Zijie Wang

Association between NFKB1 −94ins/del ATTG Promoter Polymorphism and Cancer Susceptibility: An Updated Meta-Analysis

Nuclear factor-κB is associated with the pathogenesis of numerous malignancies, and the functional polymorphism −94ins/del ATTG (rs28362491) in the human NFKB1 gene is associated with cancer risk. Previous studies on the association between the −94ins/del ATTG polymorphism and cancer risk reported conflicting results. To clarify this relationship, we performed a meta-analysis of 21 case-control studies involving 6127 cases and 9238 controls. We used pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs) to assess the association. We found that the NFKB1 promoter −94ins/del ATTG polymorphism was significantly associated with cancer risk in four genetic models (ins/ins versus del/del, OR = 1.47, 95% CI = 1.11–1.93; dominant model, OR = 1.26, 95% CI = 1.03–1.53; recessive model, OR = 1.26, 95% CI = 1.05–1.51; ins allele versus del allele, OR = 1.19, 95% CI = 1.05–1.35). Stratified analyses revealed a significant association between the polymorphism and ovarian, oral, and prostate cancers. Similar results were determined in an Asian population and not in a Caucasian population. Thus, our results suggested that the polymorphism can contribute to cancer risk. Moreover, the polymorphism can exert race- and cancer-specific effects on cancer risk. Further large-scale and functional studies are necessary to elucidate this possible effect.

Serum MicroRNA-99a Helps Detect Acute Rejection in Renal Transplantation.

BACKGROUND MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs, and they are becoming increasingly known as potential biomarkers for a variety of pathologies. However, the significance of circulating miRNAs in renal transplantation patients needs further studies. MATERIALS AND METHODS An miRNA array was used to profile the serum miRNAs of stable transplantation patients and transplantation patients with acute rejection (AR). We performed quantitative real-time polymerase chain reaction with the serum samples from 12 patients with AR, 11 control transplantation patients without rejection, and 15 transplantation patients with delayed graft function (DGF) for validation. Receiver operator characteristic analysis was used to assess the diagnostic capacity of serum miRNA. RESULTS The miR-99a, miR-100, miR-151a, let-7a, let-7c, and let-7f were deregulated in the serum of the patients with AR. In the validation set, only miR-99a and miR-100 were upregulated in the AR group. We further evaluated the expression levels of miR-99a and miR-100 in the DGF group. Only miR-99a was observed with the potent diagnostic value in discriminating AR patients from stable patients (area under the curve [AUC] = 0.750, 95% confidence interval [CI] = 0.529-0.971, P = .042) and DGF patients (AUC = 0.811, 95% CI = 0.600-1.000, P = .006). CONCLUSION Serum miR-99a may serve as a biomarker of AR in renal transplantation patients. Further studies are required to confirm the results.

Advanced glycation end products accelerate arteriosclerosis after renal transplantation through the AGE/RAGE/ILK pathway

BACKGROUND The effects of advanced glycation end products (AGEs) on arteriosclerosis (AS) after kidney transplantation and the molecular mechanisms involved remain unclear. METHODS Samples were collected from 30 healthy volunteers and 30 renal transplant recipients (RTRs) to determine the levels of AGEs and to observe both histological changes and α-smooth muscle actin (α-SMA) and osteopontin (OPN) expression. Furthermore, we analyzed α-SMA, OPN and integrin-linked kinase (ILK) in rat vascular smooth muscle cells (VSMCs) that were treated with AGEs and in ILK plasmid transfected rat VSMCs treated with AGEs. Finally, we measured the expression of ILK and the receptor for advanced glycation end (RAGE) products in rat VSMCs treated with AGEs and an anti-RAGE antibody. RESULTS Significant differences in the histological changes, serum AGEs, and expression of α-SMA and OPN in arterial walls were noted between healthy volunteers and RTRs. Significant OPN and ILK overexpression and reduced α-SMA expression were detected in a time-dependent manner in rat VSMCs after treatment with AGEs. Similar outcomes were observed regarding the overexpression of ILK, and these results could be prevented via RAGE inhibition. CONCLUSIONS AGEs may play a critical role in the formation and progression of AS after renal transplantation by inducing VSMCs-to-osteoblast trans-differentiation through the AGE/RAGE/ILK pathway.

