Causal relationships of gut microbiota, plasma metabolites, and metabolite ratios with diffuse large B-cell lymphoma: a Mendelian randomization study.

Background: Recent studies have revealed changes in microbiota constitution and metabolites associated with tumor progression, however, no causal relation between microbiota or metabolites and diffuse large B-cell lymphoma (DLBCL) has yet been reported. Methods: We download a microbiota dataset from the MiBioGen study, a metabolites dataset from the Canadian Longitudinal Study on Aging (CLSA) study, and a DLBCL dataset from Integrative Epidemiology Unit Open genome-wide association study (GWAS) project. Mendelian randomization (MR) analysis was conducted using the R packages, TwoSampleMR and MR-PRESSO. Five MR methods were used: MR-Egger, inverse variance weighting (IVW), weighted median, simple mode, and weighted mode. Reverse MR analyses were also conducted to explore the causal effects of DLBCL on the microbiome, metabolites, and metabolite ratios. Pleiotropy was evaluated by MR Egger regression and MR-PRESSO global analyses, heterogeneity was assessed by Cochran's Q-test, and stability analyzed using the leave-one-out method. Results: 119 microorganisms, 1,091 plasma metabolite, and 309 metabolite ratios were analyzed. According to IVW analysis, five microorganisms were associated with risk of DLBCL. The genera Terrisporobacter (OR: 3.431, p = 0.049) andgenera Oscillibacter (OR: 2.406, p = 0.029) were associated with higher risk of DLBCL. Further, 27 plasma metabolites were identified as having a significant causal relationships with DLBCL, among which citrate levels had the most significant protective causal effect against DLBCL (p = 0.006), while glycosyl-N-tricosanoyl-sphingadienine levels was related to higher risk of DLBCL (p = 0.003). In addition, we identified 19 metabolite ratios with significant causal relationships to DLBCL, of which taurine/glutamate ratio had the most significant protective causal effect (p = 0.005), while the phosphoethanolamine/choline ratio was related to higher risk of DLBCL (p = 0.009). Reverse MR analysis did not reveal any significant causal influence of DLBCL on the above microbiota, metabolites, and metabolite ratios (p > 0.05). Sensitivity analyses revealed no significant heterogeneity or pleiotropy (p > 0.05). Conclusion: We present the first elucidation of the causal influence of microbiota and metabolites on DLBCL using MR methods, providing novel insights for potential targeting of specific microbiota or metabolites to prevent, assist in diagnosis, and treat DLBCL.

JAML inhibits colorectal carcinogenesis by modulating the tumor immune microenvironment.

It is necessary to explore new targets for the treatment of colon adenocarcinoma (COAD) according to the tumor microenvironment. The expression levels of JAML and CXADR were analyzed by bioinformatics analysis and validation of clinical samples. JAML over-expression CD8+ T cell line was constructed, and the proliferation activity was detected by MTT. The production of inflammatory factors was detected by ELISA. The expression of immune checkpoint PD-1 and TIM-3 was detected by Western blot. The apoptosis level was detected by flow cytometry and apoptosis markers. The AOM/DSS mouse model of colorectal cancer was constructed. The expression levels of JAML, CXADR and PD-1 were detected by PCR and Western blot, and the proportion of CD8+ T cells and exhausted T cells were detected by flow cytometry. The expression levels of JAML and CXADR were significantly decreased in colon cancer tissues. Overexpression of JAML can promote the proliferation of T cells, secrete a variety of inflammatory factors. Overexpression of CXADR can reduce the proliferation of colorectal cancer cells, promote apoptosis, and down-regulate the migration and invasion ability of tumor cells. Both JAML agonists and PD-L1 inhibitors can effectively treat colorectal cancer, and the combined use of JAML agonists and PD-L1 inhibitors can enhance the effect. JAML can promote the proliferation and toxicity of CD8+ T cells and down-regulate the expression of immune checkpoints in colon cancer. CXADR can inhibit the proliferation of cancer cells and promote the apoptosis. JAML agonist can effectively treat colorectal cancer by regulating CD8+ T cells.

Association between C-reactive protein and all-cause mortality among critically ill patients with acute kidney injury.

AIM: To explore the relationship between C-reactive protein (CRP) and mortality in critically ill patients with acute kidney injury (AKI). MATERIALS AND METHODS: A total of 580 patients diagnosed with AKI within 48 hours of ICU admission between September 2017 and August 2019 were enrolled. Patients were followed for all-cause mortality in-hospital and then up to 2 years after discharge. We performed two multivariate regression analysis to assess the association between CRP and mortality, and conducted stratified analysis to assess whether the effect of the CRP differed across subgroups. RESULTS: According to initial CRP quartiles, patients were divided into 4 groups (quartile 1, CRP ≤ 2.87 mg/L; quartile 2, CRP: 2.87 - 25.95 mg/L; quartile 3, CRP: 25.95 - 111.51 mg/L; quartile 4, CRP > 111.51 mg/L). Patients with high CRP levels have higher APACHE-II score, longer length of stay in the ICU, and higher mortality. In multivariate regression analysis, high CRP was associated with the increased risk of in-hospital mortality after adjusting for age, gender, surgical grade, heart rate, serum potassium, serum chloride, coronary heart disease, and atherosclerotic cerebral infarction (quartile 4 vs. quartile 1, OR: 3.810, 95% CI: 2.081 - 6.973). For 2-year mortality, the increased trend was still significant with the OR (95% CI) of the quartile 4 group of 5.117 (2.678 - 9.780) after adjusting for confounders. Subgroup analyses detected in each group showed that the in-hospital and 2-year risk of mortality increased with higher CRP levels. CONCLUSION: Higher CRP level was associated with the increased risk of mortality in critically ill patients with AKI.

