, FGF-R4, and β-klotho co-receptor) was assessed at baseline and after treatment by real-time PCR. Similarly, cardiac triglycerides concentration was measured in the control group and treated animals. At baseline, FGF-21 mRNA expression in the heart did not differ between lean and obese ob/ob mice. Dapagliflozin administration significantly increased heart FGF-21 gene expression, but only in ob/ob mice (p < 0.005). Consistently, when measuring the amount of triglycerides in the cardiac tissue, SGLT2i treatment reduced the lipid content in obese ob/ob mice, while no significant effects were observed in treated lean animals (p < 0.001). The overall expression of the FGF-21 receptors was only minimally affected by dapagliflozin treatment both in obese ob/ob mice and in lean controls. Dapagliflozin administration increases FGF-21gene expression and reduces triglyceride content in myocardial tissue of ob/ob mice, while no significant effect was observed in lean controls. These results might help understand the cardiometabolic effects of SGLT2i inducing increased FGF-21 synthesis while reducing lipid content in cardiomyocytes as a possible expression of the switch to different energy substrates. This mechanism could represent a potential target of SGLT2i in obesity-related heart diseases. Show less

Fibroblast growth factor receptor 2 (FGFR2) activation is associated with endocrine therapy resistance in luminal breast cancer (BC) An Two clusters of ER+ IDC tumours were identified based on the stromal gene expression profile. While both clusters had similar tumour stages and hormone receptor statuses, multivariable analysis adjusted for clinical factors revealed a significant association between Stromal profiles modulate the prognostic significance of Show less

MicroRNA-221-3p (miR-221-3p) facilitates the advancement of breast cancer (BC) through the induction of epithelial-mesenchymal transition (EMT). Our research aimed to utilize bioinformatics to discover possible EMT-related target genes (ETGs) of miR-221-3p and examine their roles in breast cancer. We employed bioinformatics techniques to identify ten key ETGs of miR-221-3p. Subsequently, we conducted an extensive analysis of both miR-221-3p and the ten ETGs, including clinical significance and immune characteristics. The expression of miR-221-3p was notably higher in Basal-like BC compared to other subtypes and adjacent normal tissue. Our pathway analysis suggested that miR-221-3p might regulate EMT through the MAPK signaling pathway by targeting its ETGs. Among the ETGs, seven core genes (EGFR, IGF1, KDR, FGF2, KIT, FGFR1, and FGF1) exhibited downregulation in BC. Conversely, ERBB2, SDC1, and MMP14 showed upregulation in BC and displayed potential diagnostic value. The analysis of prognostication indicated that increased levels of SDC1 and MMP14 were correlated with an unfavorable prognosis, whereas elevated expression of KIT was associated with a more favorable prognosis. The infiltration of various immune cells and the expression of immune checkpoint genes (ICGs) exhibited positive correlations with most ETGs and miR-221-3p. SDC1 exhibited a greater tumor mutational burden (TMB) score, while ERBB2, KDR, FGF2, KIT, FGFR1, and FGF1 showed lower TMB scores. Furthermore, decreased ERBB2 and KDR expression levels were correlated with elevated microsatellite instability (MSI) scores. Elevated expression of ETGs was linked to decreased mRNA stemness indices (mRNAsi), whereas miR-221-3p displayed the opposite pattern. Most ETGs and miR-221-3p expression exhibited a negative correlation with IC50 values for drugs. Among the ETGs, amplification was the most significant genetic alteration, except for IGF1. In conclusion, miR-221-3p acts as a unique indicator for Basal-like BC. The examination revealed ten essential ETGs of miR-221-3p, some of which show potential as diagnostic and prognostic markers. The in-depth examination of these ten ETGs and miR-221-3p indicates their participation in the development of BC, emphasizing their promise as innovative targets for therapy in BC patients. Show less

