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PubMed2026

Fibroblast growth factor 21 prevents catecholaminergic arrhythmias in a mouse model of PKP2 arrhythmogenic cardiomyopathy.

BACKGROUND: Pathogenic variants in plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy (ACM) with intracellular calcium dysregulation as a major component of its arrhythmia phenotype. Recent adeno-associated virus (AAV)-based PKP2 gene therapy has shown promising results in a few different PKP2-associated ACM models. Fibroblast growth factor 21 (FGF21) has multiple cardioprotective effects and has recently emerged as a promising therapeutic agent for cardiovascular disease. OBJECTIVE: This study aimed to assess the efficacy and impact on calcium regulation of a novel AAV serotype 8 (AAV8)-based FGF21 gene therapy on adult cardiac-specific, tamoxifen-activated PKP2 knockout (PKP2-cKO) mice. METHODS: Experiments were performed using a PKP2-cKO murine model. AAV8-FGF21 was delivered to adult mice by a single tail vein injection 7 days before tamoxifen-activated PKP2-cKO. Cardiac functions were monitored using echocardiography and electrocardiography. Intracellular calcium transients were investigated in acute isolated adult mouse cardiomyocytes, and calcium fluorescent signals were acquired using the IonOptix system. RESULTS: Loss of PKP2 expression caused cardiac mechanical dysfunction and proarrhythmic phenotype in adult mouse models. AAV-mediated delivery of FGF21 mitigated the progression of biventricular structural changes, decreased the occurrence of adrenergic arrhythmias, and rescued intracellular calcium imbalance in the setting of PKP2 haploinsufficiency. In contrast, acute in vitro FGF21 treatment for 1 hour had no effect on intracellular calcium transients. CONCLUSION: These beneficial effects of AAV8-FGF21 on the PKP2-ACM phenotype suggest a therapeutic landscape for various targeted cardiomyopathies.

Animals↗

PubMed2026

Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours.

BACKGROUND: Alcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. The objective of this study is to identify a robust genetic instrument for FGF21 agonism and leverage it to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. METHODS: We first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait locus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a plausible genetic instrument, we subsequently performed association analyses investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalisation analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. RESULTS: Consistent association and colocalisation evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (association p = 1 × 10-18, colocalisation posterior probability = 0.90), problematic alcohol use (association p = 0.02, posterior probability = 0.64), and AUD (association p = 9 × 10-8, posterior probability = 0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. CONCLUSIONS: This study identifies a genetic instrument for FGF21 effects to provide causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.

Humans↗

PubMed2022

FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit.

Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms. Here, we demonstrate that administration of an FGF21 analog to alcohol-preferring non-human primates reduces alcohol intake by 50%. Further, we reveal that FGF21 suppresses alcohol consumption through a projection-specific subpopulation of KLB-expressing neurons in the basolateral amygdala. Our results illustrate how FGF21 suppresses alcohol consumption through a specific population of neurons in the brain and demonstrate its therapeutic potential in non-human primate models of excessive alcohol consumption.

Alcohol Drinking↗

PubMed2026

Proteomic Profile in Retinopathy of Prematurity: A Secondary Analysis of the Mega Donna Mega Randomized Clinical Trial.

