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// Fu Wang 1 , Hui Ma 1 , Wen-Jing Liang 1 , Jing-Jing Yang 1 , Xue-Qing Wang 1 , Mei-Rong Shan 1 , Yuan Chen 1 , Min Jia 2 , Ya-Ling Yin 3 , Xue-Ying Sun 4 , Jia-Ning Zhang 5 , Qi-Sheng Peng 6 , Yu-Guo Chen 1 , Li-Ying Liu 4 , Peng Li 3 , Tao Guo 1 and Shuang-Xi Wang 1 1 The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China 2 Department of Rehabilitation Medicine, Jinan Municipal Hospital of Traditional Chinese Medicine, Jinan, China 3 Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China 4 Department of Pharmacology, Pharmaceutical College, Central South University, Changsha, China 5 Biology and Chemistry, Denison University, Granville, OH, USA 6 Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China Correspondence to: Shuang-Xi Wang, email: // Tao Guo, email: // Peng Li, email: // Keywords : lovastatin, microRNA-29b, oxidative stress, PA200, endothelial dysfunction, Pathology Section Received : June 03, 2016 Accepted : September 25, 2016 Published : January 03, 2017 Abstract Aims: Proteasome-linked oxidative stress is believed to cause endothelial dysfunction, an early event in cardiovascular diseases (CVD). Statin, as HMG-CoA reductase inhibitor, prevents endothelial dysfunction in CVD. However, the molecular mechanism of statin-mediated normalization of endothelial function is not completely elucidated. Methods and Results: Lovastatin time/dose-dependently increased miR-29b expression and decreased proteasome activity in cultured human umbilical vein endothelial cells (HUVECs). Anti-miR-29b or overexpression of PA200 abolished lovastatin-induced inhibition of proteasome activity in HUVECs. In contrast, pre-miR-29b or PA200 siRNA mimics these effects of lovastatin on proteasome activity. Lovastatin inhibited oxidative stress induced by multiple oxidants including ox-LDL, H 2 O 2 , TNFα, homocysteine thiolactone (HTL), and high glucose (HG), which were reversed by inhibition of miR-29b in HUVECs. Ex vivo analysis indicated that lovastatin normalized the acetylcholine-induced endothelium-dependent relaxation and the redox status in isolated rat aortic arteries exposure to multiple cardiovascular risk factors. In vivo analysis revealed that administration of lovastatin remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats with hyperglycemia, dyslipidemia, and hyperhomocysteinemia, as well as increased miR-29b expressions, reduced PA200 protein levels, and suppression of proteasome activity in aortic tissues. Conclusion: Upregulation of miR-29b expression is a common mechanism contributing to endothelial dysfunction induced by multiple cardiovascular risk factors through PA200-dependent proteasome-mediated oxidative stress, which is prevented by lovastatin.

OBJECTIVE. The objective of our study was to compare the performance of radiologicradiomic machine learning (ML) models and expert-level radiologists for differentiation of benign and malignant solid renal masses using contrast-enhanced CT examinations. MATERIALS AND METHODS. This retrospective study included a cohort of 254 renal cell carcinomas (RCCs) (190 clear cell RCCs [ccRCCs], 38 chromophobe RCCs [chrRCCs], and 26 papillary RCCs [pRCCs]), 26 fat-poor angioleiomyolipomas, and 10 oncocytomas with preoperative CT examinations. Lesions identified by four expert-level radiologists (> 3000 genitourinary CT and MRI studies) were manually segmented for radiologicradiomic analysis. Disease-specific support vector machine radiologic-radiomic ML models for classification of renal masses were trained and validated using a 10-fold cross-validation. Performance values for the expert-level radiologists and radiologic-radiomic ML models were compared using the McNemar test. RESULTS. The performance values for the four radiologists were as follows: sensitivity of 73.7-96.8% (median, 84.5%; variance, 122.7%) and specificity of 48.4-71.9% (median, 61.8%; variance, 161.6%) for differentiating ccRCCs from pRCCs and chrRCCs; sensitivity of 73.7-96.8% (median, 84.5%; variance, 122.7%) and specificity of 52.8-88.9% for differentiating ccRCCs from fat-poor angioleiomyolipomas and oncocytomas (median, 80.6%; variance, 269.1%); and sensitivity of 28.1-60.9% (median, 84.5%; variance, 122.7%) and specificity of 75.0-88.9% for differentiating pRCCs and chrRCCs from fat-poor angioleiomyolipomas and oncocytomas (median, 50.0%; variance, 191.1%). After a 10-fold cross-validation, the radiologic-radiomic ML model yielded the following performance values for differentiating ccRCCs from pRCCs and chrRCCs, ccRCCs from fat-poor angioleiomyolipomas and oncocytomas, and pRCCs and chrRCCs from fat-poor angioleiomyolipomas and oncocytomas: a sensitivity of 90.0%, 86.3%, and 73.4% and a specificity of 89.1%, 83.3%, and 91.7%, respectively. CONCLUSION. Expert-level radiologists had obviously large variances in performance for differentiating benign from malignant solid renal masses. Radiologic-radiomic ML can be a potential way to improve interreader concordance and performance.

