Pathological significance of abnormal recepteur d'origine nantais and programmed death ligand 1 expression in colorectal cancer.

BACKGROUND: Programmed death ligand 1 (PD-L1) immunotherapy remains poorly efficacious in colorectal cancer (CRC). The recepteur d'origine nantais (RON) receptor tyrosine kinase plays an important role in regulating tumor immunity. AIM: To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC. METHODS: Gene expression data from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot. RESULTS: In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment (P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells. CONCLUSION: RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.

Differential expression of innate immunity regulation genes in chronic HIV-1 infected adults.

OBJECTIVE: Chronic activation of the innate immune system plays a central role in HIV-1 disease progression. Negative regulation of innate immunity is critical in preventing the effects of this excessive activation; however, the molecules involved in this process remain to be identified. In this study, we compared the expression of immune regulation genes between HIV-1 infected individuals and healthy control participants to identify genes involved in the regulation of innate immunity in HIV-1 infection. METHODS: We conducted gene expression analysis of a series of immune regulatory genes in viremic treatment-naïve HIV-positive donors, patients receiving highly active antiretroviral therapy (HAART) and HIV-negative healthy control participants. Reverse transcription-quantitative PCR (RT-qPCR) was conducted to determine the expression levels of genes in peripheral blood mononuclear cells isolated from all participants. The spearman correlation test and linear regression analysis were performed to evaluate the correlation between gene expression level and viral load. RESULTS: The following differentially expressed genes were identified: A20, CYLD, DDX24, MARCH5, MKRN2, PTP1B, RNF125, S1PR1, SOCS1, IFI35, RBCK1, TTLL12 and USP18. The three most differentially expressed genes were A20, S1PR1, and USP18. USP18 correlated positively with viral load. CONCLUSION: Thirteen immune regulation genes were identified in comparisons of viremic treatment-naïve HIV-positive donors, HAART-treated patients and healthy control participants, indicating the potential of these genes as therapeutic targets.

Changes in Lipid Indices in HIV+ Cases on HAART.

We assess long-term changes in lipid levels in human immunodeficiency disease- (HIV-) infected patients undergoing highly active antiretroviral treatment (HAART) and their association with diabetes mellitus (DM) and thyroid dysfunction. We observed changes in the levels of total cholesterol (TC) and total triglyceride (TG) of 63 HIV-infected patients in the 6 years from starting HAART and analyzed correlations between relevant parameters. TC levels of patients with normal baseline TC levels as well as those diagnosed with DM or impaired fasting glucose (IFG) increased significantly (P < 0.05) as did the TG levels of patients with normal baseline TG levels (P < 0.05). TC levels of patients with hypercholesterolemia in the year HAART was initiated were significantly higher than those of patients with normal baseline TC levels (P < 0.05) for all 6 years. TC levels of patients diagnosed with DM were significantly higher than those with euglycemia (P < 0.05) 2 and 4 years after HAART commencement. Levels of TC, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were correlated negatively with viral load, whereas levels of TC and very-low-density lipoprotein-cholesterol (VLDL-C) were correlated positively with CD4+ cell counts before HAART commencement. Linear mixed-effect model demonstrated disturbance of glucose metabolism and HAART containing nevirapine and CD4+ cell count were positively correlated with TC levels after HAART commencement. These findings suggest that there are changes in the lipid levels of patients undergoing HAART, with the potential risk of dyslipidemia.