IMPORTANCE: Identifying early proteomic profiles in infants who develop severe retinopathy of prematurity (ROP) may reveal targets for preventive interventions to reduce retinal vessel loss and the subsequent risk of severe ROP. OBJECTIVE: To assess early longitudinal profiles of blood protein levels in preterm infants with or without severe ROP and the effect of arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation. DESIGN, SETTING, AND PARTICIPANTS: This was an exploratory, post hoc analysis of serum proteome profiles in preterm infants in the double-masked Mega Donna Mega (MDM) randomized clinical trial using targeted Olink Proximity Extension Assay proteomics covering 538 analytes. The setting was 3 university hospitals in Sweden and included extremely preterm infants born before 28 weeks of gestational age (GA), from 2016 to 2019. Data were analyzed from January to March 2025. EXPOSURES: All infants received standard nutrition; additionally, half received enteral lipid supplementation with AA/DHA (100/50 mg/kg per day) from birth to term equivalent age. MAIN OUTCOMES AND MEASURES: Longitudinal protein profiles during the first month of life were examined using mixed models for repeated measures, adjusted for GA, study center, and AA/DHA supplementation, and tested for the interaction between severe ROP (stage ≥3 and/or treated) and postnatal age. RESULTS: A total of 177 extremely preterm infants (mean [SD] GA, 25.6 [1.4] weeks; 100 male [56.5%]) were included, of whom 50 (28.2%) developed severe ROP. Of 538 longitudinal analyzed proteins, 109 protein profiles in the first month of life associated with severe ROP, proteins related to immune response, apoptotic processes, blood coagulation, and lipid metabolism. The most pronounced association with severe ROP was a fast rise in fibroblast growth factor 21 (FGF-21; β = 0.68; 95% CI, 0.39-0.97; Q =.002) and tissue plasminogen activator (tPA; β = 0.21; 95% CI, 0.13-0.29; Q <.001) during the first postnatal days. The increase in serum FGF-21 level in the first week of life was associated with lower GA, lower birth weight, low enteral energy intake, and more days receiving mechanical ventilation. No association was observed between AA/DHA supplementation and the proteome. CONCLUSIONS AND RELEVANCE: In this post hoc exploratory analysis of data from the MDM randomized clinical trial, a fast rise in FGF-21 levels, a metabolic stress-induced hormone, during the first postnatal days was strongly associated with the development of severe ROP in extremely preterm infants. These findings suggest that early interventions improving bioenergetic status may help prevent severe ROP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03201588.

Humans↗

PubMed2025

Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.

Spinocerebellar ataxia 27 A (SCA27A) is a form of progressive cerebellar ataxia due to pathogenic variants in the Fibroblast Growth Factor 14 (FGF14) gene. The objective of this paper is to characterise the clinical spectrum of SCA27A microdeletions (> 50 bp, <2Mbp), and report two novel cases. Literature searches of PubMed, OMIM and ClinVar were carried out. We identified SCA27A microdeletions in 32 cases across 11 families. The phenotypic presentation is: 75% (24/32) nystagmus, 46% (15/32) ataxia, 21% (7/32) episodic ataxia, 21% (7/32) tremor, 15% (5/32) dysarthria, 34% (11/32) learning disability, 28% (8/32) neuropsychiatric disease. The presentation is variable within and between families. Episodic symptoms, nystagmus, learning disability and neuropsychiatric symptoms occur at an earlier age. Patient 1 represents the first case with a 58 kb FGF14 deletion who presented with a paroxysmal movement disorder. Patient 2 carries a 545 kb deletion and developed episodic ataxia and trigeminal neuralgia, a novel feature not previously described in this cohort. We report two cases of heterozygous FGF14 microdeletions: Patient 1 (58 kb) and Patient 2 (545 kb), expanding the phenotypic spectrum of FGF14 structural variants to 32 cases across 11 families. We review potential mechanism from pre-clinical studies relating FGF14 haploinsufficiency to cerebellar, cognitive, neuropsychiatric symptoms, as well as trigeminal neuralgia. We propose the hypothesis that the episodic symptoms in SCA27A align with the molecular pathology of a channelopathy and propose management strategies based on this insight.

Humans↗

PubMed1979

Cytogenetic analysis of the sensitivity to anti-viral and anti-cell growth activities of human fibroblast interferon in aneuploid human tumor cell lines. Brief report.

The ability of human fibroblast interferon to suppress colony formation and papovavirus T-antigen expression in six human tumor cell lines did not appear to correlate with their content of chromosomes 16 and 21. Additional factors or chromosomes may be involved in the manifestation of interferon action in aneuploid cells.

