Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression.

OBJECTIVE: Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression. How neutrophils promote lung cancer progression, however, has not been established. METHODS: Kaplan-Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients. The effect of neutrophils on lung cancer was determined using the Transwell migration assay, a proliferation assay, and a murine tumor model. Gene knockdown was used to determine poly ADP-ribose polymerase (PARP)-1 function in lung cancer-educated neutrophils. Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9 (MMP-9). Immunoprecipitation coupled to mass spectrometry (IP/MS) was used to identify the proteins interacting with PARP-1. Co-immunoprecipitation (Co-IP) was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase (ALOX5). Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression. RESULTS: An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients (P < 0.001). Neutrophil activation promoted lung cancer cell invasion, migration, and proliferation in vitro, and murine lung cancer growth in vivo. Mechanistically, PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification (PARylation). Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production, and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth. CONCLUSIONS: We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression, which exacerbates lung cancer progression.

The correlation between serum uric acid and diabetic kidney disease in type 1 diabetes patients in Anhui, China.

BACKGROUND/AIM: To assess the correlation between serum uric acid (UA) level and diabetic kidney disease (DKD) in Type 1 diabetes (T1DM) patients in Anhui, China. METHODS: A total of 231 patients diagnosed with T1DM in our hospital were enrolled between January 2014 and December 2016. Urinary albumin-creatinine ratio (ACR) in patients with hyperuricemia was compared with those without hyperuricemia. The relationship between serum UA level and urinary ACR was examined by Spearman's correlational analysis and multiple stepwise regression analysis. The binary logistic multivariate regression analysis was performed to analyze the correlated factors for type 1 DKD. RESULTS: The average serum UA levels were 257.7 [215.0, 338.0]µmol/L. The median levels of urinary ACR were significantly higher in patients with hyperuricemia than those without hyperuricemia. In multiple stepwise regression analysis, Serum UA levels were positively correlated with the urinary ACR. The logistic multivariate regression analysis showed that hyperuricemia (OR: 5.24, 95% CI: 1.40-19.65, P = 0.014) had an independent positive correlation with DKD in T1DM patients, and the odds of Serum UA to DKD were both elevated as the serum UA levels rose no matter whether adjustment for traditional confounders. The area under the receiver operating characteristic curve was 0.62 (95% CI: 0.55-0.70) in assessing the discrimination of the serum UA level for DKD in T1DM patients. CONCLUSIONS: In Chinese patients with T1DM, the serum UA level is positively correlated with urinary ACR and DKD. The correlation between Serum UA and DKD gradually increases with serum UA levels. Serum UA level is not a good predictor for DKD in T1DM patients. Serum UA may directly contribute to initiating DKD, while it has little direct but an indirect effect on an already established DKD in T1DM patients.

The correlation between serum uric acid and diabetic kidney disease in adult-onset type 1 diabetes patients in China.

BACKGROUND/AIM: To assess the correlation between serum uric acid (UA) level and diabetic kidney disease among adult-onset Type 1 diabetes mellitus (T1DM) patients in China. METHODS: A total of 184 patients with adult-onset T1DM between January 2014 and December 2016 were recruited, with demographics and medical data collected. Comparisons were performed between according to different serum UA gender-specific quartiles. Relationship between serum UA level with urinary ACR and eGFR was also assessed. RESULTS: Median urinary ACR and eGFR were 21.55 [10.79, 45.02] mg/g and 113.86 [88.43, 143.61] ml/min/1.73 m2, respectively. The median UA was 257.4 (208.2-334.8) µmol/L. Participants with higher serum UA levels had higher urinary ACR and lower eGFR than those with lower UA (P < 0.05). Higher serum UA level was significantly associated with higher urinary ACR in Spearman's correlational analysis (P = 0.006) and multiple stepwise regression analysis (P = 0.013). The association between serum UA and urinary ACR was not linear, but showed a curve correlation, which also showed in the sensitivity analysis. Serum UA in the upper gender-specific quartile, was associated with lower eGFR (P < 0.001) and showed an independent negative correlation with eGFR in multiple stepwise regression analysis (P < 0.001). CONCLUSIONS: The serum UA level was negatively correlated with eGFR and had a curve correlation with urinary ACR in adult-onset T1DM patients of China.

The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-ß.