Role of endothelial-to-mesenchymal transition induced by TGF-β1 in transplant kidney interstitial fibrosis

Chronic allograft dysfunction (CAD) induced by kidney interstitial fibrosis is the main cause of allograft failure in kidney transplantation. Endothelial‐to‐mesenchymal transition (EndMT) may play an important role in kidney fibrosis. We, therefore, undertook this study to characterize the functions and potential mechanism of EndMT in transplant kidney interstitial fibrosis. Proteins and mRNAs associated with EndMT were examined in human umbilical vein endothelial cells (HUVECs) treated with transforming growth factor‐beta1 (TGF‐β1) at different doses or at different intervals with western blotting, qRT‐PCR and ELISA assays. Cell motility and migration were evaluated with motility and migration assays. The mechanism of EndMT induced by TGF‐β1 was determined by western blotting analysis of factors involved in various canonical and non‐canonical pathways. In addition, human kidney tissues from control and CAD group were also examined for these proteins by HE, Massons trichrome, immunohistochemical, indirect immunofluorescence double staining and western blotting assays. TGF‐β1 significantly promoted the development of EndMT in a time‐dependent and dose‐dependent manner and promoted the motility and migration ability of HUVECs. The TGF‐β/Smad and Akt/mTOR/p70S6K signalling pathways were found to be associated with the pathogenesis of EndMT induced by TGF‐β1, which was also proven in vivo by the analysis of specimens from the control and CAD groups. EndMT may promote transplant kidney interstitial fibrosis by targetting the TGF‐β/Smad and Akt/mTOR/p70S6K signalling pathways, and hence, result in the development of CAD in kidney transplant recipients.

Clinical Efficacy and Safety of Pamidronate Therapy on Bone Mass Density in Early Post-Renal Transplant Period: A Meta-Analysis of Randomized Controlled Trials

Introduction The overall effect of pamidronate on bone mass density (BMD) in the early renal transplant period varies considerably among studies. The effects of pamidronate on graft function have not been determined. Materials and Methods A comprehensive search was conducted in PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase independently by two authors. Randomized controlled trials of pamidronate evaluating bone loss in the first year of renal transplantation were included. Methods reported in the “Cochrane Handbook for Systematic Reviews of Interventions 5.0.2” were used to evaluate changes of lumbar spine and femoral neck BMD, and serum creatinine, calcium and intact parathyroid hormone (iPTH) levels. Fixed or random effect models were used as appropriate. Results Six randomized trials evaluating 281 patients were identified. One hundred forty-four were treated with pamidronate and 137 were control patients. Administration of pamidronate was associated with significant reduction of bone loss in the lumbar spine, compared to the control group (standardized mean difference (SMD)  = 24.62 [16.25, 32.99]). There was no difference between the pamidronate treated and control femoral neck BMD (SMD  = 3.53 [−1.84, 8.90]). A significant increase in the serum creatinine level of the intervention group was seen, compared to the control group. The serum calcium and iPTH of the pamidronate and control groups were not different after 1 year (serum creatinine: SMD  = −3.101 [−5.33, −0.89]; serum calcium: SMD  = 2.18 [−0.8, 5.16]; serum iPTH: SMD  = 0.06 [−0.19, 0.31]). Heterogeneity was low for serum calcium and iPTH and high for serum creatinine. Conclusions This meta-analysis demonstrated the beneficial clinical efficacy of pamidronate on BMD with no association with any alteration in graft function during the first year of renal transplantation. Significant heterogeneity precludes the conclusion of the relationship between serum creatinine and pamidronate.