Aneuploidy↗

PubMed2026

Small-Molecule Degradation of the MicroRNA-21 Precursor Rescues Pathogenic Pathways in Cellular Models of Fibrosis.

MicroRNAs (miRNAs) are short RNA molecules that bind to target mRNAs, resulting in translational repression and gene silencing. Overexpression of microRNA-21 (miR-21) is associated with various human diseases, including autosomal dominant polycystic kidney disease (ADPKD) and pulmonary fibrosis. In this study, a previously described heterobifunctional molecule, TGP-21-RiboTAC, that degrades the miR-21 precursor (pre-miR-21) in triple-negative breast cancer cells was investigated in polycystic kidney cell lines and a lung fibroblast cell line. In the former, TGP-21-RiboTAC degraded pre-miR-21 and derepressed miR-21's downstream targets, programmed cell death 4 (PDCD4) and peroxisome proliferator-activated receptor alpha (PPARα), known drivers of ADPKD. The heterobifunctional molecule also inhibited cyst growth and rescued the metabolic alterations that occur in ADPKD. In the lung fibroblast cell line, MRC-5, TGP-21-RiboTAC also reduced pre- and mature miR-21 levels, rescued transforming growth factor β (TGF-β)-induced repression of SMAD family member 7 (SMAD7), and inhibited cell invasion. Collectively, these studies demonstrate the potential of targeted RNA degradation as therapeutic agents that retard the development of organ fibrosis.

MicroRNAs↗

PubMed1977

[Different types of cells in tissue cultures of normal bovine iris (author's transl)].

Calf iris tissue cultured in TCM 199 was studied under the electron microscope at 5, 14, and 21 days. Melanocytes and clump cells (macrophages), and mast cells could be distinguished, as well as fibroblasts, round cells, and non striated muscle cells, Melanocytes lost their pigment granules temporarily, but not their ability to produce new ones again after a certain adaptation period. The morphology of clump and mast cells was only slightly altered. In incubation, fibroblasts and round cells were found to have spheroid surfaces. After a 3 week's culture, muscle cells showed signs of growth.

Animals↗

PubMed1979

Variation in S phase in synchronous human cell lines.

Growth parameters of diploid and trisomic human fibroblasts were determined. The rate of growth of both classes of cells was examined in asynchronous cultures, and diploid and trisomic cells had similar growth rates. Synchronous cultures were developed using simple mitotic selection. The patterns and length of the DNA synthetic period (S phase) were found to be altered in trisomy 21 cells when compared to diploid human or to heteroploid HeLa cells. Early S-phase synthesis was absent or reduced and the overall length of the S phase was extended. However, the trisomic cells have apparently normal rates of DNA chain elongation and normal replicon sizes.

Cell Cycle↗

PubMed1976

Effects of hypoxia on cardiac growth in neonatal rat.

To determine whether low oxygen environments enhance cardiac cell division in the neonatal period, newborn rat pups were reared for 21 days in 12-15% oxygen. Left ventricle and right ventricle weights were 30 and 180% greater than controls matched for body weight (P less than 0.001) as were left ventricle/body weight ratios (3.68+/-0.26 vs. 2.99+/-0.05 mg LV/g body wt,P less than 0.001). Left ventricular total DNA and DNA concentration was 95 and 48% greater than controls (P less than 0.001). Autoradiography confirmed that this increase in ventricular DNA resulted from an increased rate of division of cardiac muscle cells, fibroblast, and vascular endothelial cells. When [3H]thymidine was injected on day ), autoradiographs prepared on day 21 reflected an increased dilution of label in hypoxic rats consistent with enhanced proliferation. The labeling index and grains per nucleus of ventricular muscle cells was 25% (P less than 0.01) and 20% (P less than 0.02) less than controls, Thus, hypoxic stress applied early in the neonatal period augments the rate of division and ultimate number of cardiac muscle cells. Whether this enhancement results from a primary effect of oxygen or from secondary hemodynamic factors remains unknown.