(Pro)renin receptor (PRR) is highly expressed in renal tubules, which is involved in physiological and pathological processes. However, the role of PRR, expressed in renal tubular epithelial cells, in diabetic kidney disease (DKD) remain largely unknown. In this study, kidney biopsies, urine samples, and public RNA-seq data from DKD patients were used to assess PRR expression and cell pyroptosis in tubular epithelial cells. The regulation of tubular epithelial cell pyroptosis by PRR was investigated by in situ renal injection of adeno-associated virus9 (AAV9)-shRNA into db/db mice, and knockdown or overexpression of PRR in HK-2 cells. To reveal the underlined mechanism, the interaction of PRR with potential binding proteins was explored by using BioGrid database. Furthermore, the direct binding of PRR to dipeptidyl peptidase 4 (DPP4), a pleiotropic serine peptidase which increases blood glucose by degrading incretins under diabetic conditions, was confirmed by co-immunoprecipitation assay and immunostaining. Higher expression of PRR was found in renal tubules and positively correlated with kidney injuries of DKD patients, in parallel with tubular epithelial cells pyroptosis. Knockdown of PRR in kidneys significantly blunted db/db mice to kidney injury by alleviating renal tubular epithelial cells pyroptosis and the resultant interstitial inflammation. Moreover, silencing of PRR blocked high glucose-induced HK-2 pyroptosis, whereas overexpression of PRR enhanced pyroptotic cell death of HK-2 cells. Mechanistically, PRR selectively bound to cysteine-enrich region of C-terminal of DPP4 and augmented the protein abundance of DPP4, leading to the downstream activation of JNK signaling and suppression of SIRT3 signaling and FGFR1 signaling, and then subsequently mediated pyroptotic cell death. This study identified the significant role of PRR in the pathogenesis of DKD; specifically, PRR promoted tubular epithelial cell pyroptosis via DPP4 mediated signaling, highlighting that PRR could be a promising therapeutic target in DKD. Show less

Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation. Show less

Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1R Show less

With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts. Show less

Survival of dormant, disseminated breast cancer cells contributes to tumor relapse and metastasis. Women with a body mass index greater than 35 have an increased risk of developing metastatic recurrence. Herein, we investigated the effect of diet-induced obesity (DIO) on primary tumor growth and metastatic progression using both metastatic and systemically dormant mouse models of breast cancer. This approach led to increased PT growth and pulmonary metastasis. We developed a novel protocol to induce obesity in Balb/c mice by combining dietary and hormonal interventions with a thermoneutral housing strategy. In contrast to standard housing conditions, ovariectomized Balb/c mice fed a high-fat diet under thermoneutral conditions became obese over a period of 10 weeks, resulting in a 250% gain in fat mass. Obese mice injected with the D2.OR model developed macroscopic pulmonary nodules compared with the dormant phenotype of these cells in mice fed a control diet. Analysis of the serum from obese Balb/c mice revealed increased levels of FGF2 as compared with lean mice. We demonstrate that serum from obese animals, exogenous FGF stimulation, or constitutive stimulation through autocrine and paracrine FGF2 is sufficient to break dormancy and drive pulmonary outgrowth. Blockade of FGFR signaling or specific depletion of FGFR1 prevented obesity-associated outgrowth of the D2.OR model. Overall, this study developed a novel DIO model that allowed for demonstration of FGF2:FGFR1 signaling as a key molecular mechanism connecting obesity to breakage of systemic tumor dormancy and metastatic progression. Show less

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, β-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E β-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 ( Show less