MiR-122 promotes renal cancer cell proliferation by targeting Sprouty2

MicroRNAs are short non-coding RNAs, which have been implicated in several biological processes. Aberrant expression of the microRNA miR-122 has frequently been reported in malignant cancers. However, the mechanism underlying the effects of miR-122 in renal cell carcinoma remains unknown. The aim of this study was to determine the biological function of miR-122 in renal cell carcinoma and to identify a novel molecular target regulated by miR-122. We measured the expression levels of Sprouty2 in six renal cell carcinoma tissue samples and adjacent non-tumor tissues by western blot analysis. We then used reverse transcription polymerase chain reaction to measure miR-122 levels in 40 primary renal cell carcinoma and adjacent non-malignant tissue samples. The effects of miR-122 down-regulation or Sprouty2 knockdown were evaluated via Cell Counting Kit-8 assay, flow cytometry, and western blot analysis. The relationship between miR-122 and Sprouty2 was determined using dual-luciferase reporter assays. Sprouty2 was down-regulated in renal cell carcinoma tissue samples compared with adjacent normal tissue. In contrast, miR-122 was up-regulated in primary renal cell carcinoma tissue samples compared with adjacent normal tissue samples. Down-regulation of miR-122 substantially weakened the proliferative ability of renal cell carcinoma cell lines in vitro. In contrast, Sprouty2 knockdown promoted the in vitro proliferation of renal cell carcinoma cell lines. The spry2 gene could therefore be a direct target of miR-122. In conclusion, miR-122 could act as a tumor promoter and potentially target Sprouty2. MiR-122 promotes renal cell carcinoma cell proliferation, migration, and invasion and could be a molecular target in novel therapies for renal cell carcinoma.

Direct-acting antiviral agent efficacy and safety in renal transplant recipients with chronic hepatitis C virus infection: A Prisma-compliant study

Background: The efficacy and safety of direct-acting antivirals (DAAs) for treating hepatitis C virus (HCV)-infected renal transplant recipients (RTRs) has not been determined. Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and assessed the quality of eligible studies using the Joanna Briggs Institute scale. DAA efficacy and safety were assessed using standard mean difference (SMD) with 95% confidence intervals (95%CIs). Results: Six studies (360 RTRs) were included. Two hundred thirty six RTRs (98.3%) achieved sustained virological response within 12 weeks; HCV infection was cleared in 239 RTRs after 24-week treatment. Liver function differed significantly pre- and posttreatment (alanine aminotransferase, SMD: 0.96, 95%CIs: 0.65, 1.26; aspartate aminotransferase, SMD: 0.89, 95%CIs: 0.60, 1.18); allograft function pre- and posttreatment was not statistically different (serum creatinine, SMD: −0.13, 95%CIs: −0.38, 0.12; estimated glomerular filtration rate, SMD: 0.20, 95%CIs: −0.11, 0.51). General symptoms (fatigue nausea dizziness or headache) were the most common adverse events (AEs) (39.3%). Severe AEs, that is, anemia, portal vein thrombosis, and streptococcus bacteraemia and pneumonia, were present in 1.1%, 0.6%, and 1.1% of RTRs, respectively. Conclusion: Our findings suggest that DAAs are highly efficacious and safe for treating HCV-infected RTRs and without significant AE.

Performance of the ImmuKnow Assay in Differentiating Infection and Acute Rejection After Kidney Transplantation: A Meta-Analysis