Animals↗

PubMed1979

Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm.

This article describes 41 examples of an unusual fibrohistiocytic sarcoma which occurred primarily in the extremities of young individuals between the ages of 5 and 25 years (median 13 years). It manifested as a nodular subcutaneous growth that seldom caused tenderness or pain, and clinically was often mistaken for a hematoma or a hemangioma. Grossly, the tumor presented as a circumscribed, multinodular or multicystic, hemorrhagic mass that ranged in size from 0.7 to 10 cm (median 2.5 cm). On microscopic examination, it consisted principally of 1) solid arrays or nests of fibroblast- and histiocyte-like cells, not infrequently containing varying amounts of intracellular hemosiderin or lipid, 2) focal areas of hemorrhage or hemorrhagic cyst-like spaces, sometimes occupying the major portion of the tumor, and 3) aggregates of chronic inflammatory cells, chiefly lymphocytes and plasmacytes, a feature that caused confusion with a lymph node metastasis in several cases. Follow-up information, available in 24 patients, revealed a variable clinical course. Twenty-one patients were alive, 11 with recurrence (including one with 9 recurrences in a 21-year period) one with recurrence and metastasis and one with metastasis. Three patients had died of metastasis 1, 3, and 13 years respectively, after the initial surgical therapy. The exact histogenesis is still obscure. Most likely it is a tumor of fibroblast- and histiocyte-like cells, akin to malignant fibrous histiocytoma, but different in its age incidence, microscopic appearance and behavior.

Adolescent↗

PubMed1979

Detection of gap junctions between the progeny of a canine macrophage colony-forming cell in vitro.

An in vitro monocyte-macrophage colony-forming cell (M-CFC) has been detected in canine bone marrow (BM). The colonies derived from these progenitor cells were similar to murine-derived M-CFC (MacVittie and Porvaznik, 1978, J. Cell Physiol. 97:305--314) colonies, since they showed a singular macrophage line of differentiation, a lag of 14--16 days before initiating colony formation, and they survived significantly longer in culture in the absence of colony-stimulating factor (CSF) than granulocyte-macrophage colony-forming cells (GM-CFC). Endotoxin (Salmonella typhosa lipopolysaccharide W)-stimulated dog serum was used as the CSF (7% vol/vol). Canine-derived M-CFC progeny were identified as macrophages on the basis of morphology, phagocytosis, and the presence of Fc receptors for IgG. Gap junctions were observed only in canine BM, M-CFC-derived colonies using freeze-fracture and lanthanum tracer techniques. They were not observed in any GM-CFC-derived colonies. The number of gap junctions observed in freeze-fracture replicas of BM, M-CFC-derived colonies (21 colonies from three different dogs) showed a significantly positive correlation (Kendall's tau = 0.70, P less than 0.001) with the size of the colony fracture plane area. Gap junctions were observed displaying hexagonal lattices of 9.3 nm +/- 0.08 (SE) particles with a center-to-center spacing of 10.4 nm +/- 1.0 (SE) on membrane P-fracture faces. On membrane E-fracture faces, highly ordered arrays of pits with 8.7 nm +/- 0.12 (SE) center-to-center spacing were observed. Arrays of both particles and pits were also observed in fracture-face breakthroughs within a gap junction. Thus, gap junctions can form in vitro between the cells of macrophage progeny of a canine M-CFC under appropriate growth conditions. The significance of this observation is that there may be a structural basis for cell-to-cell collaboration between BM macrophages and other capable cells that either pass into the tissue for modification or develop there into mature cell forms.

Animals↗

PubMed1979

Diabetes mellitus and genetic prediabetes. Decreased replicative capacity of cultured skin fibroblasts.

