Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.

Objective:To observe and analyze the correlation between the changes of macular microvascular structure and the level of intracocular fluid cytokines in patients with diabetic macular edema (DME).Methods:A prospective clinical study. From December 2022 to June 2024, 20 patients with 25 eyes of DME diagnosed by Department of Ophthalmology of Linyi People's Hospital were included in the study. Among them, 14 males had 17 eyes and 6 females had 8 eyes. Age was (55.08±10.34) years. Optical coherence tomography (OCT) and OCT angiography (OCTA) were used to scan the macular region at a range of 6 mm×6 mm. Central retinal thickness (CRT), blood flow density of superficial retinal capillary plexus (SCP) and area of fovea avascular zone (FAZ) were measured. The anterior aqueous humor was extracted before the first intravitreal injection of anti-vascular endothelial growth factor (VEGF), the concentrations of interleukin (IL-6), IL-8, VEGF, vascular cell adhesion molecule (VCAM), placental growth factor (PLGF) and monocyte chemotactic protein-1 (MCP-1) were detected. The correlation between macular microvascular structure and aqueous humor cytokines was analyzed by Spearman correlation analysis.Results:The CRT of the affected eyes was (617.40±167.64) μm, the SCP flow density was (39.56±1.55)%, and the FAZ area was (0.46±0.13) mm 2. The concentrations of IL-6, IL-8, VEGF, VCAM, PLGF and MCP-1 in aqueous humor were (301.36±690.52), (29.15±20.56), (71.37±29.32) and (5 621.22±7 241.06), (72.40±13.43), (464.07±163.26) pg/ml, respectively. Correlation analysis showed that there was a significant positive correlation between CRT and the concentrations of aqueous cytokines VEGF and PLGF ( r=0.460, 0.462, P<0.05). FAZ area was positively correlated with VEGF and MCP-1 concentrations ( r=0.414, 0.465; P<0.05). There was a significant negative correlation between SCP blood flow density and IL-6 ( r=0.401, P<0.05). Conclusion:There was a significant correlation between the morphological structure of macular area and the damage degree of microvessels around macular area in DME patients and the concentration of aqueous cytokines.

Objective:To observe and analyze the correlation between the changes of macular microvascular structure and the level of intracocular fluid cytokines in patients with diabetic macular edema (DME).Methods:A prospective clinical study. From December 2022 to June 2024, 20 patients with 25 eyes of DME diagnosed by Department of Ophthalmology of Linyi People's Hospital were included in the study. Among them, 14 males had 17 eyes and 6 females had 8 eyes. Age was (55.08±10.34) years. Optical coherence tomography (OCT) and OCT angiography (OCTA) were used to scan the macular region at a range of 6 mm×6 mm. Central retinal thickness (CRT), blood flow density of superficial retinal capillary plexus (SCP) and area of fovea avascular zone (FAZ) were measured. The anterior aqueous humor was extracted before the first intravitreal injection of anti-vascular endothelial growth factor (VEGF), the concentrations of interleukin (IL-6), IL-8, VEGF, vascular cell adhesion molecule (VCAM), placental growth factor (PLGF) and monocyte chemotactic protein-1 (MCP-1) were detected. The correlation between macular microvascular structure and aqueous humor cytokines was analyzed by Spearman correlation analysis.Results:The CRT of the affected eyes was (617.40±167.64) μm, the SCP flow density was (39.56±1.55)%, and the FAZ area was (0.46±0.13) mm 2. The concentrations of IL-6, IL-8, VEGF, VCAM, PLGF and MCP-1 in aqueous humor were (301.36±690.52), (29.15±20.56), (71.37±29.32) and (5 621.22±7 241.06), (72.40±13.43), (464.07±163.26) pg/ml, respectively. Correlation analysis showed that there was a significant positive correlation between CRT and the concentrations of aqueous cytokines VEGF and PLGF ( r=0.460, 0.462, P<0.05). FAZ area was positively correlated with VEGF and MCP-1 concentrations ( r=0.414, 0.465; P<0.05). There was a significant negative correlation between SCP blood flow density and IL-6 ( r=0.401, P<0.05). Conclusion:There was a significant correlation between the morphological structure of macular area and the damage degree of microvessels around macular area in DME patients and the concentration of aqueous cytokines.

Chronic inflammation is critical in the onset and progression of atherosclerosis (AS). The lipopolysaccharide (LPS) level in the circulation system is elevated in AS patients and animal models, which is correlated with the severity of AS. Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype, aggravate inflammation, and ultimately contribute to the exacerbation of AS, LPS in the circulation system was supposed to be the therapeutic target for AS treatment. In the present study, polymyxin (PMB) covalently conjugated to PEGylated liposomes (PLPs) were formulated to adsorb LPS through specific interactions between PMB and LPS. In vitro, the experiments demonstrated that PLPs could adsorb LPS, reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells. In vivo, the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines, decreased the proportion of M1-type macrophages in AS plaque, stabilized AS plaque, and downsized the plaque burdens in arteries, which eventually attenuated the progression of AS. Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.

Objective To evaluate the resistance of multidrug-resistant Mycobacterium tuberculosis ( M. tb) strains to bedaquiline ( BDQ) and to analyze the relationships between their genotypes and BDQ-re-sistant phenotypes in order to provide a scientific basis for rational use of BDQ for the treatment of multidrug-resistant tuberculosis ( MDR-TB) in clinical practice. Methods A total of 387 clinical M. tb strains, inclu-ding 100 pan-susceptible strains and 287 strains isolated from patients with MDR ( MDR-TB strains) , were enrolled in this study. Of the 287 MDR-TB strains, 77 strains were collected in Chongqing in 2015 and the other strains were collected in a national drug-resistant tuberculosis survey conducted in China during 2007 to 2008. Minimum inhibitory concentrations (MIC) of BDQ against those strains were detected. Genotypes of those strains were analyzed by Spoligotyping. Differences in the resistant rates against BDQ between Beijing genotype and non-Beijng genotype MDR-TB strains were comparatively analyzed. Results MIC50 and MIC90 of BDQ against the 287 MDR-TB strains were 0. 03 μg/ml and 0. 25 μg/ml, respectively. Nineteen out of the 287 MDR-TB strains (6. 6%) were resistant to BDQ. Based on the Spoligotyping, 195 strains were clas-sified into Beijing genotype, and the other 92 strains belonged to non-Beijing genotype. Statistical analysis revealed that the BDQ-resistant rate in Being genotype strains (4. 6%, 9/195) was lower than that in non-Beijing genotype strains (10. 9%, 10/92, χ2=3. 955, P=0. 047). In addition, the MIC50 and MIC90 of BDQ against pan-susceptible strains were 0. 03 μg/ml and 0. 12 μg/ml, respectively. Sixty-three pan-sus-ceptible strains belonged to Beijing genotype and the other 37 strains belonged to non-Beijing genotype. None of the pan-susceptible strains was resistant to BDQ. Conclusion This study indicates that BDQ showed stronger in vitro antibacterial activity against the MDR-TB strains isolated in China. A correlation between non-Beijing genotype and BDQ resistance is observed in those MDR strains. MDR strains of Beijing genotype are more susceptible to BDQ than those of non-Beijing genotype.