In Vitro and In Vivo Evaluation of Synergistic Effects of Everolimus in Combination with Antifungal Agents on Exophiala dermatitidis.

To investigate the combined function of the novel oral mTOR inhibitor, everolimus, with antifungal agents and their potential mechanisms against Exophiala dermatitidis, the CLSI microliquid-based dilution method M38-A2, chequerboard technique, and disk diffusion testing were performed. The efficacy of everolimus was evaluated in combination with itraconazole, voriconazole, posaconazole, and amphotericin B against 16 clinically isolated strains of E. dermatitidis. The synergistic effect was determined by measuring the MIC and fractional inhibitory concentration index. Dihydrorhodamine 123 was used for the quantification of ROS levels. The differences in the expression of antifungal susceptibility-associated genes were analyzed following different types of treatment. Galleria mellonella was used as the in vivo model. While everolimus alone showed minimal antifungal effects, combinations with itraconazole, voriconazole, posaconazole, or amphotericin B resulted in synergy in 13/16 (81.25%), 2/16 (12.5%), 14/16 (87.75%), and 5/16 (31.25%) of isolates, respectively. The disk diffusion assay revealed that the combination of everolimus and antifungal drugs showed no significant increase in the inhibition zones compared with the single agent, but no antagonistic effects were observed. Combination of everolimus and antifungal agents resulted in increased ROS activity (everolimus + posaconazole versus posaconazole [P < 0.05], everolimus + amphotericin B versus amphotericin B [P < 0.002]). Simultaneously, compared to mono-treatment, the combination of everolimus + itraconazole suppressed the expression of MDR2 (P < 0.05) and the combination of everolimus + amphotericin B suppressed the expression of MDR3 (P < 0.05) and CDR1B (P < 0.02). In vivo, combinations of everolimus and antifungal agents improved survival rates, particularly the combination of everolimus + amphotericin B (P < 0.05). In summary, the in vivo and in vitro experiments performed in our study suggest that the combination of everolimus with azoles or amphotericin B can have synergistic effects against E. dermatitidis, potentially due to the induction of ROS activity and inhibition of efflux pumps, providing a promising new approach for the treatment of E. dermatitidis infections. IMPORTANCE Cancer patients with E. dermatitidis infection have high mortality if untreated. Clinically, the conventional treatment of E. dermatitidis is poor due to the long-term use of antifungal drugs. In this study, we have for the first time investigated the interaction and action mechanism of everolimus combined with itraconazole, voriconazole, posaconazole, and amphotericin B on E. dermatitidis in vitro and in vivo, which provided new ideas and direction for further exploring the mechanism of drug combination and clinical treatment of E. dermatitidis.

Mid-wave infrared polarization imaging system for detecting moving scene.

In this Letter, a polarimetric analyzer is designed for a mid-wave infrared camera. This kind of infrared camera transforms into the mid-wave infrared polarization imaging system to measure the infrared polarization characteristics of the object in the moving scene. The polarimetric analyzer is designed by using the ultra-high-speed and high-position method to drive the polarizer to rotate uniformly at the speed of 900 rpm. The polarization state of the object scene is changed, and the mid-wave infrared camera synchronously acquires the infrared intensity image in different polarized directions, those of 0°, 120°, and 240°. Then, a Stokes vector model is established with the basic rotation angles, and a sort-iteration method is proposed to process the original infrared intensity image. Three continuously neighboring infrared intensity images are used to calculate the degree of linear polarization (DoLP) and the angle of polarization (AoP), which make the infrared polarization image the same imaging frame as the infrared intensity image. Test results show that the mid-wave infrared polarization imaging system can complete the acquisition of the DoLP and the AoP images well with the frame frequency of 45 fps, which is suitable for the infrared polarization detection of the moving scenes. The study has great potential for polarization remote sensing and marine object detection.