Transforming growth factor-ß (TGF-ß) plays a critical role in regulating cell growth and differentiation. Epithelial to mesenchymal transition (EMT) induced by TGF-ß promotes cancer cell migration, invasion, and proliferation. Pirfenidone (5-methyl-1-phenyl-2(1 H)-pyridone, PFD), an approved drug for treating pulmonary and renal fibrosis, is a potent TGF-ß inhibitor and found reduced incidence of lung cancer and alleviated renal function decline. However, whether PFD plays a role in controlling renal cancer progression is largely unknown. In the present study, we demonstrated that high TGF-ß1 expression was negatively associated with ten-year overall survival of patients with renal cancer. Functionally, blockade of TGF-ß signaling with PFD significantly suppressed the progression of renal cancer in a murine model. Mechanistically, we revealed that PFD significantly decreased the expression and secretion of TGF-ß both in vitro and in vivo tumor mouse model, which further prevented TGF-ß-induced EMT and thus cell proliferation, migration, and invasion. Importantly, the downregulation of TGF-ß upon PFD treatment shaped the immunosuppressive tumor microenvironment by limiting the recruitment of tumor-infiltrating MDSCs. Therefore, our study demonstrated that PFD prevents renal cancer progression by inhibiting TGF-ß production of cancer cells and downstream signaling pathway, which might be presented as a therapeutic adjuvant for renal cancer.

The Related Factors of Hyperuricemia in IgA Nephropathy.

INTRODUCTION: Many factors, such as increased serum creatinine, increased blood pressure and abnormal urine protein, may lead to poor prognosis of IgA nephropathy (IgAN). The features of IgAN are also affected by uric acid, but its effect on the prognosis is less reported. We therefore systematically investigated the possible correlation of IgAN with hyperuricemia (HUA) and their prognosis. METHODS: Two groups (HUA group and uric acid normal group) were included of 178 IgAN patients. The indexes in the clinic and pathology were compared; logistic regression and renal survival were used to speculate the correlated factors of HUA in IgAN and their prognosis. RESULTS: HUA group had higher serum urea nitrogen, serum creatinine, total cholesterol, 24-hour urinary protein quantity, percentage of CKD3⁃5, the thickness of arteriole, glomerular mesangial hyperplasia, tubular atrophy, glomerulosclerosis, interstitial fibrosis and the area of infiltration of inflammatory cells (ICI), lower eGFR and serum albumin-to-creatinine ratios (P < .05). Total cholesterol and ICI in X2 were independent related factors of HUA given by the analysis of logistic regression (P < .05). No correlation was found in HUA and normal group used by Kaplan- Meier (P > .05). CONCLUSION: Severer renal pathological injures (glomeruli, tubules or interstitium) were found in IgAN. Besides, total cholesterol and the area of infiltration of inflammatory cells were independent related factors of hyperuricemia in IgAN.

Serum Albumin at Start of Peritoneal Dialysis Predicts Long-Term Outcomes in Anhui Han Patients on Continuous Ambulatory Peritoneal Dialysis: A Retrospective Cohort Study.

OBJECTIVE: This study assessed the relationship between serum albumin (ALB) at start of peritoneal dialysis (PD) and long-term outcomes of continuous ambulatory PD (CAPD) in Anhui Han patients. METHODS: A total of 149 Anhui Han CAPD patients were enrolled in this study and followed up for 3 years. They were initially diagnosed with the end-stage renal disease and underwent surgical PD catheter placement from January 2009 to December 2013. According to serum ALB at start of PD, the patients were divided into two groups: low ALB group (ALB < 35 g/L) and high ALB group (ALB ≥35 g/L). Demographic, hematologic, biochemical, and dialysis-related data were collected. Kaplan-Meier survival analysis and log-rank test were conducted to compare patient mortality, cardiovascular mortality and technique failure between the low ALB group and the high ALB group. Cox regression analysis was performed to analyze the risk factors, calculate the hazard ratio (HR), adjusted HR (AHR) and 95% confidence interval (CI). RESULTS: The low ALB group showed a greater number of diabetes mellitus compared with the high ALB group. Patient mortality, cardiovascular mortality, and technique failure in the high ALB group were significantly lower than those in the low ALB group. In Cox regression analysis, serum ALB < 35 g/L was an independent predictor of patient mortality (AHR 3.043, 95% CI 1.085-8.536, p = 0.034), cardiovascular mortality (AHR 11.587, 95% CI 1.466-91.574, p = 0.020), and technique failure (AHR 3.148, 95% CI 1.603-6.182, p = 0.001) in CAPD patients after adjustment for sex, age, estimated glomerular filtration rate, primary renal disease, diabetes mellitus, and cardiovascular disease. CONCLUSIONS: In Anhui Han patients on CAPD, the levels of serum ALB at start of PD are inversely correlated with patient mortality, cardiovascular mortality, and technique failure, and the long-term outcomes of patients with hypoalbuminemia at start of PD are poor. To improve the long-term outcomes of Anhui Han CAPD patients, patients with hypoalbuminemia at start of PD should be closely monitored.