Supplemental Digital Content is available in the text., Background: GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. Methods: Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization. Results: We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin. Conclusions: Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.

Cloud task scheduling is a hot technology today, how to effectively improve the utilization of resources, time efficiency, load balancing, is the focus and difficult of the study. The time efficiency, load balancing of K-Min algorithm still need to be improved, so this paper proposes cloud computing task scheduling algorithm based on modified K-Means (Improved K-Min), firstly, This paper improves the k-means algorithm using the BFA and PSO,then according to the length attribute of the task, resource requirements, the algorithm uses the improved K-means for packet processing tasks, then performs Min-Min scheduling algorithm within the group. Through theoretical research and simulation of Cloud-sim platform, when the number of tasks is 300, experimental result is best, comparing with Min-Min algorithm, the total task completion time improved 17.13%.

The naphthenic acids found in petroleum may cause serious corrosion problems for processing equipment. In this study, naphthenic acids were removed by catalytic esterification with methanol to reduce the occurrence of corrosion in refinery equipment and to improve the properties of the oil. The influence of the reaction conditions on the esterification reaction was investigated. SnO–Al2O3 was used as the catalyst for the esterification of naphthenic acid in crude oil with methanol in a fixed-bed catalytic reactor. The experimental results demonstrated that a high reaction temperature and a low space velocity promote esterification. For a continuous fixed-bed reactor, the optimum reaction conditions were determined to be a methanol to oil ratio of 2 wt%, a reaction temperature of 300 °C and a space velocity of 2.5 h−1. The total acid number of the crude oil was reduced from 2.8 mgKOH/g to a value below 0.5 mgKOH/g. Furthermore, esterification can be improved by removing water from the crude oil.

A sensitive and specific method was developed and validated for the determination of paeoniflorin in rat brain with liquid chromatography–tandem mass spectrometry. Sample pretreatment involved protein precipitation following solid-phase extraction. Paeoniflorin and geniposide (internal standard) were separated isocratically on a Waters Symmetry C18 column (150 mm × 2.1 mm i.d., 5 μm), using a mobile phase of methanol/water with 0.1% formic acid (50:50, v/v) at a flow-rate of 200–300 μL/min in 4 min. A Finngan LTQ tandem mass spectrometer equipped with electrospray ionization source was operated in the positive ion mode. Selective reaction monitoring was performed to quantify paeoniflorin and the internal standard at m / z transitions of 503 → 381 and 411 → 231, respectively. A good linearity was found in the range of 2–500 ng/mL ( R 2 = 0.9939). The intra- and inter-batch assay precisions (coefficient of variation, CV) at 5, 50 and 400 ng/mL ( n = 5) ranged from 6.3% to 9.7% and 1.2% to 7.2%, respectively, and the accuracies were from 95.9% to 101.6% and 99.4% to 102.9%, respectively. The mean recoveries of paeoniflorin were 81.2%, 80.9% and 82.3% at 5, 50 and 400 ng/mL ( n = 5), respectively, and the mean recovery of the internal standard was 76.7% with a concentration of 50 ng/mL ( n = 5). Stability studies showed that paeoniflorin was stable in different conditions. Finally, the method was successfully applied to the pharmacokinetic study of paeoniflorin in rat brain following a single subcutaneous administration (10 mg/kg) to rats.

