In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC).

Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.

Homotypic cell membrane-cloaked biomimetic nanocarrier for the accurate photothermal-chemotherapy treatment of recurrent hepatocellular carcinoma.

BACKGROUND: Tumor recurrence in patients after surgery severely reduces the survival rate of surgical patients. Targeting and killing recurrent tumor cells and tissues is extremely important for the cancer treatment. RESULTS: Herein, we designed a nano-biomimetic photothermal-controlled drug-loading platform HepM-TSL with good targeting ability and immunocompatibility for the treatment of recurrent hepatocellular carcinoma. HepM-TSL can accurately target the recurrent tumor area with the aid of the cloaked homotypic cell membrane and release the chemotherapy drugs in a controlled manner. In vivo results have confirmed that HepM-TSL loaded with drugs and photosensitizer achieves the synergistic treatment of recurrent hepatocellular carcinoma with good therapeutic effect and slight side effects. CONCLUSION: Accordingly, HepM-TSL provides a sound photothermal-chemotherapy synergistic strategy for the treatment of other recurrent cancers besides of recurrent hepatocellular carcinoma.

Evaluation of metal pollution characteristics using water and moss in the Luanchuan molybdenum mining area, China.

Luanchuan is rich in molybdenum resources, and mining activities are frequent, but over-mining can cause serious metal pollution to the local environment. To explore the degree of metal pollution caused by mining activities, the content characteristics and spatial distribution of metals in mining areas were studied by measuring the concentrations of Fe, Mn, Zn, Ba, Mo, Cu, Cr, Co, V, and W in surface water and mosses of mining areas. In addition, the metal pollution index (HPI), contamination factor (CF), and pollution load index (PLI) were used to evaluate metal pollution, and factor analysis was used to analyze the sources of metals. The results of the analysis of surface water at the mine site indicate the most abundant element in surface water, with a maximum concentration of 3713.8 µg/L, and its content far exceeds the water quality standard of Class III of the Environmental Quality Standard for Surface Water. The results of the HPI analysis showed that nearly 90% of the surface water was moderately contaminated (HPI ≥ 15). The results of the analysis of atmospheric deposition at the mine site confirm that the metal elements with a high threat to the atmospheric environment are Mo and W. The results of PLI indicate that the level of atmospheric deposition pollution in the study area is severe (PLI > 4). Factor analysis indicated that rock weathering and mining activities were the main sources of metals. This study provides a theoretical basis for the investigation and control of metal pollution in similar metal mining areas.

Current knowledge of the immune reconstitution inflammatory syndrome in Whipple disease: a review.

Immune reconstitution inflammatory syndrome (IRIS) is characterized by exaggerated and dysregulated inflammatory responses that occur as a result of reconstitution of adaptive or innate immunity. A wide range of microorganisms have been found to be associated with IRIS, such as human immunodeficiency virus (HIV), Mycobacterium and actinobacteria. Whipple disease (WD) is an infectious disorder caused by the Gram-positive bacterium Tropheryma whipplei (T. whipplei) and IRIS also serves as a complication during its treament. Although many of these pathological mechanisms are shared with related inflammatory disorders, IRIS in WD exhibits distinct features and is poorly described in the medical literature. Novel investigations of the intestinal mucosal immune system have provided new insights into the pathogenesis of IRIS, elucidating the interplay between systemic and local immune responses. These insights may be used to identify monitoring tools for disease prevention and to develop treatment strategies. Therefore, this review synthesizes these new concepts in WD IRIS to approach the feasibility of manipulating host immunity and immune reconstitution of inflammatory syndromes from a newer, more comprehensive perspective and study hypothetical options for the management of WD IRIS.