American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Oct 2019
Multicenter StudyMulticenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension.
Rationale: Pulmonary arterial hypertension (PAH) is a degenerative arteriopathy that leads to right ventricular (RV) failure. BRD4 (bromodomain-containing protein 4), a member of the BET (bromodomain and extra-terminal motif) family, has been identified as a critical epigenetic driver for cardiovascular diseases. Objectives: To explore the therapeutic potential in PAH of RVX208, a clinically available BET inhibitor. ⋯ This reversed the PAH phenotype in isolated PAH microvascular endothelial cells and smooth muscle cells in vitro, and in diverse PAH rat models. RVX208 also supported the pressure-loaded RV in vivo. Together, these data support the establishment of a clinical trial with RVX208 in patients with PAH.
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Am. J. Respir. Crit. Care Med. · Oct 2019
Quantitative Lipidomics in Pulmonary Alveolar Proteinosis.
Rationale: Pulmonary alveolar proteinosis (PAP) is characterized by filling of the alveolar spaces by lipoprotein-rich material of ill-defined composition, and is caused by molecularly different and often rare diseases that occur from birth to old age. Objectives: To perform a quantitative lipidomic analysis of lipids and the surfactant proteins A, B, and C in lavage fluids from patients with proteinosis of different causes in comparison with healthy control subjects. Methods: During the last two decades, we have collected BAL samples from patients with PAP due to autoantibodies against granulocyte-macrophage colony-stimulating factor; genetic mutations in CSF2RA (colony-stimulating factor 2 receptor α-subunit), MARS (methionyl aminoacyl-tRNA synthetase), FARSB (phenylalanine-tRNA synthetase, β-subunit), and NPC2 (Niemann-Pick disease type C2); and secondary to myeloid leukemia. ⋯ The surfactant lipid class phosphatidylcholine expanded 17-fold, lysophosphatidylcholine expanded 54-fold, and the surfactant proteins A, B, and C expanded 144-, 4-, and 17-fold, respectively. These changes did not differ among the various diseases that cause PAP. Conclusions: This insight into the alveolar lipidome may provide monitoring tools and lead to new therapeutic strategies for PAP.
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Am. J. Respir. Crit. Care Med. · Oct 2019
Risk Factors for Functional Decline and Impaired Quality of Life after Pediatric Respiratory Failure.
Rationale: Poor outcomes of adults surviving critical illness are well documented, but data in children are limited. Objectives: To identify factors associated with worse postdischarge function and health-related quality of life (HRQL) after pediatric acute respiratory failure. Methods: We assessed functional status at baseline, discharge, and 6 months after pediatric ICU discharge and HRQL 6 months after discharge in 2-week- to 17-year-olds mechanically ventilated for acute respiratory failure in the RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) trial. ⋯ Independent predictors of impaired growth and development included methadone (OR = 2.27; 95% CI = 1.18-4.36) and inadequate pain management (OR = 2.94; 95% CI = 1.39-6.19). Impaired HRQL was associated with older age, non-white or Hispanic race, cancer, and inadequate sedation management (OR = 3.15; 95% CI = 1.74-5.72). Conclusions: Postdischarge morbidity after respiratory failure is common and associated with admission factors, exposure to critical care therapies, and pain and sedation management.
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Am. J. Respir. Crit. Care Med. · Oct 2019
YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib.
Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. ⋯ Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.