👤 Damian Malinowski

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome. Show less

Coronary artery disease is caused by changes in the coronary arteries due to the atherosclerotic process and thrombotic changes. A very important role in the development of the atherosclerotic process in the coronary vessels is played by the inflammatory process and the immune response. Due to the important role of lipids and the coagulation process in the atherosclerotic process, research has also focused on genes affecting lipid metabolism and the coagulation system. Lipoprotein lipase (LPL) is an enzyme that metabolises lipids, hydrolysing triglycerides to produce free fatty acids and glycerol. Protein C (PC) is an essential component of coagulation and fibrinolysis. It is activated on the endothelial surface by the membrane-bound thrombin-thrombomodulin complex. Platelet-derived growth factor (PDGF) has a number of important functions in processes related to fibroblast and smooth muscle cell function. Due to their influence on lipid metabolism and coagulation processes, LPL, PROCR (endothelial cell protein C receptor) and PDGF may affect the atherosclerotic process and, thus, the risk of coronary heart disease. The aim of the study was to examine the associations between the The study included 232 patients with unstable angina and 144 healthy subjects as the control group. Genotyping was performed using real-time PCR. There were no statistically significant differences in the distribution of the polymorphisms tested between the patients with unstable angina and the control subjects. The results showed associations between the The results of our study did not show that the Show less

Coronary artery disease (CAD) is a syndrome resulting from myocardial ischaemia of heterogeneous pathomechanism. Environmental and genetic factors contribute to its development. Atherosclerotic plaques that significantly narrow the lumen of coronary arteries cause symptoms of myocardial ischaemia. Acute coronary incidents are most often associated with plaque rupture or erosion accompanied by local activation of the coagulation system with thrombus formation. Plaque formation and stability are influenced by endothelial function and vascular smooth muscle cell function. In this study, we investigated the association between polymorphisms in genes affecting endothelial and vascular smooth muscle cell (VSMC) function and the occurrence of unstable angina pectoris. The aim of this study was to evaluate the association between the Show less

Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnant women leading to various complications. Consequently, factors predisposing its development are being sought. Previous studies have shown that the pathogenesis of GDM is similar to that of type 2 diabetes, and it is therefore thought that the two diseases may have a common genetic basis. The aim of this study was to examine the associations between thyroid adenoma-associated ( Show less

This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives. A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool. A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study. Show less

Gestational diabetes mellitus (GDM) is the carbohydrate intolerance that can occur in pregnancy. Genetic polymorphisms associated with type 2 diabetes could be considered as genetic determinants of GDM. The aim of this study was to examine the association between GCK, GCKR, FADS1, DGKB/TMEM195 and CDKAL1 gene polymorphisms and the development of gestational diabetes. These genetic polymorphisms are involved in glucose and lipid metabolism and are associated with increased risk for diabetes type 2. This case-control study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance. The diagnosis of GDM was based on a 75-gram oral glucose tolerance test at 24 to 28 weeks' gestation. There was a statistically significant association between FADS1 rs174550 gene polymorphism and GDM. Among women with GDM, a predominance of C-allele carriers (CC and TC genotypes) was observed (CC+TC vs. TT; p=0.00065; OR=1.97, 95% CI, 1.33 to 2.92), and this association remained significant after correction for multiple testing. In the case of the GCK rs1799884 polymorphism, there was a predominance of the T allele in women with GDM; however, this association reached only borderline statistical significance (p=0.08). Women with higher numbers of GCK rs1799884 T alleles more commonly required insulin treatment; likewise, the CDKAL1 rs10946398 CC genotype was associated with the need for insulin therapy. However, these associations do not pass the statistical significance threshold after correction for multiple testing. The results of our study suggest an association between the rs174550 FADS1 polymorphism and GDM risk. Show less