Serum circulating free DNA of syncytin-1 as a novel molecular marker for early diagnosis of non-small-cell lung cancer.

Background: Liquid biopsy has been receiving attention as an emerging detection technology in the clinical application of non-small-cell lung cancer (NSCLC). Methods: We quantified serum circulating free DNA (cfDNA) of syncytin-1 in 126 patients and 106 controls, analyzed the correlation of level with pathological parameters and explored diagnostic utility. Results: The cfDNA of syncytin-1 levels in NSCLC patients were higher than healthy controls (p < 0.0001). These levels were associated with smoking history (p = 0.0393). The area under the curve of cfDNA of syncytin-1 was 0.802, and combination of cfDNA of syncytin-1/cytokeratin 19 fragment antigen 21-1/carcinoembryonic antigen markers improved diagnostic efficiency. Conclusion: The cfDNA of syncytin-1 was detected in NSCLC patients and can be used as a novel molecular marker for early diagnosis.

High expression levels of TLR9 and PD-L1 indicates a poor prognosis in patients with angioimmunoblastic T-cell lymphoma: a retrospective study of 88 cases in a single center.

Background: The role of TLR9 expressed by tumor cells in evading immune surveillance was confirmed. PD-L1 expression in tumor cells plays a key role in tumor immune escape, which is associated with poor prognosis. However, the clinical relevance of TLR9 and PD-L1 expression in angioimmunoblastic T-cell lymphoma (AITL) has not been evaluated. Materials and methods: In this study, we identified differentially expressed genes in AITL samples by bioinformatic analysis, and we first examined TLR9 and PD-L1 expression by immunohistochemical staining in patients with AITL and compared these data with clinical features and survival time. Results: It was found that the expression of PD-L1 and multiple TLRs was higher in AITL than normal T-cell samples, and TLR9 and PD-L1 expression displayed complex interactions by bioinformatic analysis. The rates of TLR9 and PD-L1 high expression were 69% and 50%, respectively. High expression of either TLR9 or PD-L1 indicated a poor survival rate for patients with AITL. Multivariate analysis further confirmed that high expression levels of TLR9 and PD-L1 were unfavorable prognostic factors for AITL. We further found inferior overall survival in AITL with clinical features of ECOG status ≥ 2, advanced-stage, elevated serum LDH levels, elevated serum ß2-MG levels, and high IPI score. Conclusion: TLR9 and PD-L1 expression may be a novel predictor of prognosis for patients with AITL and may serve as potential therapeutic strategy.

TLR9 expression is associated with PD-L1 expression and indicates a poor prognosis in patients with peripheral T-cell lymphomas.

Toll-like receptor9 (TLR9), a member of pattern recognition receptors, play an important role in tumor immunologic surveillance. However, the clinical impact of TLR9 and programmed cell death-ligand 1 (PD-L1) in peripheral T-cell lymphomas (PTCL) remains unclear. In this study, we examined the expression of TLR9 and PD-L1 by immunohistochemical staining in patients with PTCL, and evaluated the clinical significance between expression and clinicopathological features. We found that the rates of high expression of TLR9 and PD-L1 on tumor cells were 65.3% and 45.8% in PTCL, respectively. TLR9 expression was associated with PD-L1 expression in PTCL. Moreover, TLR9 expression was associated with gender, ECOG score, Ki-67 expression, while PD-L1 expression was associated with the number of extranodal involvement and platelet count. High expression of either TLR9 or PD-L1 indicated a poor survival rate for patients with PTCL. Multivariate analysis confirmed that high expression of TLR9 and PD-L1 were unfavorable prognostic factors for patients with PTCL. Thus, TLR9 and PD-L1 expression might be important on the point of prognostic markers in PTCL.

The prognostic value of toll-like receptor5 and programmed cell death-ligand1 in patients with peripheral T-cell non-Hodgkin lymphoma.

TLR5 is expressed in a variety of tumors. However, the clinical impact of TLR5 in Peripheral T-cell non-Hodgkin lymphomas (PTCLs) remains unclear. We analyzed differentially expressed genes in PTCLs samples from Gene Expression Omnibus database. We examined TLR5 and programed cell death-ligand1 (PD-L1) expression by immunohistochemistry in PTCLs tissues. Gene expression profiling shown PD-L1 and TLR5 expression was higher in PTCLs than in normal samples. The rates of high TLR5 and PD-L1 expression were 12.5% and 45.8%. We found association between TLR5 and PD-L1 expression. Low TLR5 expression or high PD-L1 expression was correlated with shorter overall survival and inferior disease-free survival. Multivariate Cox regression analysis shown low TLR5 expression, high PD-L1 expression, gender, and high IPI score were prognostic factors (p < .05). PTCLs patients with low TLR5 expression and high PD-L1 expression had worse prognosis. TLR5 and PD-L1 may serve as potential therapeutic targets in PTCLs patients.