The Need for Precision Therapies as Determined by Genetic Signature for Cystic Fibrosis

Cystic fibrosis (CF) is a devastating genetic infant-onset disease [...]

Prognostic model of AU-rich genes predicting the prognosis of lung adenocarcinoma

Background AU-rich elements (ARE) are vital cis-acting short sequences in the 3’UTR affecting mRNA stability and translation. The deregulation of ARE-mediated pathways can contribute to tumorigenesis and development. Consequently, ARE-genes are promising to predict prognosis of lung adenocarcinoma (LUAD) patients. Methods Differentially expressed ARE-genes between LUAD and adjacent tissues in TCGA were investigated by Wilcoxon test. LASSO and Cox regression analyses were performed to identify a prognostic genetic signature. The genetic signature was combined with clinicopathological features to establish a prognostic model. LUAD patients were divided into high- and low-risk groups by the model. Kaplan–Meier curve, Harrell’s concordance index (C-index), calibration curves and decision curve analyses (DCA) were used to assess the model. Function enrichment analysis, immunity and tumor mutation analyses were performed to further explore the underlying molecular mechanisms. GEO data were used for external validation. Results Twelve prognostic genes were identified. The gene riskScore, age and stage were independent prognostic factors. The high-risk group had worse overall survival and was less sensitive to chemotherapy and radiotherapy (P < 0.01). C-index and calibration curves showed good performance on survival prediction in both TCGA (1, 3, 5-year ROC: 0.788, 0.776, 0.766) and the GSE13213 validation cohort (1, 3, 5-year ROC: 0.781, 0.811, 0.734). DCA showed the model had notable clinical net benefit. Furthermore, the high-risk group were enriched in cell cycle, DNA damage response, multiple oncological pathways and associated with higher PD-L1 expression, M1 macrophage infiltration. There was no significant difference in tumor mutation burden (TMB) between high- and low-risk groups. Conclusion ARE-genes can reliably predict prognosis of LUAD and may become new therapeutic targets for LUAD.

Abstract P139: Genetic Signature Of Accelerated Cardiac Fibrosis Due To Trpa1 Ablation

While our previous study demonstrated that loss of transient receptor potential ankyrin 1 ( Trpa1 ) accelerates age-related cardiac fibrosis in mice, the underlying mechanism of potential anti-fibrotic property of TRPA1 remains largely unknown. TRPA1 is a sensor of oxidative stress and may play a protective role in age-related diseases. In this study, we performed quantitative polymerase chain reaction array analyses of the mRNA expression of 84 fibrosis-related genes in the myocardial tissue of 12-month-old Trpa1 -/- mice with significant cardiac fibrosis and age-matched wild-type mice without cardiac fibrosis. The mRNA levels of Col1a2 and Col3a1 in the myocardial tissue were similar between Trpa1 -/- and wild-type mice, suggesting comparable cardiac collagen synthesis in the two strains. Matrix metalloproteinases are major enzymes responsible for degradation of collagen fibers. The results show that the mRNA levels of matrix metalloproteinases, including Mmp1a , Mmp2 , Mmp3 , Mmp8 , Mmp9 , Mmp13 , and Mmp14 , in the heart were similar between Trpa1 -/- and wild-type mice. Nevertheless, we identified 7 significantly changed genes in the heart between the two strains. The expression levels of Acta2 , Inhbe , Ifng , and Ccl11 were significantly increased with fold changes of 3.1, 1.9, 1.9, and 1.5 (all P < 0.05), respectively, while Timp3 , Stat6 , and Ilk were significantly decreased with fold changes of 0.3, 0.5, and 0.7 (all P < 0.05), respectively, in the heart of Trpa1 -/- mice compared with wild-type mice. Acta2 , the most upregulated gene in Trpa1 -/- hearts, is a marker of myofibroblasts. Its upregulation indicates increased differentiation from fibroblasts into myofibroblasts in Trpa1 -/- hearts compared with wild-type hearts. Timp3 , the most downregulated gene in Trpa1 -/- hearts, codes an extracellular matrix protein TIMP3, which not only inhibits matrix metalloproteinases but also regulate post-translational modification of collagen fibers. Taken together, these findings suggest that upregulation of Acta2 and downregulation of Timp3 may serve as genetic signature or play a role in accelerated age-related cardiac fibrosis due to TRPA1 ablation.

Genetic evidence for environment-dependent hybrid incompatibilities in threespine stickleback

Hybrid incompatibilities occur when interactions between opposite-ancestry alleles at different loci reduce the fitness of hybrids. Most work on incompatibilities has focused on those that are 'intrinsic', meaning they affect viability and sterility in the laboratory. Theory predicts that ecological selection can also underlie hybrid incompatibilities, but tests of this hypothesis are scarce. In this article, we compiled genetic data for F2 hybrid crosses between divergent populations of threespine stickleback fish (Gasterosteus aculeatus L.) that were born and raised in either the field (semi-natural experimental ponds) or the laboratory (aquaria). We tested for differences in excess heterozygosity between these two environments at ancestry informative loci—a genetic signature of selection against incompatibilities. We found that excess ancestry heterozygosity was elevated by approximately 3% in crosses raised in ponds compared to those raised in aquaria. Previous results from F1 hybrids in the field suggest that pond-specific (single-locus) heterosis is unlikely to explain this finding. Our study suggests that, in stickleback, a coarse signal of environment-dependent hybrid incompatibilities is reliably detectable and that extrinsic incompatibilities have evolved before intrinsic incompatibilities.