Germline pathogenic variants in checkpoint kinase 2 (CHEK2) are associated with a moderately increased risk of breast cancer (BC). The spectrum of clinicopathologic features and genetics of these tumors has not been fully established. We characterized the histopathologic and clinicopathologic features of 44 CHEK2-associated BCs from 35 women, and assessed responses to neoadjuvant chemotherapy. A subset of cases (n = 23) was additionally analyzed using targeted next-generation DNA sequencing (NGS). Most (94%, 33/35) patients were heterozygous carriers for germline CHEK2 variants, and 40% had the c.1100delC allele. Two patients were homozygous, and five had additional germline pathogenic variants in ATM (2), PALB2 (1), RAD50 (1), or MUTYH (1). CHEK2-associated BCs occurred in younger women (median age 45 years, range 25-75) and were often multifocal (20%) or bilateral (11%). Most (86%, 38/44) were invasive ductal carcinomas of no special type (IDC-NST). Almost all (95%, 41/43) BCs were ER + (79% ER + HER2-, 16% ER + HER2 + , 5% ER-HER2 +), and most (69%) were luminal B. Nottingham grade, proliferation index, and results of multiparametric molecular testing were heterogeneous. Biallelic CHEK2 alteration with loss of heterozygosity was identified in most BCs (57%, 13/23) by NGS. Additional recurrent alterations included GATA3 (26%), PIK3CA (226%), CCND1 (22%), FGFR1 (22%), ERBB2 (17%), ZNF703 (17%), TP53 (9%), and PPM1D (9%), among others. Responses to neoadjuvant chemotherapy were variable, but few patients (21%, 3/14) achieved pathologic complete response. Most patients (85%) were without evidence of disease at time of study (n = 34). Five patients (15%) developed distant metastasis, and one (3%) died (mean follow-up 50 months). Almost all CHEK2-associated BCs were ER + IDC-NST, with most classified as luminal B with or without HER2 overexpression. NGS supported the luminal-like phenotype and confirmed CHEK2 as an oncogenic driver in the majority of cases. Responses to neoadjuvant chemotherapy were variable but mostly incomplete. Show less

The human epidermal growth factor receptor 2 (HER2) negative luminal B1 subtype of breast cancer has been reported with a poorer outcome than luminal A in recent studies. This study aimed to investigate the molecular alterations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of luminal B1 breast cancer in Taiwan. We enrolled patients with luminal B1 breast cancer in our study. They were classified as patients who received curative surgery and adjuvant or neoadjuvant chemotherapy as the low-risk group, and who had advanced or metastatic disease or early relapse during the follow-up time as the high-risk group. Using targeted sequencing, we evaluated genomic alterations, interpreting variants with the ESMO Scale of clinical actionability of molecular targets (ESCAT). A total of 305 luminal B1 breast cancer patients underwent targeted sequencing analyses. The high-risk patients reported more actionable genes and called variants than the low-risk group (P < 0.05). PIK3CA (42%), FGFR1 (25%), and BRCA1/2 (10.5%) were the most prevalent ESCAT actionable alterations in luminal B1 breast cancer. There was no difference in the prevalence of actionable mutations between these two groups, except for ERBB2 oncogenic mutations, which were more prevalent among the high-risk than the low-risk group (P < 0.05). Alterations in PTEN, ERBB2, and BRCA1/2 were associated with disease relapse events in luminal B1 breast cancer. PIK3CA, FGFR1, and BRCA1/2 were the most prevalent actionable alterations among Taiwanese luminal B1 breast cancer. Moreover, PTEN and BRCA1/2 was significantly associated with disease relapse. Show less

Fibroblast growth factors (FGFs) and bone morphogenic proteins (BMPs) play various important roles in the development of the central nervous system. However, the roles of FGF and BMP signaling in the development of the olfactory bulb (OB) are largely unknown. In this study, we first showed the expression of FGF receptors (FGFRs) and BMP receptors (BMPRs) in OB RGCs, radial glial cells (RGCs) in the developing OB, which generate the OB projection neurons, mitral and tufted cells. When the FGF signaling was inhibited by a dominant-negative form of FGFR1 (dnFGFR1), OB RGCs accelerated their state transition to mitral cell precursors without affecting their transcription cascade and fate. However, the mitral cell precursors could not radially migrate to form the mitral cell layer (MCL). In addition, FGF signaling inhibition reduced the expression of a BMP antagonist, Noggin, in the developing OB. When BMP signaling was suppressed by the ectopic expression of Noggin or a dominant-negative form of BMPR1a (dnBMPR1a) in the developing OB, the defect in MCL formation caused by the dnFGFR1 was rescued. However, the dnBMPR1a did not rescue the accelerated state transition of OB RGCs. These results demonstrate that FGF signaling is important for OB RGCs to maintain their self-renewal state and MCL formation. Moreover, the suppression of BMP signaling is required for mitral cells to form the MCL. This study sheds new light on the roles of FGFs and BMPs in OB development. Show less

