Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer.

Given the heterogeneity of solid tumors, single-target CAR-T cell therapy often leads to recurrence, especially in ovarian cancer (OV). Here, we constructed a Tandem-CAR targeting two antigens with secretory activity (IL-12) to improve the effects of CAR-T cell therapy. Twenty coexpressed upregulated genes were identified from the GEO database, and we found FOLR1 (folate receptor 1) and MSLN (mesothelin) were specifically and highly expressed in cancer tissues and only 11.25% of samples were negative for both antigens. We observed an increased proliferation rate for these three CAR-T cells, and Tandem CAR-T cells could efficiently lyse antigen-positive OV cells in vitro and secrete higher levels of cytokines than single-target CAR-T cells. More importantly, in vivo experiments indicated that Tandem CAR-T cells markedly decreased tumor volume, exhibited enhanced antitumor activity, and prolonged mouse survival. Furthermore, the infiltration and persistence of T cells in the Tandem-CAR group were higher than those in the MSLN-CAR and Control-T groups but comparable to those in the FOLR1-CAR group. Collectively, this study demonstrated that Tandem CAR-T cells secreting IL-12 could enhance immunotherapeutic effects by reducing tumor antigen escape and increasing T cell functionality, which could be a promising therapeutic strategy for OV and other solid tumors.

Short-term ambient nitrogen dioxide exposure is associated with increased risk of spontaneous abortion: A hospital-based study.

There are increasing concerns with regard to spontaneous abortion (SAB), the loss of pregnancy without external intervention before 20 weeks of gestation, among reproductive-aged women. To date, limited evidence is available concerning the association between SAB and air pollutants, especially in developing countries. Daily baseline outpatient data for SAB from January 1, 2014, to December 31, 2018 (1826 days) were obtained in Chongqing, a metropolis of southwest China. The over-dispersed Poisson generalized additive model with control of meteorological conditions and day of week was used to estimate the short-term effects of ambient air pollution on the daily number of SAB outpatients. A total of 42,334 SAB outpatient visits for SAB were recorded. No statistically significant association was observed between SAB and CO, PM2.5, PM10, O3, and SO2. The positive association only appeared for NO2: positive associations between SAB and NO2 were observed in both single-day models (lag 0, lag 1, lag 3, and lag 4) and cumulative exposure models (lag 01, lag 03, and lag 05) and the most significant effects were observed at lag 05 (3.289%; 95% CI: 1.568%, 5.011%). Moreover, the women with higher ages (30-39 and > 39) were more sensitive than those with lower ages (18-29), and the effect estimates were more evident in cool seasons. Collectively, our results suggested that short-term NO2 exposure was associated with higher risk of SAB, especially in elder women and cool seasons, which may contribute to further understand the role of air pollution on SAB and other adverse obstetric outcomes.

An integrated metabonomic and proteomic study on Kidney-Yin Deficiency Syndrome patients with diabetes mellitus in China.

AIM: To investigate specific changes in metabolites and proteins of Kidney-Yin Deficiency Syndrome (KYDS) patients with diabetes mellitus (DM) in China. METHODS: KYDS (n=29) and non-KYDS (n=23) patients with DM were recruited for this study. The KYDS was diagnosed by two senior TCM clinicians separately. The metabonomic and proteomic profiles of the patients were assessed using a metabonomic strategy based on NMR with multivariate analysis and a proteomic strategy based on MALDI-TOF-MS, respectively. RESULTS: Eighteen upregulated peptides and thirty downregulated peptides were observed in the plasma of the KYDS patients. Comparing the proteomic profiles of the KYDS and non-KYDS groups, however, no significantly differentially expressed peptides were found. At the same time, major metabolic alterations were found to distinguish the two groups, including eight significantly changed metabolites (creatinine, citrate, TMAO, phenylalanine, tyrosine, alanine, glycine and taurine). The levels of creatinine, citrate, TMAO, phenylalanine and tyrosine were decreased, whereas the levels of alanine, glycine and taurine were increased in the KYDS patients. These biochemical changes were found to be associated with alterations in amino acid metabolism, energy metabolism and gut microflora. CONCLUSION: The identification of distinct expression profiles of metabolites and signaling pathways in KYDS patients with DM suggests that there are indeed molecular signatures underlying the principles of 'Syndrome Differentiation' in traditional Chinese medicine.

Antidepressant-like effects and memory enhancement of a herbal formula in mice exposed to chronic mild stress.

Shen Yuan Gan (SYG) is a Chinese herbal prescription composed of total saponins of Panax ginseng and total oligosaccharide esters of Polygala tenuifolia (2:1). Our previous studies have demonstrated that SYG has antidepressant-like effects in various mouse models of behavioral depression. The present study aimed to test whether SYG affected chronic mild stress (CMS)-induced depression and cognitive impairment in mice. We found that a 5-week CMS schedule induced significant degradation of the coat state, decreased sucrose intake in the sucrose-preference test, and increased the latency to feed in the noveltysuppressed feeding test. All of these CMS-induced changes were ameliorated by SYG (100 and 200 mg/kg) and fluoxetine (10 mg/kg). In addition, SYG restored the decreased monoamine neurotransmitter concentrations (serotonin, dopamine, norepinephrine and acetylcholine) induced by CMS in the prefrontal cortex. Interestingly, SYG ameliorated CMS-induced cognitive impairment in the step-through test, and increased the acetylcholine level in the prefrontal cortex. These results suggest that SYG has an antidepressant-like action and enhances cognition by modulating the serotonin, dopamine, norepinephrine, and acetylcholine levels in the prefrontal cortex.