Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.

Photonics Scanning Pentaprism System for the Integrated Inspection of Large-Aperture Telescopes.

To improve their spatial resolution and detection capabilities, future ground-based optical telescopes will have a size of 30 m, and the aperture of space telescopes will be increased to 10 m. Such large optical systems necessitate the development of large integrated testing equipment. In this study, spectrum and system alignment measurements and wavefront quality checking were performed using the sub-aperture detection method and a fiber-connected Photonics Scanning Pentaprism (PSP). First, the system was aligned using an optical truss, ensuring that the optical axis was properly positioned. Second, using a sub-aperture light beam though the entrance pupil, light spots were formed on the focal plane and transmitted to the spectrometer via fibers to obtain the corresponding spectral components. Then, by taking measurements at different system positions, a full-aperture spectrum response could be reached. Lastly, by photon-integrated interference on the focal plane, intensity interference fringes could be projected at the entrance pupil of the system. And the wavefront quality of the system could be verified by observing the fringe deformation. The measurement accuracy of the optical axis of the system is better than 2 mrad. The spectral measurement accuracy was better than 5%, and the wavefront measurement accuracy surpassed 0.1 wavelengths (1 wavelength = 633 nm). This study effectively enhanced the detection and in situ calibration capabilities of large telescope systems, ensuring that the performance requirements can be met in the design of future telescopes.

Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis.

Two new ruthenium(II) complexes [Ru(dip)2(PPßC)]PF6 (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)2(PPßC)]PF6 (Ru2, phen = 1, 10-phenanthroline) with ß-carboline derivative PPßC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC50 values ranging from 0.5 to 3.6 µM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.

Photo-Fenton-like Metal-Protein Self-Assemblies as Multifunctional Tumor Theranostic Agent.

Emerging Fenton-like activity of copper ions has inspired great exploration for tumor microenvironment-activated tumor therapy due to the toxic ·OH production for chemodynamic therapy and extra oxygen generation for photodynamic therapy (PDT). Still, the ·OH produced by copper ions is not satisfied even when copper ions are placed in a low pH environment (pH ≈ 5.0). To amplify its Fenton-like activity, in this work, one kind of Cu2+ -protein self-assemblies (C-m-ABs) loaded with photosensitizer indocyanine green (ICG) is constructed, which can catalyze H2 O2 generating more amounts of ·OH under light irradiation once Cu2+ is reduced to Cu+ by glutathione. Such fantastic phenomena confirms that C-m-ABs can act as a photo-Fenton-like agent. Furthermore, C-m-ABs can dramatically accelerate O2 generation (catalase activity) to enhance the PDT of ICG. After loading with the anticancer drug doxorubicin, C-m-ABs are further self-assembled into novel nanobelts, which simultaneously exhibit superior photo-heat conversion effects, enhanced r1 relaxation (21.416 s-1 mm-1 ) and stimuli-responsive drug release behaviors. High cytotoxicity in vitro, effective tumor accumulation capacity observed by fluorescence/photoacoustic/magnetic resonance imaging, and enhanced chemo-/photodynamic/photothermal therapeutic performance are achieved. Based on these results, a photo-Fenton-like metal-protein self-assemblies demonstrate great potential for tumor theranostics.

[Effects of glucocorticoid and histamine on MUC5AC mRNA and protein expression in human nasal polyps].

OBJECTIVE: To study the effects of dexamethasone and histamine on the expression of MUC5AC mRNA and protein in human nasal polyps. METHOD: All samples were randomly divided into control group, histamine stimulating group and dexamethasone group. The expression of MUC5AC mRNA and MUC5AC protein in nasal polyps were respectively detected by the methods of reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical assay. RESULT: The expression of MUC5AC mRNA (0.6389 +/- 0.0526) and protein (0.1934 +/- 0.0137) in histamine stimulating group were significantly higher than those of control group (0.3495 +/- 0.0357 and 0.1172 +/- 0.0173, respectively) and reduced (0.4988 +/- 0.0603 and 0.1444 +/- 0.0075, respectively) after treatment with dexamethasone. CONCLUSION: Histamine upregulates MUC5AC mRNA and protein expression. Dexamethasone downregulates MUC5AC mRNA and protein expression, which may be one of the mechanisms of downregulating mucus overproduction by dexamethasone in nasal polyps.