Identifying Cancer Driver Pathways Based on the Mouth Brooding Fish Algorithm.

Identifying the driver genes of cancer progression is of great significance in improving our understanding of the causes of cancer and promoting the development of personalized treatment. In this paper, we identify the driver genes at the pathway level via an existing intelligent optimization algorithm, named the Mouth Brooding Fish (MBF) algorithm. Many methods based on the maximum weight submatrix model to identify driver pathways attach equal importance to coverage and exclusivity and assign them equal weight, but those methods ignore the impact of mutational heterogeneity. Here, we use principal component analysis (PCA) to incorporate covariate data to reduce the complexity of the algorithm and construct a maximum weight submatrix model considering different weights of coverage and exclusivity. Using this strategy, the unfavorable effect of mutational heterogeneity is overcome to some extent. Data involving lung adenocarcinoma and glioblastoma multiforme were tested with this method and the results compared with the MDPFinder, Dendrix, and Mutex methods. When the driver pathway size was 10, the recognition accuracy of the MBF method reached 80% in both datasets, and the weight values of the submatrix were 1.7 and 1.89, respectively, which are better than those of the compared methods. At the same time, in the signal pathway enrichment analysis, the important role of the driver genes identified by our MBF method in the cancer signaling pathway is revealed, and the validity of these driver genes is demonstrated from the perspective of their biological effects.

Metformin regulates macrophage polarization via the Shh signaling pathway to improve pulmonary vascular development in bronchopulmonary dysplasia.

Metformin has potential anti-inflammatory properties and accelerates wound healing by enhancing vascular development. In this study, we aimed to investigate the effects of metformin on pulmonary vascular development and the underlying mechanism. Newborn mice were subcutaneously injected with metformin from day 2 after exposure to hyperoxia. Pulmonary vascular development, inflammation, and Shh signaling pathway-related protein expression were evaluated by western blotting and immunofluorescence staining. M2 macrophage polarization was measured by flow cytometry. The effect of metformin on macrophage polarization was determined using RAW264.7 macrophages exposed to 90% oxygen in vitro. The role of metformin and purmorphamine on M1 and M2 polarization was observed by flow cytometry. M2 polarization of pulmonary macrophages was inhibited after hyperoxic exposure, and metformin increased the number of M2 macrophages in the lung on postnatal day 14. Metformin upregulated CD31 expression and suppressed inflammation in the lung of mice exposed to hyperoxia on postnatal days 7 and 14. Metformin downregulated the Gli1 expression in macrophages in the lung after exposure to hyperoxia on postnatal day 14. In vitro studies showed that metformin inhibited the Gli1 expression in RAW264.7 macrophages exposed to 90% oxygen, which was reversed after purmorphamine pretreatment. Exposure to 90% oxygen inhibited the polarization of M2 macrophages, whereas metformin increased the number of M2 macrophages. Purmorphamine reversed the effects of metformin on M2 polarization and vascular endothelial growth factor (VEGF) upregulation in RAW264.7 macrophages exposed to hyperoxia. In conclusion, metformin regulates macrophage polarization via the Shh signaling pathway to improve pulmonary vascular development in bronchopulmonary dysplasia.

Pollen-Inspired Shell-Core Aerosol Particles Capable of Brownian Motion for Pulmonary Vascularization.

Nebulization is the most widely used respiratory delivery technique with non-invasive properties. However, nebulized drugs often fail to function due to the excretion and immune clearance of the respiratory system. In this work, inspired by pollen in nature, novel shell-core aerosol particles (APs) capable of Brownian motion are constructed for respiratory delivery. Drugs-loaded poly(lactic-co-glycolic acid) nanoparticles are prepared by emulsification to form the inner core, and the membranes of macrophages are extracted to form the outer shell. The optimized size and the shell-core structure endow APs with Brownian motion and atomization stability, thus enabling the APs to reach the bronchi and alveoli deeply for effective deposition. Camouflaging the macrophage membranes equips the APs with immune evasion. In vitro experiments prove that deferoxamine (DFO)-loaded APs (DFO@APs) can promote the angiogenesis of human umbilical vein endothelial cells. A hyperoxia-induced bronchopulmonary dysplasia (BPD) model is constructed to validate the efficiency of DFO@APs. In BPD mice, DFO@APs can release DFO in the alveolar interstitium, thus promoting the reconstruction of microvasculature, ultimately inducing lung development for treating BPD. In conclusion, this study develops "pollen"-inspired shell-core aerosol particles capable of Brownian motion, which provides a novel idea and theoretical basis for respiratory administration.

