👤 A Mari

Fibroblast growth factor (FGF) signaling plays an important role in the pathogenesis of various respiratory diseases, including idiopathic pulmonary fibrosis (IPF). FGF ligands can exert both pro- and anti-fibrotic effects, depending on the responding cell, the expression levels of FGF receptors (FGFR1-4) and the context of other signaling molecules such as Transforming growth factor β (TGF-β). We evaluated here the effect of a modified version of a soluble FGFR3 decoy receptor (designated as "sFGFR3-Fc"), that specifically sequesters pro-fibrotic FGFR3 ligands, FGF1, FGF2 and FGF9 as a potential anti-fibrotic drug. We showed that FGF2 stimulated proliferation and expression of various fibrotic markers in human pulmonary fibroblasts from healthy donors and IPF patients. The sFGFR3-Fc was able to reduce these FGF2-mediated responses and also partially attenuate the pro-fibrotic phenotype induced by TGF-β, including gel contraction. Furthermore, single cell transcriptomic analyses revealed heterogeneity of IPF-derived fibroblasts for FGF2 response and confirmed the potential efficacy of sFGFR3-Fc in decreasing the expression of a subset of TGF-β1 pathway genes. Finally, sFGFR3-Fc was shown to improve the progression of pulmonary fibrosis using both a preventive and therapeutic strategy, evaluated in the standard single bleomycin (BLM) instillation mouse model as well as in a more severe model of repeated BLM instillations, as evidenced by the reduction in ECM deposits, the recovery of body weight and the restoration of lung function. Our data highlight the interplay between the TGF-β and the FGF signaling pathways and demonstrate the potential of targeting pro-fibrotic FGFR3 ligands as therapeutic strategy for IPF. Show less

To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). Bayesian network analyses and complementary two-sample Mendelian randomization were used to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with liver fat in the IMI-DIRECT prospective cohort study. Data included frequently sampled metabolic challenge tests, MRI-derived abdominal and hepatic fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults without diabetes, with harmonized protocols enabling replication. High basal insulin secretion rate (BasalISR), estimated via C-peptide deconvolution, emerged as the primary potential causal driver of liver fat accumulation in both cohorts. BasalISR, a clearance-independent measure of β-cell insulin output distinct from peripheral insulin levels, was independently linked to hepatic steatosis. Visceral adipose tissue exhibited bidirectional associations with liver fat, suggesting a self-reinforcing metabolic loop. Of 446 analyzed proteins, 34 mapped to these metabolic networks (27 in the non-diabetes network, 18 in the T2D network, and 11 shared). Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses identified GUSB in females and LEP in males as the strongest protein predictors of liver fat. BasalISR may better capture early β-cell-driven disturbances contributing to MASLD. These findings outline a multifactorial, sex- and disease stage-specific proteo-metabolic architecture of hepatic steatosis and identify potential biomarkers or therapeutic targets. Show less

FGFR3 mutations are among the most frequent genomic alterations in urothelial cancer (UC) being mainly associated with the luminal papillary (LumP) subtype. With the establishment of fibroblast growth factor receptor (FGFR) inhibitors, the treatment of UC is now shifting more and more towards personalized medicine. A systematic review using Medline and scientific meeting records was carried out according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines to assess the potential role of FGFR inhibitors in combination with additional therapies for the management of UC. Ongoing trials were identified via a systematic search on ClinicalTrials.gov. A total of eleven full-text papers, ten congress abstracts, and 5 trials on ClinicalTrials.gov were identified. Following the BLC2001 and THOR study, erdafitinib is the only approved FGFR1-4 inhibitor for metastatic UC with susceptible FGFR2/3 alterations following platinum-based chemotherapy. According to the THOR data of cohort 2, erdafitinib should not be recommended in patients who are eligible for and have not received prior immune checkpoint inhibitors (ICIs). One phase 3 trial is currently evaluating the intravesical device system (TAR210) in FGFR-altered intermediate non-muscle invasive bladder cancer (MoonRISe-1). Preclinical evidence suggests that combination-based approaches could be considered to improve the efficacy of FGFR inhibitors in patients with UC. Nine phase 1b/2 trials are focusing on the combination of FGFR inhibitors with ICIs, chemotherapy, or enfortumab vedotin. In metastatic disease, some preliminary analyses have reported promising results from these combinations (e.g. NORSE and FORT-2 trial). However, no phase 3 trial is terminated, so there is currently no level 1 evidence with long-term outcomes to support the combination of FGFR inhibitors with ICIs, chemotherapy, or targeted therapies. A better understanding of the different mechanisms of action to inhibit FGFR signaling pathways, optimal patient selection and treatment approaches is still needed. Show less

