[Characteristics of renal cortical perfusion and its association with renal function among elderly patients with renal artery stenosis].

Objective: To evaluate the characteristics of renal cortical blood perfusion assessed by contrast-enhanced ultrasound (CEUS) in elderly patients with renal artery stenosis (RAS) and its relationship with renal function. Methods: Ninety-three elderly patients diagnosed with RAS, who were admitted in Beijing Hospital during June 2017 and December 2018, were retrospectively enrolled. According to the degree of RAS, 186 renal arteries were divided into normal renal artery group (n=79), mild RAS group (30% to 49%, n=59), moderate RAS group (50% to 70%, n=33), and severe RAS group (70% to 99%, n=15). Renal cortical blood perfusion and renal glomerular filtration rate (GFR) were measured by CEUS and radionuclide renal dynamic imaging. According to the renal GFR, 186 kidneys were divided into normal renal function group (GFR≥35 ml/min, n=42) and mild renal insufficiency group (35 ml/min>GFR≥25 ml/min, n=51), moderate renal insufficiency group (25 ml/min>GFR≥15 ml/min, n=75) and severe renal insufficiency group (GFR<15 ml/min, n=18). The renal cortical blood perfusion time-intensity curve (TIC) and related parameters were analyzed, including the area under the curve (AUC), the slope of the ascending branch (A), the peak intensity (PI), the peak time (TTP) and the mean transit time (MTT), the kidneys of different RAS groups and patients with different renal function groups were analyzed. Pearson correlation analysis was used to evaluate the correlation between renal cortical blood perfusion parameters and renal GFR. Results: (1) Renal cortical blood perfusion and GFR: CEUS showed that parameter A of TIC was significantly reduced, while TTP was prolonged in the mild renal artery stenosis group compared with the normal renal artery group (both P<0.05), GFP was similar between the two groups. Cortical perfusion parameters, such as AUC, A, PI and GFR were significantly lower, while TTP and MTT were significantly prolonged in the moderate and severe renal artery stenosis group than in the normal and mild stenosis groups (all P<0.05). Compared with the moderate stenosis group, AUC, A, PI and GFR were significantly lower while TTP, MTT were significantly prolonged in the severe renal artery stenosis group (all P<0.05). (2) TIC showed that the renal perfusion parameters, AUC, PI and A were significantly lower, while TTP was significantly longer in the mild renal dysfunction group than in the normal renal function group (all P<0.001). The changes aggravated in proportion with renal dysfunction. (3) Correlation between perfusion parameters and GFR: Pearson correlation analysis showed that the AUC (r=0.774, P<0.05), A (r=0.815, P<0.05) and PI (r=0.772, P<0.05) were positively correlated with GFR; serum creatinine level (r=-0.841, P<0.05), renal function grading (r=-0.731, P<0.05), TTP (r=-0.803, P<0.05) and MTT (r=-0.741, P<0.05) were negative correlated with GFR. The degree of stenosis was negatively correlated with GFR (r=-0.427, P<0.05). Conclusion: Cortical perfusion parameters differ significantly among patients with various degree of RAS and renal dysfunction. The renal cortical blood perfusion parameters are correlated with renal GFR.

[Diagnostic value of contrast-enhanced ultrasound for accessory renal artery among patients suspected of renal artery stenosis].

Objective: To evaluate the value of contrast-enhanced ultrasound (CEUS) in the diagnosis of accessory renal artery (ARA) in patients suspected of renal artery stenosis. Methods: Cases were derived from patients suspected diagnosis of renal artery stenosis during October 2017 and July 2018 by CEUS.A total of 28 kidneys with ARA in 25 cases were diagnosed by dynamic continuous observation by two ultrasound physicians separately. If there was disagreement, the superior physician would made the judgment. DSA or CTA examination was performed at the same period, and its consistency with CEUS diagnosis of ARA was analyzed. Results: DSA or CTA identified RAS in 32 ARA, color-coded duplex ultrasonography (CCDS) in 12 and CEUS in 28. The sensitivity in detecting ARA was 37.5% for CCDS and 84.4% for CEUS, the specificity was 0% for CCDS and 94.4% for CEUS, while the accuracy was significantly different with CCDS compared with CEUS (60.0% vs 88.0%). Thus, CEUS significantly improved the ARA detection rate compared with CCDS (84.4% vs 37.5%, χ(2)=15.56, P<0.01). Compared with CTA or DSA, CEUS showed good consistency in ARA diagnosis (kappa value was 0.752, P<0.05). Conclusion: CEUS can display and evaluate ARA in real time accurately, which provides a new technology for further clinical research of ARA.

[Diagnostic value of contrast-enhanced sonography and digital subtraction angiography for renal artery stenosis].

Objective: To evaluate the diagnostic value of contrast-enhanced ultrasound (CEUS) and digital subtraction angiography (DSA) for renal artery stenosis (RAS). Methods: Fifty-seven hypertensive patients suspected for RAS admitted in Beijing Hospital from September 2017 to August 2018 were enrolled. All 114 renal arteries were assessed by CEUS and DSA. RAS was subdivided into low-(30%-50%), moderate-(50%-69%) and high-grade (70%-99%) subgroups. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were compared between CEUS and DSA results. Results: Fifty-seven hypertensive patients (31 males, mean age 57.1 years) involving 114 renal arteries were included. Overall, DSA identified RAS in 71(62.3%) renal arteries, mild RAS, 34(29.8%); moderate RAS, 23(20.2%); severe RAS, 14(12.3%). With CEUS, the sensitivity, specificity, accuracy, PPV and NPV for detecting mild-grade RAS were 85.3%, 97.3%, 91.5%, 96.7% and 87.8%; for detecting moderate-grade RAS were 82.6%, 97.9%, 92.9%, 95.0% and 92.2%; for detecting high-grade RAS were 85.7%, 98.2%, 95.8%, 92.3% and 96.5%. The measure of agreement kappa was 0.92 between CEUS and DSA. Conclusion: CEUS is a safe and accurate method for the diagnosis and severity classification of RAS, especially those with kidney injury.

