A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non–small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.

Chronic obstructive pulmonary disease (COPD) is a chronic and irreversible inflammatory lung disease, presently posing a significant burden to health care systems across the world.^1-6 Long-acting β₂-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the mainstay therapies for COPD^7,8; however, these agents were found to increase the risk of cardiovascular disease (CVD), although the findings varied, concluding that there was no increased risk^9-14 or that there was a 1.1- to 4.5-fold increased cardiovascular risk.^15-18 These studies, even a large randomized clinical trial (RCT),⁹ generally observed few cardiovascular events, excluded patients with severe illness,^9-11 and obtained incomplete medication records^17,18 as well as dropped more than 50% of eligible patients.¹⁵ All of these limitations could potentially weaken the causality or generalizability of the association.

Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels. I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×10⁵ cells) and high (1×10⁶ cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined. I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism. Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.

Chronic obstructive pulmonary disease (COPD) is a persistent inflammatory disease with irreversible airway limitation currently affecting 210 million people globally.^1,2 The disease is a leading cause of mortality worldwide³ and is the eighth contributing factor to years lived with disability, which has increased by 72.3% from 1990 to 2013.⁴ Acute respiratory failure (ARF) is a serious complication that frequently occurs in patients with COPD during acute exacerbation or is induced by a particular cause.⁵ After an episode of ARF, 80% of patients with COPD are rehospitalized and require intensive care or mechanical ventilator support; 63% experience another severe respiratory outcome, and 49% die within 1 year.^6,7