Metformin upregulates the expression of Gli1 in vascular endothelial cells in hyperoxia-exposed neonatal mice.

Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar and vascular development in premature infants. Metformin protects against the cardiovascular impairment induced by diabetes. The aim of this study was to investigate whether metformin could also enhance pulmonary vascular development in hyperoxic neonatal mice and investigate possible mechanisms involved. C57BL/6J newborn mice were randomly assigned to either of two groups - the room air group or the hyperoxia group - within 12 h postnatally. The mice were subcutaneously injected with metformin (100 mg/kg) or saline for 14 days. Lung morphology and PECAM-1 (CD31) expression in the lung were evaluated at postnatal days 7 and 14. Ki-67 and Gli1 expression in vascular endothelial cells was evaluated at postnatal day 14 by immunofluorescence staining. Flow cytometry (FCM) was also used to analyze Gli1 expression. Human umbilical vein endothelial cell (HUVECs) were used to investigate the role of metformin in vascular proliferation and tubular formation under 90% oxygen in vitro by cell counting Kti-8 (CCK8) assays and tube formation assays. Exposure to hyperoxia resulted in impaired lung development in newborn mice. Metformin enhanced the terminal airspace and radial alveolar count in newborn mice thus exposed. Immunohistochemistry staining and western blot assays revealed that metformin enhanced the expression of CD31 in hyperoxia-exposed newborn mice. Immunofluorescence staining showed that metformin enhanced the expression of Ki-67 in vascular endothelial cells. Furthermore, both immunofluorescence staining and FCM demonstrated that metformin increased Gli1 expression in vascular endothelial cells. Additionally, cell counting Kit-8 (CCK8) and viability assays of HUVECs in vitro both indicated that metformin improved the vascular proliferation and tube formation of HUVECs under 90% oxygen. These results indicated that metformin enhanced lung vascular development and upregulated the expression of Gli1 in the pulmonary vascular endothelial cells in hyperoxic neonatal mice.

N-Terminal Pro-B-Type Natriuretic Peptide as a Biomarker of Bronchopulmonary Dysplasia or Death in Preterm Infants: A Retrospective Cohort Analysis.

Objectives: To investigate the association between serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) level on the first day of life and a composite outcome of bronchopulmonary dysplasia (BPD) or death in a cohort of infants born before 32 weeks of gestation. Methods: We retrospectively identified infants born before 32 weeks of gestation who had serum NT-proBNP levels measured when they were admitted to the Neonatal Intensive Care Unit shortly after birth. The outcome of BPD or death was assessed at 36 weeks of postmenstrual age. The association of serum NT-proBNP levels with BPD or death was evaluated. Receiver operator characteristic (ROC) curve analysis was used to evaluate the predictive performance of serum NT-proBNP levels. Results: A 100 and 47 preterm infants had serum NT-proBNP levels measured on the first day of life. Serum NT-proBNP level was significantly higher in preterm infants who developed moderate/severe BPD or died [3,855 (2,567-6,369) vs. 1,259 (950-2,035) in control infants, P < 0.001]. On binary regression analysis, a high natural logarithm of serum NT-proBNP levels was associated with increased risk of moderate/severe BPD or death adjusted for gestational age, birth weight, birth weight z-score, and Apgar scores at 1 and 5 min (odds ratio [OR] = 5.195, 95% confidence interval [CI] 2.667-10.117, P < 0.001). ROC analysis identified a NT-proBNP level of 2002.5 pg/mL to have 87.5% sensitivity and 74.7% specificity for predicting moderate/severe BPD or death. The area under the curve (AUC) was 0.853 (95% CI 0.792-0.914). Conclusion: Serum NT-proBNP level measured on the first day of life is a promising biomarker for predicting the development of moderate/severe BPD or death in preterm infants. Our findings warrant a larger prospective study to incorporate measurement of NT-proBNP in prognosticating outcomes in very preterm infants.