Background: Chimeric antigen receptor T (CAR-T) cell therapy has made significant advances for hematological malignancies but encounters obstacles in the treatment of solid tumors mainly due to tumor immunosuppressive microenvironment.Methods: Immunohistochemistry analysis was performed to examine the cellular expression of nectin cell adhesion molecule-4 (Nectin4) and fibroblast activation protein (FAP) in a variety of malignant solid tumors. Then, we engineered the fourth-generation Nectin4-targeted CAR-T (Nectin4-7.19 CAR-T) and FAP-targeted CAR-T (FAP-12 CAR-T) cells to evaluate their safety and efficacy in vitro and in vivo.Results: In our study, we firstly demonstrated the aberrant overexpression of Nectin4 on both primary and metastatic solid tumors and FAP on cancer-associated fibroblasts. Then, we found that our fourth-generation Nectin4-7.19 CAR-T cells expressed IL-7 and CCL19 efficiently and exhibited superior proliferation, migration, and cytotoxicity compared to the second-generation Nectin4 CAR-T cells, while FAP-12 CAR-T cells exerted their ability of targeting both murine and human FAP effectively in vitro. In a fully immune-competent mouse model of metastatic colorectal cancer, lymphodepletion pretreated mice achieved complete remission with human Nectin4-targeted murine CAR-T (Nectin4 mCAR-T) cells. In the NSG mouse model of lung metastases, Nectin4-7.19 CAR-T cells eradicated metastatic tumors and prolonged survival in combination with FAP-12 CAR-T cells.Conclusions: These findings showed that Nectin4-7.19 CAR-T cells had potential therapeutic efficacy and exerted a synergistic role with FAP-12 CAR-T cells, further demonstrating that Nectin4 and FAP were able to serve as promising targets for safe and effective CAR-T therapy of malignant solid tumors.

Objective: The present study aimed to explore the combined associations of depression and cognitive impairment with functional disability and mortality, and whether the joint effects of depression and cognitive impairment on mortality were influenced by functional disability.Methods: A total of 2,345 participants aged 60 and above from the 2011–2014 cycle of the National Health and Nutrition Examination Survey (NHANES) were included in the analyses. Questionnaires were used to evaluated depression, global cognitive function and functional disability (including disability in activities of daily living (ADLs), instrumental activities of daily living (IADLs), leisure and social activities (LSA), lower extremity mobility (LEM), and general physical activity (GPA)). Mortality status was ascertained up to December 31, 2019. Multivariable logistic regression was performed to investigate the associations of depression and low global cognition with functional disability. Cox proportional hazards regression models were conducted to evaluate the effect of depression and low global cognition on mortality.Results: Interactions between depression and low global cognition were observed when exploring associations of depression and low global cognition with IADLs disability, LEM disability, and cardiovascular mortality. Compared with normal participants, participants with both depression and low global cognition had the highest odds ratios of disability in ADLs, IADLs, LSA, LEM, and GPA. Besides, participants with both depression and low global cognition also had the highest hazard ratios of all-cause mortality and cardiovascular mortality, and these associations remained after adjusting for disability in ADLs, IADLs, LSA, LEM, and GPA.Conclusion: Older adults with both depression and low global cognition were more likely to have functional disability, and had the highest risk of all-cause mortality and cardiovascular mortality.

Adipose tissue macrophage (ATM) has been shown to play a key role in the pathogenesis of obesity-associated adipose tissue inflammation and metabolic diseases. However, the upstream factors that integrate the environmental signals to control ATM activation and adipose inflammation in obesity remain elusive. Here, we identify BAF60a, a subunit of the SWI/SNF chromatin remodeling complexes, as the central checkpoint regulator of obesity-induced ATM activation, adipose tissue inflammation and systemic metabolic impairment. BAF60a expression was robustly downregulated in the adipose tissue stromal vascular fractions (SVFs) in type 2 diabetic mice. Myeloid-specific BAF60a ablation (BaMKO) promotes ATM pro-inflammatory activation, exacerbating diet-induced obesity, insulin resistance and metabolic dysfunction. Conversely, myeloid-specific overexpression of BAF60a in mice attenuates macrophage pro-inflammatory activation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that BAF60a inactivation triggers the expression of pro-inflammatory gene program through chromatin remodeling. Moreover, motif analysis of ATAC-Seq and CUT&Tag-Seq data identifies the transcription factor Atf3 that physically interacts with BAF60a to suppress the pro-inflammatory gene expression, thereby controlling ATM activation and metabolic inflammation in obesity. Consistently, myeloid-specific Atf3 deficiency also promotes the pro-inflammatory activation of macrophage. Together, this work uncovers BAF60a/Atf3 axis as the key regulator in obesity-associated ATM activation, adipose tissue inflammation and metabolic diseases.

