No abstract

The increasing use of immune checkpoint inhibitors in tumors has brought new hope of survival to patients with advanced tumors. However, the immune system activated by immune checkpoint inhibitors, mainly activated T‐cells, can attack normal tissues and organs in the body and lead to a variety of adverse effects. In the lung, these attacks can induce checkpoint inhibitor pneumonitis (CIP). CIP is different from known pulmonary interstitial pneumonitis, and has the potential to be fatal if not treated correctly. In this review, we summarize the characteristics of CIP and provide advice on how to manage this disease.

Objectives This study sought to test the hypothesis that hyperpolarization-activated cyclic nucleotide–gated (HCN)–based biological pacing might be improved significantly by hyperpolarizing the action potential (AP) threshold via coexpression of the skeletal muscle sodium channel 1 (SkM1). Background Gene-based biological pacemakers display effective in vivo pacemaker function. However, approaches used to date have failed to manifest optimal pacemaker properties, defined as basal beating rates of 60 to 90 beats/min, a brisk autonomic response achieving maximal rates of 130 to 160 beats/min, and low to absent electronic backup pacing. Methods We implanted adenoviral SkM1, HCN2, or HCN2/SkM1 constructs into left bundle branches (LBB) or left ventricular (LV) epicardium of atrioventricular-blocked dogs. Results During stable peak gene expression on days 5 to 7, HCN2/SkM1 LBB-injected dogs showed highly stable in vivo pacemaker activity superior to SkM1 or HCN2 alone and superior to LV-implanted dogs with regard to beating rates (resting approximately 80 beats/min; maximum approximately 130 beats/min), no dependence on electronic backup pacing, and enhanced modulation of pacemaker function during circadian rhythm or epinephrine infusion. In vitro isolated LV of dogs overexpressing SkM1 manifested a significantly more negative AP threshold. Conclusions LBB-injected HCN2/SkM1 potentially provides a more clinically suitable biological pacemaker strategy than other reported constructs. This superiority is attributable to the more negative AP threshold and injection into the LBB.

Background Biological pacing performed solely via HCN2 gene transfer in vivo results in relatively slow idioventricular rates and only moderate autonomic responsiveness. We induced biological pacing using the Ca2+-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes to those with single gene HCN2 transfer. Methods and Results We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches (LBB) of atrioventricular-blocked dogs. During steady-state gene expression (days 5-7), differences between AC1, HCN2/AC1 and HCN2 alone were evident in basal beating rate, escape time, and dependence on electronic back-up pacing. In HCN2, AC1, and HCN2/AC1, these parameters were, respectively: Basal beating rate: 50±1.5bpm, 60±5.0bpm, and 129±28.9bpm (P<0.05 for HCN2/AC1 vs. HCN2 or AC1 alone); Escape time: 2.4±0.2 sec, 1.3±0.2 sec, and 1.1±.0.4sec (P<0.05 for AC1 and HCN2/AC1 vs. HCN2); and % Electronic beats: 34±8%, 2±1%, and 6±2% (P<0.05 for AC1 and HCN2/AC1 vs. HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability (HRV) and circadian rhythm analyzed via 24h Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 as well as a high degree of sympathetic modulation in animals injected with HCN2/AC1. Conclusions AC1 or HCN2/AC1 overexpression in LBB provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.