BACKGROUND The ImmuKnow test is an assay for determining the functional activity of immunocytes, which reflects cell-mediated immune responses in populations undergoing organ transplantation. METHODS Electronic and manual searches were conducted to identify studies of the ImmuKnow test. After methodological quality assessment and data extraction, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were assessed, and summary receiver operating characteristic analysis was performed systematically. The extent of heterogeneity was explored. RESULTS Six studies were identified for analysis. The pooled sensitivity, specificity, PLR, NLR, and DOR of ImmuKnow for predicting the risk of infection were 0.51 (95% confidence interval [CI], 0.45-0.57), 0.75 (95% CI, 0.71-0.78), 1.97 (95% CI, 0.91-4.26), 0.67 (95% CI, 0.38-1.19), and 3.56 (95% CI, 0.80-15.89), respectively. A DOR of 13.81 (95% CI, 0.79-240.44), with a sensitivity of 0.51 (95% CI, 0.40-0.61), a specificity of 0.90 (95% CI, 0.87-0.93), a PLR of 4.45 (95% CI, 0.91-21.74), and an NLR of 0.35 (95% CI, 0.08-1.45), was found in the analysis of the predictive value for acute rejection. The summary receiver operating characteristic curve values for ImmuKnow in distinguishing patients with infections from those with acute rejections were 0.631 ± 0.215 and 0.986 ± 0.015, respectively. CONCLUSIONS Our analysis did not support the use of the ImmuKnow assay to predict or monitor the risks of infection and acute rejection in renal transplant recipients. Further studies are needed to confirm the relationships between the ImmuKnow assay and infection and acute rejection in kidney transplantation.

Antifibrotic Effects of Hepatocyte Growth Factor on Endothelial-to-Mesenchymal Transition via Transforming Growth Factor-Beta1 (TGF-β1)/Smad and Akt/mTOR/P70S6K Signaling Pathways

Background The related mechanisms involved in allograft interstitial fibrosis and chronic allograft dysfunction (CAD), following renal transplant, remain largely unknown. Here, we explored the role of hepatocyte growth factor (HGF) treatment on the endothelial-to-mesenchymal transition (EndMT) as a new way to target and prevent kidney fibrosis and improve outcomes for renal transplant recipients. Method/Material We extracted proteins and mRNAs from human umbilical vein endothelial cells (HUVECs) and human renal glomerular endothelial cells (HRGECs) treated with transforming growth factor-beta1 (TGF-β1) and/or varying doses of HGF, and assessed the effect of HGF on the EndMT using western blotting, qRT-PCR, and ELISA assays. We utilized cell motility and migration assays to evaluate cell movement, and applied western blotting to assess the mechanism by which TGF-β1 induced the EndMT. Results HGF significantly attenuated the development of TGF-β1-induced EndMT in a concentration-dependent way, and weakened the abilities of motility and migration of both HUVECs and HRGECs. Moreover, our results reveal that the antifibrotic effect of HGF on the EndMT was associated with the TGF-β/Smad and Akt/mTOR/p70S6K signaling pathways. Conclusions Our study suggests that HGF treatment significantly attenuates the development of EndMT induced by TGF-β1 via the TGFβ/Smad and Akt/mTOR/P70S6K signaling, which provides novel insights into the prevention and treatment of interstitial fibrosis and CAD following renal transplant.

Evaluation of the NMP22 BladderChek test for detecting bladder cancer: a systematic review and meta-analysis

Background We examined the usefulness of the nuclear matrix protein 22 (NMP22) BladderChek test for detecting bladder cancer. Materials and Methods A literature search was performed using PubMed, Embase, the Cochrane Library, and Web of Science. The diagnostic accuracy of the NMP22 BladderChek test was evaluated via pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC). Inter-study heterogeneity was explored using meta-regression and subgroup analyses. Results We included 23 studies in the systematic review and 19 in the quantitative meta-analysis. Overall sensitivity and specificity were 56% (52–59%) and 88% (87–89%), respectively; pooled PLR and NLR were 4.36 (3.02–6.29) and 0.51 (0.40–0.66), respectively; DOR was 9.29 (5.55–15.55) with an AUC of 0.8295. The mean sensitivity for Ta, T1, ≥ T2, Tis, G1, G2, and G3 disease was 13.68%, 29.49%, 74.03%, 34.62%, 44.16%, 56.25%, and 67.34%, respectively. Conclusions The NMP22 BladderChek test shows good discrimination ability for detecting bladder cancer and a high-specificity algorithm that can be used for early detection to rule out patients with higher bladder cancer risk. It also has better potential for screening higher-grade and higher-stage tumors, and better diagnostic performance in Asians.