Expression of Concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation.

The Editors-in-Chief are issuing an editorial expression of concern to alert readers that after publication of this article1 concerns have been raised with respect to the integrity of Figs 1c, 1e, 2b, 6b, and 7a. Chongqing Medical University is investigating these concerns and appropriate editorial action will be taken once the outcome of this investigation is known. The authors do not agree with this notice.

MIR-92 stimulates VEGF by inhibiting von Hippel-Lindau gene product in epithelial ovarian cancer.

The molecular mechanisms underlying regulation of vascular endothelial growth factor (VEGF) in epithelial ovarian cancer (EOC) remain poorly defined. VEGF, a potent angiogenic factor, is up-regulated in a variety of cancers and contributes to angiogenesis in tumor tissues. The level of VEGF correlates with progression of malignancy. We previously reported that miR-92 is abnormally elevated in the plasma of EOC patients. Here, we tested the hypothesis that miR-92 inhibits von Hippel-Lindau gene product (VHL), a tumor suppressor gene, and in turn de-represses HIF-1α, a known key transcription factor for VEGF, to stimulate VEGF expression. Using a variety of biomedical methods including Western blot, RT-PCR, gene silencing, luciferase assay, and chromatin immunoprecipitation in both surgically-resected specimens and EOC cell culture, we established that EOC cells have elevated levels of HIF-1α and miR-92 expression, but the expression of VHL is reduced. We further demonstrated that miR-92 can target the VHL transcript to repress its expression. We also found that stabilized HIF-1α can form an active complex with transcriptional coactivator p300 and phosphorylated-STAT3 at the VEGF promoter to stimulate its expression. In addition, matrix metalloproteinases MMP-2 and MMP-9 are positively regulated by HIF-1α. These results suggest that miR-92 can potentially be considered as a novel therapeutical target in treatment of EOS.

Microarray analysis of microRNA deregulation and angiogenesis-related proteins in endometriosis.

We examined the aberrant microRNA (miRNA) expression profile responsible for the changes in angiogenesis observed in endometriotic lesions. This study revealed characteristic miRNA expression profiles associated with endometriosis in endometrial tissue and endometriotic lesions from the same patient, and their correlation with the most important angiogenic and fibrinolytic factors. miRNA expression was quantified using a microRNA array and reverse-transcription microRNA polymerase chain reaction. Levels of vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor 2 (EGFR2), phosphatase and tensin homolog (PTEN), and C-X-C chemokine receptor type 4 (CXCR4) were quantified using enzyme-linked immunosorbent assay. The endometrial tissue showed significantly lower levels of miR-200b, miR-15a-5p, miR-19b-1-5p, miR-146a-5p, and miR-200c, and higher levels of miR-16-5p, miR-106b-5p, and miR-145-5p. VEGFA was significantly upregulated, whereas EGFR2, PTEN, and CXCR4 were markedly downregulated, in the endometriotic tissues compared to that in the normal endometrial tissues. In conclusion, differences in the miRNA levels could modulate the expression of VEGFA, EGFR2, PTEN, and CXCR4, and may play an important role in the pathogenesis of endometriosis. The higher angiogenic and proteolytic activities observed in the eutopic endometrium might facilitate the implantation of endometrial cells at ectopic sites.

IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation.

Bone morphogenetic protein 2 (BMP2) is known to activate unfolded protein response (UPR) signaling molecules, such as BiP (IgH chain-binding protein), PERK (PKR-like ER-resistant kinase), and IRE1α. Inositol-requiring enzyme-1a (IRE1a), as one of three unfolded protein sensors in UPR signaling pathways, can be activated during ER stress. Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. However, the influence on IRE1a in BMP2-induced osteoblast differentiation has not yet been elucidated. Herein we demonstrate that overexpression of IRE1a inhibits osteoblast differentiation, as revealed by reduced activity of alkaline phosphatase (ALP) and osteocalcin; however, knockdown of IRE1a via the RNAi approach stimulates osteoblastogenesis. Mechanistic studies revealed that the expression of IRE1a during osteoblast was a consequence of JunB transcription factor binding to several AP1 sequence (TGAG/CTCA) in the 5'-flanking regulatory region of the IRE1a gene, followed by transcription. In addition, GEP induces IRE1a expressions and this induction of IRE1a by GEP depends on JunB. Furthermore, IRE1a inhibition of GEP-induced osteoblastogenesis relies on JunB. Besides, GEP is required for IRE1a inhibition of BMP2-induced bone formation. Collectively, these findings demonstrate that IRE1a negatively regulates BMP2-induced osteoblast differentiation and this IRE1a inhibition effect depends on GEP growth factor. Thus, IRE1a, BMP2, GEP growth factor, and JunB transcription factor form a regulatory loop and act in concert in the course of osteoblastogenesis.