To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). We used Bayesian network analyses to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with fatty liver using data from the IMI-DIRECT prospective cohort study. Measurements were made of glucose and insulin dynamics (using frequently-sampled metabolic challenge tests), MRI-derived abdominal and liver fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults free from diabetes at enrolment. The common protocols used in these two cohorts provided the opportunity for replication analyses to be performed. When the direction of the effect could not be determined with high probability through Bayesian networks, complementary two-sample Mendelian randomization (MR) was employed. High basal insulin secretion rate (BasalISR) was identified as the primary causal driver of liver fat accumulation in both diabetes and non-diabetes. Excess visceral adipose tissue (VAT) was bidirectionally associated with liver fat, indicating a self-reinforcing metabolic loop. Basal insulin clearance (Clinsb) worsened as a consequence of liver fat accumulation to a greater degree before the onset of T2D. Out of 446 analysed proteins, 34 mapped to these metabolic networks and 27 were identified in the non-diabetes network, 18 in the diabetes network, and 11 were common between the two networks. Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses revealed distinct proteomic drivers: GUSB and LEP were most predictive of liver fat in females and males, respectively. Basal insulin hypersecretion is a modifiable, causal driver of MASLD, particularly prior to glycaemic decompensation. Our findings highlight a multifactorial, sex- and disease-stage-specific proteo-metabolic architecture of hepatic steatosis. Proteins such as GUSB, ALDH1A1, LPL, and IGFBPs warrant further investigation as potential biomarkers or therapeutic targets for MASLD prevention and treatment. Show less

Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10-9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10-9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity. Show less

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at Show less

We highlight the importance of exome sequencing in solving a clinical case of a child who died at 14 months after a series of respiratory crises. He was the half-brother of a girl diagnosed at 7 years with the early-onset seizure variant of Rett syndrome due to CDKL5 mutation. We performed a test for CDKL5 in the boy, which came back negative. Driven by the mother's compelling need for a diagnosis, we moved forward performing whole exome sequencing analysis. Surprisingly, two missense mutations in compound heterozygosity were identified in the RAPSN gene encoding a receptor-associated protein with a key role in clustering and anchoring nicotinic acetylcholine receptors at synaptic sites. This gene is responsible for a congenital form of myasthenic syndrome, a disease potentially treatable with cholinesterase inhibitors. Therefore, an earlier diagnosis in this boy would have led to a better clinical management and prognosis. Our study supports the key role of exome sequencing in achieving a definite diagnosis in severe perinatal diseases, an essential step especially when a specific therapy is available. Show less

Some studies have suggested an overlap of clinical and genetic findings between essential tremor (ET) and Parkinson's disease (PD). The first genome-wide association study in ET showed a significant association with the rs9652490 SNP of the leucine-rich repeat and Ig domain containing 1 (LINGO1) gene. Since patients with PD have higher LINGO1 expression levels compared to healthy controls, and animal models of PD show elevated LINGO1 protein levels after experimentally induced damage in the striatum, it can be inferred that LINGO1 is probably involved in PD pathophysiology. In this study, we performed a genetic association analysis of the rs9652490 and rs11856808 SNPs in Italian PD patients and controls to assess the role of these variants in our population. A total of 567 patients with PD and 468 control subjects were enrolled in five Movement Disorder centers located in Central-Southern Italy. Both variants were significantly associated with PD under a recessive model of inheritance before applying the Bonferroni correction. The GG genotype of rs9652490 and the TT genotype of rs11856808 were less frequent in patients than in controls, suggesting a protective effect against the disease. However, after stringent correction, only the P-values obtained from allele and genotype comparisons of the rs11856808 SNP remained significant. Our findings suggest that LINGO1 plays a certain role in the development of PD in the Italian population and represents an interesting candidate gene responsible for PD, due to its involvement in neurological processes. Show less

The genes coding for apolipoprotein A1 (APOA1), apolipoprotein C3 (APOC3) and apolipoprotein A4 (APOA4) are tandemly organised within a short region on chromosome 11q23-q24. Polymorphisms of these genes have been extensively investigated in lipoprotein disorders and cardiovascular diseases, but poorly investigated in healthy ageing. The aim of this study was to describe possible modifications of the APOA1, APOC3, and APOA4 gene pool by cross-sectional studies carried out in a healthy ageing population whose ages ranged from 18 to 109 years (800 subjects, 327 males and 473 females, free of clinically manifested disease, and with emato-chemical parameters in the norm). APOA1-MspI-RFLP (-75 nt from the transcription starting site), APOC3-SstI-RFLP (3'UTR, 3238 nt), and APOA4-HincII-RFLP (Asp127/Ser127) were analysed according to age and sex. A significant age-related variation of the APOA1 gene pool was observed in males. An analysis of the allele average effect exerted by APOA1-MspI-RFLP A/P alleles (Absence/Presence of the restriction site) on lipidemic parameters in 46-80 year old males showed that allele A decreased, while allele P significantly increased, serum LDL-cholesterol. Unexpectedly, the P allele was over-represented in the group of the oldest old subjects, thus giving evidence of another "genetic paradox of centenarians". Show less