Oncogenic FGFR1/2/3 rearrangements are found in various cancers. Reported cases in head and neck (HN) are mainly squamous cell carcinomas (SCCs) with FGFR3::TACC3 fusions, a subset of which also harbour high-risk human papillomavirus (HPV). However, the knowledge of the clinicopathological spectrum of FGFR-rearranged head and neck carcinomas (FHNC) is limited. A retrospective MSK-fusion clinical sequencing cohort 2016-23 was searched to identify malignant tumours in the HN region harbouring FGFR1/2/3 fusion. FHNC were characterised by histological examination, immunohistochemistry and molecular analysis. Electronic medical records were reviewed. Three FHNC were identified. Two cases (cases 1 and 2) involved sinonasal tract and were high-grade carcinomas with squamous, basaloid, glandular and/or ductal-myoepithelial features. Case 1 arose in a 79-year-old man and harboured FGFR2::KIF1A fusion. Case 2 arose in a 58-year-old man, appeared as HPV-related multiphenotypic sinonasal carcinoma (HMSC), and was positive for FGFR2::TACC2 fusion and concurrent high-risk HPV, non-type 16/18. Case 3 was FGFR3::TACC3 fusion-positive keratinising SCCs arising in the parotid of a 60-year-old man. All three cases presented at stage T4. Clinical follow-up was available in two cases; case 1 remained disease-free for 41 months post-treatment and case 3 died of disease 2 months after the diagnosis. FHNC include a morphological spectrum of carcinomas with squamous features and may occur in different HN locations, such as parotid gland and the sinonasal tract. Sinonasal cases can harbour FGFR2 rearrangement with or without associated high-risk HPV. Timely recognition of FHNC could help select patients potentially amenable to targeted therapy with FGFR inhibitors. Further studies are needed (1) to determine if FGFR2 rearranged/HPV-positive sinonasal carcinomas are biologically distinct from HMSC, and (2) to elucidate the biological and clinical significance of FGFR2 rearrangement in the context of high-risk HPV. Show less

Only rare cases of acute myeloid leukemia (AML) have been shown to harbor a t(8;11)(p11.2;p15.4). This translocation is believed to involve the fusion of NSD3 or FGFR1 with NUP98; however, apart from targeted mRNA quantitative PCR analysis, no molecular approaches have been utilized to define the chimeric fusions present in these rare cases. Here we present the case of a 51-year-old female with AML with myelodysplastic-related morphologic changes, 13q deletion and t(8;11), where initial fluorescence in situ hybridization (FISH) assays were consistent with the presence of NUP98 and FGFR1 rearrangements, and suggestive of NUP98/FGFR1 fusion. Using a streamlined clinical whole-genome sequencing approach, we resolved the breakpoints of this translocation to intron 4 of NSD3 and intron 12 of NUP98, indicating NUP98/NSD3 rearrangement as the likely underlying aberration. Furthermore, our approach identified small variants in WT1 and STAG2, as well as an interstitial deletion on the short arm of chromosome 12, which were cryptic in G-banded chromosomes. NUP98 fusions in acute leukemia are predictive of poor prognosis. The associated fusion partner and the presence of co-occurring mutations, such as WT1, further refine this prognosis with potential clinical implications. Using a clinical whole-genome sequencing analysis, we resolved t(8;11) breakpoints to NSD3 and NUP98, ruling out the involvement of FGFR1 suggested by FISH while also identifying multiple chromosomal and sequence level aberrations. Show less

We report here about two novel tumours classified as extraventricular neurocytomas (EVN) using DNA-methylation profiling, associated with NTRK2 fusions instead of the usual FGFR1 alterations so far attributed to this tumoural entity. We present the second detailed case of an intraventricular presentation in the MC EVN. Our findings broaden the spectrum of MC EVN and have implications in terms of diagnosis, therapy and terminology. Show less