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Gram-negative bacteria can naturally produce nanosized spherical outer membrane vesicles (OMVs) with a lipid bilayer membrane, possessing immunostimulatory capabilities to be potentially applied in tumor therapy. However, the systemic toxicity induced by pathogen-associated molecular patterns (PAMPs) of OMVs is the main obstacle for their clinical translation. Herein, melanin-loaded OMVs were produced with a genetic engineering strategy and further coated with calcium phosphate (CaP) to reduce their toxicity to enhance tumor treatment effects. Wild-type bacterium Escherichia coliNissle 1917 (EcN) was genetically engineered to highly express tyrosinase to catalyze the intracellular synthesis of melanin, giving melanin-loaded OMVs (OMVMel). To reduce the systemic toxicity in tumor therapy, OMVMelwas coated with CaP by surface mineralization to obtain OMVMel@CaP. In comparison with OMVMel, OMVMel@CaP showed lower systemic inflammatory responses in healthy mice and less damage to the liver, spleen, lung, and kidney, so the administration dose could be increased to enhance the antitumor effect. In the acidic tumor microenvironment, the CaP shell disintegrated to release OMVMelto trigger antitumor immune responses. Under costimulation of OMVMelacting as immunoadjuvants and the damage-associated molecular patterns (DAMPs) released by the photothermal effect, the efficiency of tumor photothermal/immunotherapy was largely boosted through promoting the infiltration of matured DCs, M1 macrophages, and activated CD8+T cells, decreasing the ratio of MDSCs in tumors.

Chemodynamic therapy (CDT) destroys cancer cells by converting H2O2or O2into reactive oxygen species (ROS), but its therapeutic efficacy is restricted by the antioxidant capacity of tumor. Previous solutions focused on strengthening the nanodrugs with the ability to increase ROS production or weaken the antioxidant capacity of cancer cells. Conversely, we here develop a mild nanodrug with negligible side effects. Specifically, the Au@Pt nanozyme decorated on a bacterial surface (Bac-Au@Pt) is reported to achieve precise CDT. Due to the tumor targeting ability of bacteria and catalytic property of Au@Pt nanozyme under acidic conditions, this nanosystem can release ROS to tumor cells effectively. In addition, the interferon gamma released by T cells specifically decreases the intracellular reductants in tumor cells, while having no obvious effect on normal cells. Therefore, a low dose of Bac-Au@Pt achieves a satisfactory therapeutic efficacy to tumor cells and is nontoxic to normal cells even at their acidic components. This nanosystem enables CDT and immunotherapy to mutually benefit and improve by each other, providing a promising strategy to achieve high anticancer efficacy even with a low dose usage.

Computer-controlled subaperture polishing technology is limited by its propensity to introduce midspatial frequency (MSF) error (ripple error), which significantly inhibits the performance improvement of optical systems. The pseudo-random polishing path is an important method for suppressing MSF error. However, a pseudo-random path that ensures both path smoothness and planning efficiency is difficult to generate. This paper proposes a novel, to the best of our knowledge, pseudo-random path planning method employing a reconstructive points algorithm that efficiently achieves full coverage of the workpiece under massive sampling points at once. Moreover, the generation time for millions of path points is reduced to less than 3 minutes. Additionally, a path modification method is proposed that achieves smooth processing on a machine tool with few additional path points; the vibration magnitude under the proposed smooth path can be reduced to 0.749 g (gravity acceleration), which is the same as that of a raster path. A precise speed management method is also proposed to ensure precise surface error corrections. Overall, the experimental results show that the peak valley of the form error can be converted to 0.115λ using the proposed algorithm without introducing a periodic MSF error.

Bacteria show promise for use in the field of combination cancer therapy because of their abilities to accumulate in tumors and their roles as natural immunologic adjuvants. However, the huge size of bacteria decreases their chances of being delivered into tumor cells. Moreover, their toxins may cause systemic toxicity in living organisms. Here, we proposed a method to in situ synthesize Au nanoparticles on the surface of Escherichia coli(E. coli), followed by sonication to acquire Au nanoparticles loaded membrane nanosheets (AuMNs) for use in photothermal and combination cancer therapy. Compared to E. coli-loaded Au nanoparticles (E. coli@Au), the small size of membrane nanosheets can be successfully delivered into tumor cells. In addition, the enrichment of AuMNs in tumor site is significantly enhanced via EPR effect, facilitating to activate photothermal conversion under 808 nm laser. Besides, the function of bacteria as natural immunologic adjuvants to promote anti-PD-L1 efficacy is still retained in AuMNs, while the inflammation and damage to viscera caused by AuMNs were milder than E. coli@Au. This study aims to decrease the systemic toxicity of bacteria and promote anti-PD-L1 efficacy in bacteria-mediated combination therapy, so as to open up a new avenue for drug delivery via natural processes.

Optical smoothing is a very effective method to restrict mid-to-high spatial frequency errors generated by computer-controlled sub-aperture polishing technologies. According to Preston’s equation, pressure distribution is the key factor in describing the smoothing effect of a tool. Although the classic bridging model can solve pressure distribution during the smoothing process, it is only suitable for a tool that consists of a rigid base, compliant interlayer, thin metal plate, and pitch polishing layer. In this paper, a mathematical model applicable for any multi-layer polishing tool is proposed, which helps to calculate the pressure distribution dependent on the thickness of the layer, mid-spatial frequency errors at different periods, and the structures of polishing tools. Based on the model, the pressure distributions and smoothing rates of a rigid tool and a semi-flexible tool are deduced and compared in detail. Validity and improvement in accuracy are verified by comparison with the finite element model. In addition, three groups of experiments using a rigid tool and a semi-flexible tool for smoothing 4 mm and 8 mm period errors generated by magnetorheological finishing are carried out to validate the model. The simulation result of the smoothing rates of the errors after every smoothing process matches well with the experiment results.

Background People living with HIV (PLWH) have a worse prognosis than the general population. Locally advanced or metastatic bladder cancer (BCa) in PLWH has gradually been increasing in recent years. Immune checkpoint inhibitors can improve antitumor activity in the general population, but relevant data in PLWH are unknown. We thus evaluated the efficacy and safety of tislelizumab in PLWH with locally advanced or metastatic BCa.Methods This retrospective study included 24 patients with locally advanced or metastatic BCa, both HIV positive or negative who underwent tislelizumab treatment (200 mg i.v. every 3 weeks, Q3W) from the multi-centers between December 2019 and March 2022. Demographic details, clinical data, and cancer status were collected. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and treatment-related adverse events (TRAEs) were recorded and evaluated.Results A total of 24 individuals were chosen for this study, 10 had HIV and the other 14 did not. The median OS in the HIV-negative group was 62.3 (95% CI, 52.6 to 72.2) was no longer than that of the PLWH group 41.9 (95% CI, 32.9 to 51.0) weeks (HR .7, [95% CI, .17 to 3.30], P= .70). Furthermore, the median PFS in the HIV-negative group was 50.0 (95% CI, 36.2 to 63.9) was also no longer than that of the PLWH group 35.9 (95% CI, 25.5 to 46.3) (HR, 1.34, [95% CI, .38 to 4.69], P= .63). Of 24 patients, treatment-related adverse events, grade 3 or 4 occurred in 2 in the PLWH group and 3 in the HIV-negative group.Conclusion This retrospective multi-center study suggested that tislelizumab may provide encouraging antitumor activity and could be generally well tolerated. In this retrospective analysis of patients with locally advanced or metastatic BCa, it seems that PLWH may have similar overall and progression-free survival compared to HIV-negative cases.