The idea that the gene(s) that cause diabetes mellitus can be expressed in extrapancreatic cells has been examined by tissue culture techniques. Skin biopsies were obtained from 25 normal subjects (N), 26 overt diabetics (D), 16 of juvenile onset (JOD) and 9 of maturity onset (MOD), and 21 subjects genetically predisposed to diabetes (P) on the basis of maturity-onset diabetes in both parents. Each biopsy was subdivided, multiple skin fragments were explanted in vitro, and several parameters of cellular outgrowth were monitored in primary and secondary cultures until cell division ceased because of senescence. In general, the rank order of growth vigor was N greater than P greater than D although differences were often marginal and statistically significant between N and JOD and(or) MOD. Outgrowth of epithelial cells was more vigorous in N explants in early stages, but later, JOD and MOD cells grew better than those of N. Outgrowth of fibroblast cells from N explants was more vigorous both at early and later stages and required less time to achieve maximum percent outgrowth. In secondary cultures, N cells grew faster than the other three groups so that fewer days elapsed between subcultures but significant differences were only seen between N and one or two of the other groups over some of the first seven subcultures. The onset of cellular senescence occurred earlier in P and JOD cultures both in mean population doublings and calendar time. N cultures had a higher percent surviving clones after picking than MOD, and a shorter recloning time than clones of JOD. The replicative life-spans of cultures (mean population doublings +/- SE) were N = 52.54 +/- 2.24, P = 47.84 +/- 2.43, JOD = 47.12 +/- 2.99, and MOD = 46.40 +/- 4.04, but differences did not reach significance for N vs the other three groups. The data demonstrate that cellular growth is impaired in both JOD and MOD types of cultures and to a generally lesser extent in P cultures. This is consistent with intrinsic genetic defects but the possibility that persistent deleterious effects of in vivo pathophysiology contribute alone or in combination cannot be ruled out. Therefore, the diabetic defect(s) can be expressed in extrapancreatic cells of mesenchymal origin. This system should prove useful in exploring the interplay between genetic and environmental factors in diabetes, the mechanisms(s) of hyperglycemia and other metabolic derangements, and the propensity that affected individuals have to develop degenerative diseases.

Adolescent↗

PubMed2026

Efficacy and safety of infigratinib in patients with refractory advanced gastric or gastroesophageal junction adenocarcinoma harboring FGFR2 gene amplification: a single-arm, multicenter phase 2 trial.

BACKGROUND: FGFR2 has garnered attention as a promising therapeutic target for gastric cancer (GC) because of its role in GC progression. Infigratinib, an FGFR1-3 selective tyrosine kinase inhibitor, has shown potential in preclinical GC models. METHODS: Infigratinib was evaluated in a phase 2 trial for patients with FGFR2-amplified GC or gastroesophageal junction (GEJ) adenocarcinoma who had failed two or more lines of systemic treatment for locally advanced or metastatic disease. A total of 21 patients received 125 mg of infigratinib orally once daily on a "3 weeks on, 1 week off" schedule. RESULTS: Infigratinib showed preliminary antitumor activity in this molecularly selected population, as reflected by a confirmed objective response rate of 23.8% (95% CI, 8.2-47.2) with median progression-free survival of 3.4 months and median overall survival of 6.7 months. The most common grade 3-4 adverse events were elevated aspartate aminotransferase, decreased white blood cell count, and neutropenia. No treatment-related deaths occurred. Exploratory genomic analyses identified alterations in individual patients with disease progression that may be associated with resistance; however, these findings were based on a limited number of cases and should be interpreted as hypothesis-generating. CONCLUSIONS: The findings support continued investigation of FGFR-targeted strategies in FGFR2-amplified GC/GEJ adenocarcinoma, while underscoring the need for larger studies, refined biomarker selection, and deeper characterization of resistance mechanisms. TRIAL REGISTRATION: NCT05019794, Registered 28 July 2021, https://clinicaltrials.gov/study/NCT05019794 .

Humans↗