Some studies have investigated the impact of intermittent fasting (IF) for patients with multiple sclerosis (MS). We aimed to conduct a comprehensive systematic review to analyze and summarize all clinical studies concerning the effects of IF on patients with MS. We conducted an exhaustive review of information available in the Embase, Cochrane, and PubMed databases up until 1 September 2023. All clinical research relating to the impacts of IF for patients with MS were included. In total, this systematic review encompassed 5 studies, which included four RCTs and one pilot study. Each study involved was assessed of high quality. The results from these studies demonstrate that IF protocols could potentially serve as an effective dietary strategy for managing symptoms and improving the quality of life in individuals afflicted with MS. In conclusion, IF might be a potential beneficial dietary intervention for MS. However, the number of trials in this field is relatively limited. The large-scale clinical trials to investigate the effects of IF for MS are urgently needed, which may be helpful to manage this intricate neuroimmune disorder.Systematic review registration: https://inplasy.com, identifier INPLASY2023100021.

Objective: The role of C-X-C motif chemokine 12 (CXCL12) in atherosclerotic cardiovascular diseases (ASCVDs) has emerged as one of the research hotspots in recent years. Studies reported that the higher blood CXCL12 level was associated with increased major adverse cardiovascular events (MACEs), but the results were inconsistent. The objective of this study was to clarify the prognostic value of the blood CXCL12 level in patients with coronary artery disease (CAD) through meta-analysis.Methods: All related studies about the association between the blood CXCL12 level and the prognosis of CAD were comprehensively searched and screened according to inclusion criteria and exclusion criteria. The quality of the included literature was evaluated using the Newcastle-Ottawa Scale (NOS). The heterogeneity test was conducted, and the pooled hazard risk (HR) or the odds ratio (OR) with a 95% confidence interval (CI) was calculated using the fixed-effect or random-effects model accordingly. Publication bias was evaluated using Begg's funnel plot and Egger's test. Sensitivity analysis and subgroup analysis were also conducted.Results: A total of 12 original studies with 2,959 CAD subjects were included in the final data combination. The pooled data indicated a significant association between higher CXCL12 levels and MACEs both in univariate analysis (HR 5.23, 95% CI 2.48–11.04) and multivariate analysis (HR 2.53, 95% CI 2.03–3.16) in the CXCL12 level as the category variable group. In the CXCL12 level as the continuous variable group, the result also indicated that the higher CXCL12 level significantly predicted future MACEs (multivariate OR 1.55, 95% CI 1.02–2.35). Subgroup analysis of the CXCL12 level as the category variable group found significant associations in all acute coronary syndrome (ACS) (univariate HR 9.72, 95% CI 4.69–20.15; multivariate HR 2.47, 95% CI 1.79–3.40), non-ACS (univariate HR 2.73, 95% CI 1.65–4.54; multivariate HR 3.49, 95% CI 1.66–7.33), Asian (univariate HR 7.43, 95% CI 1.70–32.49; multivariate HR 2.21, 95% CI 1.71–2.85), Caucasian (univariate HR 3.90, 95% CI 2.73–5.57; multivariate HR 3.87, 95% CI 2.48–6.04), short-term (univariate HR 9.36, 95% CI 4.10–21.37; multivariate HR 2.72, 95% CI 1.97–3.76), and long-term (univariate HR 2.86, 95% CI 1.62–5.04; multivariate HR 2.38, 95% CI 1.76–3.22) subgroups. Subgroup analysis of the CXCL12 level as the continuous variable group found significant associations in non-ACS (multivariate OR 1.53, 95% CI 1.23–1.92), Caucasian (multivariate OR 3.83, 95% CI 1.44–10.19), and long-term (multivariate OR 1.62, 95% CI 1.37–1.93) subgroups, but not in ACS (multivariate OR 1.36, 95% CI 0.67–2.75), Asian (multivariate OR 1.40, 95% CI 0.91–2.14), and short-term (multivariate OR 1.16, 95% CI 0.28–4.76) subgroups. No significant publication bias was found in this meta-analysis.Conclusion: The higher blood CXCL12 level is associated with increased MACEs in patients with CAD, and the blood CXCL12 level may serve as an important prognostic index for CAD. Integrating the blood CXCL12 level into CAD risk assessment tools may provide more comprehensive messages for evaluating and managing patients with CAD.