The development of CAR design for tumor CAR-T cell therapy.

In recent years, the chimeric antigen receptor modified T cells (Chimeric antigen receptor T cells, CAR-T) immunotherapy has developed rapidly, which has been considered the most promising therapy. Efforts to enhance the efficacy of CAR-based anti-tumor therapy have been made, such as the improvement of structures of CAR-T cells, including the development of extracellular antigen recognition receptors, intracellular co-stimulatory molecules and the combination application of CARs and synthetic small molecules. In addition, effects on the function of the CAR-T cells that the space distance between the antigen binding domains and tumor targets and the length of the spacer domains have are also being investigated. Given the fast-moving nature of this field, it is necessary to make a summary of the development of CAR-T cells. In this review, we mainly focus on the present design strategies of CAR-T cells with the hope that they can provide insights to increase the anti-tumor efficacy and safety.

The relationship between haemoglobin level and type 1 diabetic nephropathy in Han patients in Anhui, China.

BACKGROUND/AIM: Recent studies have shown that low haemoglobin (Hb) levels promote the progression of chronic kidney disease. This study assessed the relationship between Hb level and type 1 diabetic nephropathy (DN) in Han patients in Anhui, China. METHODS: There was a total of 236 patients diagnosed with type 1 diabetes mellitus (T1DM) seen between January 2014 and December 2016 in our centre. Haemoglobin levels in patients with DN were compared with those without DN. The relationship between Hb level and the urinary albumin-creatinine ratio (ACR) was examined by Spearman's correlational analysis and multiple stepwise regression analysis. The binary logistic multivariate regression analysis was performed to analyse the correlated factors for type 1 DN, calculate the odds ratio (OR) and 95% confidence interval (CI). The predicting value of Hb level for DN was evaluated by area under receiver operation characteristic curve (AUROC) for discrimination and Hosmer-Lemeshow goodness-of-fit test for calibration. RESULTS: The average Hb levels in the DN group (116.1 ± 20.8 g/L) were significantly lower than the non-DN group (131.9 ± 14.4 g/L), P < 0.001. Hb levels were independently correlated with the urinary ACR in multiple stepwise regression analysis. The logistic multivariate regression analysis showed that the Hb level (OR: 0.936, 95% CI: 0.910-0.963, P < 0.001) was inversely correlated with DN in patients with T1DM. In sub-analysis, low Hb level (Hb < 120 g/L in female, Hb < 130 g/L in male) was still negatively associated with DN in patients with T1DM. The AUROC was 0.721 (95% CI: 0.655-0.787) in assessing the discrimination of the Hb level for DN. The value of P was 0.593 in Hosmer-Lemeshow goodness-of-fit test. CONCLUSIONS: In patients with T1DM, the Hb level is inversely correlated with urinary ACR and DN.

Nutritional status in short daily hemodialysis versus conventional hemodialysis patients in China.

PURPOSE: Malnutrition is the main determinant of mortality and morbidity in maintenance hemodialysis patients. In many countries except for China, it has been reported that short daily hemodialysis (SDHD) could improve nutritional status. We will report here the nutritional results obtained in the SDHD therapy period compared with conventional hemodialysis (cHD) therapy period in Chinese patients. METHODS: This study compared 29 SDHD patients (SDHD group), each patient served as his own control, with 30 cHD patients (cHD group) serving as the parallel controls. The hematologic parameters, anthropometric measurements, modified quantitative subjective global assessment (MQSGA) score, weekly standard Kt/V (std Kt/V) and average daily intake of protein were measured at baseline (SDHD0 or cHD0 period), at 3 months (SDHD1 or cHD1 period) and at 6 months (SDHD2 or cHD2 period). RESULTS: The average daily intake of protein, dry weight, body mass index, mid-arm circumference, mid-arm muscle circumference, serum albumin, prealbumin, cholesterol, hemoglobin, weekly std Kt/V values at SDHD2 were higher than the corresponding values at SDHD0 (p < 0.05, p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.001 and p < 0.001, respectively). Meanwhile, the average daily intake of protein, serum albumin, prealbumin, cholesterol, hemoglobin, weekly std Kt/V values at SDHD2 were higher than the corresponding values at cHD2 (p < 0.05, p < 0.001, p < 0.05, p < 0.05, p < 0.001 and p < 0.001, respectively), whereas the MQSGA score at SDHD2 was lower than the score at SDHD0 and cHD0 (p < 0.05, respectively). CONCLUSIONS: SDHD may improve the nutritional status compared with cHD in Chinese patients undergoing maintenance hemodialysis.