Spatiotemporally Comparative Analysis of HIV, Pulmonary Tuberculosis, HIV-Pulmonary Tuberculosis Coinfection in Jiangsu Province, China.

Purpose: Pulmonary tuberculosis (PTB) is a severe chronic communicable disease that causes a heavy disease burden in China. Human Immunodeficiency Virus (HIV) and PTB coinfection dramatically increases the risk of death. This study analyzes the spatiotemporal dynamics of HIV, PTB and HIV-PTB coinfection in Jiangsu Province, China, and explores the impact of socioeconomic determinants. Patients and Methods: The data on all notified HIV, PTB and HIV-PTB coinfection cases were extracted from Jiangsu Provincial Center for Disease Control and Prevention. We applied the seasonal index to identify high-risk periods of the disease. Time trend, spatial autocorrelation and SaTScan were used to analyze temporal trends, hotspots and spatiotemporal clusters of diseases. The Bayesian space-time model was conducted to examine the socioeconomic determinants. Results: The case notification rate (CNR) of PTB decreased from 2011 to 2019 in Jiangsu Province, but the CNR of HIV and HIV-PTB coinfection had an upward trend. The seasonal index of PTB was the highest in March, and its hotspots were mainly distributed in the central and northern parts, such as Xuzhou, Suqian, Lianyungang and Taizhou. HIV had the highest seasonal index in July and HIV-PTB coinfection had the highest seasonal index in June, with their hotspots mainly distributed in southern Jiangsu, involving Nanjing, Suzhou, Wuxi and Changzhou. The Bayesian space-time interaction model showed that socioeconomic factor and population density were negatively correlated with the CNR of PTB, and positively associated with the CNR of HIV and HIV-PTB coinfection. Conclusion: The spatial heterogeneity and spatiotemporal clusters of PTB, HIV and HIV-PTB coinfection are exhibited obviously in Jiangsu. More comprehensive interventions should be applied to target TB in the northern part. While in southern Jiangsu, where the economic level is well-developed and the population density is high, we should strengthen the prevention and control of HIV and HIV-PTB coinfection.

Engineering c-Met-CAR NK-92 cells as a promising therapeutic candidate for lung adenocarcinoma.

Mesenchymal-epithelial transition factor (C-Met) has been acknowledged as a significant therapeutic target for treating lung adenocarcinoma (LUAD). However, the potential application of chimeric antigen receptors (CAR)-modified natural killer (NK) cells targeting c-Met in LUAD is rarely explored. In this study, bioinformatic databases were searched and a tissue microarray (TMA) was enrolled to investigate expression status and prognostic role of c-Met in LUAD. Then, four types of c-Met-CAR structures were designed and prepared. The engineering CAR-NK cells containing c-Met-CARs were transfected, verified and characterized. The tumor-inhibitory role of c-Met-CAR-NK cells was finally evaluated in vitro and in vivo. The results demonstrated that c-Met expression elevated and confirmed that high c-Met expression was significantly associated with unfavorable prognosis in LUAD. Then, C-Met-CAR-NK cells were successfully constructed and DAP10 designed in CAR structure was a favorable stimulator for NK cell activation. CCN4 containing DAP10 co-stimulator exhibited the strongest cytotoxicity compared with other CAR-NK cells. Furthermore, CCN4 cells also exerted the prominent tumor-inhibitory effect on xenograft tumor growth. Collectively, this study suggests that DAP10 is a potent stimulator in CAR structure for NK cell activation, and CCN4-based immunotherapy may represent a promising strategy for the treatment of c-Met-positive LUAD.

A novel regulated network mediated by downregulation HIF1A-AS2 lncRNA impairs placental angiogenesis by promoting ANGPTL4 expression in preeclampsia.

Preeclampsia (PE) is the predominant medical condition leading to maternal and fetal mortality, and the lack of effective treatment increases its risk to the public health. Among the numerous predisposing factors, the ineffectual remodeling of the uterine spiral arteries, which can induce abnormal placental angiogenesis, has been focused to solve the pathogenesis of PE. According to the preceding research results, abnormal expression of long non-coding RNAs (lncRNA)s could be associated with the pathological changes inducing PE. To be more specific, lncRNA HIF1A-AS2 was proposed for its potential to participate in the molecular mechanisms underlying PE. In vitro, in trophoblast cell lines HTR-8/SVneo and human umbilical vein endothelial cells HUVECs, HIF1A-AS2 knockdown inhibited cell proliferation, migration and tube formation. Mechanistically, transcription factor FOXP1 could regulate the expression of HIF1A-AS2. Moreover, a series of assays, including RNA pull down and mass spectrometry, RNA immunoprecipitation and chromatin immunoprecipitation assay, revealed that HIF1A-AS2 interacted with Lamin A/C (LMNA) to inhibit ANGPTL4 expression in trophoblast cells, thus further participating in the progression of PE. Taken together, these findings suggested that further analysis on HIF1A-AS2 could contribute to the development of prospective therapeutic strategy for PE.

A novel immune checkpoint siglec-15 antibody inhibits LUAD by modulating mφ polarization in TME.

BACKGROUND: Siglec-15 (S15) is a type-I transmembrane protein and is considered a new candidate of immune checkpoint inhibitor for cancer immunotherapy. METHODS: In the present study, we first constructed and characterized a chimeric S15-specific monoclonal antibody (S15-4E6A). Then, the antitumor effectiveness and modulatory role of S15-4E6A in macrophages (mφs) were explored in vitro and in vivo. Finally, the underlying mechanism by which S15mAb inhibits LUAD was preliminarily explored. RESULTS: The results demonstrated the successful construction of S15-4E6A, and S15-4E6A exerted an efficacious tumor-inhibitory effect on LUAD cells and xenografts. S15-4E6A could promote M1-mφ polarization while inhibiting M2-mφ polarization, both in vitro and in vivo. CONCLUSIONS: S15-based immunotherapy that functions by modulating mφ polarization may be a promising strategy for the treatment of S15-positive LUAD.

A SARS-CoV-2 neutralizing antibody discovery by single cell sequencing and molecular modeling.

Although vaccines have been developed, mutations of SARS-CoV-2, especially the dominant B.1.617.2 (delta) and B.1.529 (omicron) strains with more than 30 mutations on their spike protein, have caused a significant decline in prophylaxis, calling for the need for drug improvement. Antibodies are drugs preferentially used in infectious diseases and are easy to get from immunized organisms. The current study combined molecular modeling and single memory B cell sequencing to assess candidate sequences before experiments, providing a strategy for the fabrication of SARS-CoV-2 neutralizing antibodies. A total of 128 sequences were obtained after sequencing 196 memory B cells, and 42 sequences were left after merging extremely similar ones and discarding incomplete ones, followed by homology modeling of the antibody variable region. Thirteen candidate sequences were expressed, of which three were tested positive for receptor binding domain recognition but only one was confirmed as having broad neutralization against several SARS-CoV-2 variants. The current study successfully obtained a SARS-CoV-2 antibody with broad neutralizing abilities and provided a strategy for antibody development in emerging infectious diseases using single memory B cell BCR sequencing and computer assistance in antibody fabrication.