PD-L2 drives resistance to EGFR-TKIs: dynamic changes of the tumor immune environment and targeted therapy.

There is a lack of effective treatments to overcome resistance to EGFR-TKIs in EGFR mutant tumors. A deeper understanding of resistance mechanisms can provide insights into reducing or eliminating resistance, and can potentially deliver targeted treatment measures to overcome resistance. Here, we identified that the dynamic changes of the tumor immune environment were important extrinsic factors driving tumor resistance to EGFR-TKIs in EGFR mutant cell lines and syngeneic tumor-bearing mice. Our results demonstrate that the acquired resistance to EGFR-TKIs is accompanied by aberrant expression of PD-L2, leading a dynamic shift from an initially favorable tumor immune environment to an immunosuppressive phenotype. PD-L2 expression significantly affected EGFR mutant cell apoptosis that depended on the proportion and function of CD8+ T cells in the tumor immune environment. Combined with single-cell sequencing and experimental results, we demonstrated that PD-L2 specifically inhibited the proliferation of CD8+ T cells and the secretion of granzyme B and perforin, leading to reduced apoptosis mediated by CD8+ T cells and enhanced immune escape of tumor cells, which drives EGFR-TKIs resistance. Importantly, we have identified a potent natural small-molecule inhibitor of PD-L2, zinc undecylenate. In vitro, it selectively and potently blocks the PD-L2/PD-1 interaction. In vivo, it abolishes the suppressive effect of the PD-L2-overexpressing tumor immune microenvironment by blocking PD-L2/PD-1 signaling. Moreover, the combination of zinc undecylenate and EGFR-TKIs can synergistically reverse tumor resistance, which is dependent on CD8+ T cells mediating apoptosis. Our study uncovers the PD-L2/PD-1 signaling pathway as a driving factor to mediate EGFR-TKIs resistance, and identifies a new naturally-derived agent to reverse EGFR-TKIs resistance.

Dilatation Eustachian tuboplasty with a Eustachian tube video endoscope and supporting balloon.

OBJECTIVE: To evaluate the feasibility and safety of employing a Eustachian tube video endoscope with a supporting balloon as a viable treatment and examination option for patients with Eustachian tube dysfunction. METHODS: A study involving nine fresh human cadaver heads was conducted to investigate the potential of balloon dilatation Eustachian tuboplasty using a Eustachian tube video endoscope and a supporting balloon catheter. The Eustachian tube cavity was examined with the Eustachian tube video endoscope during the procedure, which involved the dilatation of the cartilaginous portion of the Eustachian tube with the supporting balloon catheter. RESULTS: The utilisation of the Eustachian tube video endoscope in conjunction with the supporting balloon catheter demonstrated technical ease during the procedure, with no observed damage to essential structures, particularly the Eustachian tube cavity. CONCLUSION: This newly introduced method of dilatation and examination of the Eustachian tube cavity using a Eustachian tube video endoscope and the supporting balloon is a feasible, safe procedure.

CB Nanoparticles Optimized 3D Wearable Graphene Multifunctional Piezoresistive Sensor Framed by Loofah Sponge.

Three-dimensional (3D) wearable piezoresistive sensors with excellent performance are urgently needed in many emerging fields. Herein, a hybrid piezoresistive sensor with 3D structure, which is framed by loofah sponge and coated with reduced graphene oxide modified with carbon black nanoparticles (rGO-CB@LS), was obtained via a facile solvothermal method. The ingenious use of loofah sponge (LS) provides a 3D highly ordered structure with excellent flexibility for the hybrid sensor, which assists the sensor free from the dependence on an organic substrate and eliminates the pollution to the environment. While the addition of carbon black (CB) nanoparticles can reduce the contact resistance between rGO sheets, improve the conductivity and sensitivity effectively, and shorten the response/recovery time of the sensor. An ultralight piezoresistive sensor, which is low cost and environmentally friendly, was obtained under the synergy of LS and rGO-CB, accompanied by high sensitivity and good stability. This novel sensor also exhibits excellent performance in detecting tiny and big human activities, demonstrating its great potential for a new generation of 3D wearable sensors.