The aim of this study was to examine whether cariporide, a new inhibitor of Na(+)/H(+) exchanger 1 (NHE-1), may inhibit high glucose-induced monocyte-endothelial cell adhesion and the expression of intercellular adhesion molecule-1 (ICAM-1). Cultured endothelial cells were incubated with normal glucose control (5.5 mM), cariporide control (5.5 mM glucose plus 10 microM cariporide), hyperosmolarity (5.5 mM glucose plus 16.5 mM mannitol), high glucose (HG, 22 mM), low-concentration cariporide (22 mM glucose plus 0.1 microM cariporide), medium-concentration cariporide (22 mM glucose plus 1 muM cariporide), and high-concentration cariporide (22 mM glucose plus 10 microM cariporide) for 24 h. Monocytes were isolated from peripheral human blood. Adhered monocytes were quantified by measuring their protein content. ICAM-1 expression and NHE-1 activity was determined with enzyme-linked immunosorbent assay (ELISA) and pH-sensitive fluorescent spectrophotometry. Exposure of endothelial cells to HG for 24 h caused an increase of adhesion of monocytes to endothelial cells and an increased expression of ICAM-1. However, these effects were reversed by treatment with cariporide (0.1, 1, 10 microM) in a concentration-dependent manner. Furthermore, cariporide (1 microM) was able to inhibit the activation of NHE-1 induced by HG in endothelial cells. These findings suggest that cariporide might inhibit HG-mediated monocyte-endothelial cell adhesion and expression of ICAM-1 by inhibiting the activation of NHE-1.

Using a innovative system consisted of methanogenesis,partial nitritation and anaerobic ammonium oxidation (ANAMMOX) reactors, simultaneous methane production and autotrophic nitrogen removal from domestic sewage was successfully achieved. The results showed that the effluent NH4(+) -N of the combined treatment process was below the detection limit. The effluent NO3(-)-N and NO2(-) -N were less than 0.5 mg x L(-1) and 3.6 mg x L(-1), respectively. The effluent COD of the combined treatment process was 10 mg x L(-1) and a COD removal rate of 98% was achieved. More than 80% COD was removed by the up-flow anaerobic sludge fixed bed (UAFB) and the anaerobic gas production was 3.3 L x d(-1) with a methane yield of 0.3 L x g(-1). About 39.2% of influent COD was removed in form of methane and about 6.52% was transferred to VFAs. Partial nitritation with high nitrite accumulation efficiency of 97% was realized in a Sequencing Batch Reactor (SBR). Ammonium was partly oxidized to nitrite with an ammonium: nitrite ratio of 1: 1.13, which was suitable for the sub-sequent ANAMMOX reaction. In terms of N balance, the N conversion rate of SBR was 36.59% while the anaerobic ammonium oxidation (ANAMMOX) reactor, which was the major system in nitrogen removal, removed 56.91% of N. The TN removal rate of the ANAMMOX reactor was 0.62 kg x (m3 x.d)(-1) and the ratio of NH4(+)-N removal: NO2(-) -N removal: NO3(-) -N generation was 1: 1.18: 1.25. The new process achieves energy recovery by reclaiming methane and autotrophic nitrogen removal by the partial nitritation-ANAMMOX process, and provides a new approach and technology for reforming of domestic wastewater treatment plants.

Drilling activity has increased rapidly in Iraq over the last few years. With the lack of reliable downhole data to develop a solid strategy to optimize drilling operations, the drilling performance has been inconsistent with frequent failures of drill stem components. Without the aid of quality downhole data it is very difficult to identify the root cause of these failures, and more importantly, provide a means to identify a solution to improve performance. This paper showcases a project in South Iraq where modeling of the drilling BHA's using a unique Finite Element Analysis software package identified critical natural frequencies of the drillstring. The integration of high frequency downhole vibration data collected in multiple positions of the string provided the evidence to validate the vibration road map delivered by the BHA analysis. The objective of the project was to identify the primary vibration mode, evaluate the vibrations severity, cause and source in the 12¼" vertical section and provide recommendations to achieve performance improvement through controlled step changes in bit & BHA design, drilling parameters and operational procedures. The pre-well BHA model analysis identified that the premature bit failure was a direct result of lateral vibrations induced by operating in a critical lateral harmonic zone. This was validated with the downhole vibration data. A well-established optimization process including expert detailed analysis of the high frequency downhole vibration data provided a clear understanding of the relationship between the pre-well BHA model, the drilling parameters planed and the associated downhole drilling dynamics. The impact on performance was clear. Implementation of the new recommended drilling parameters derived from the BHA analysis applied to the same bit and BHA used in Well #1 resulted on a 26% increase in drilling performance in well 2.

To study the protective function and pathophysiology of cystathionine gamma-lyase (CSE)/hydrogen sulfide (H(2)S) system in hepatic ischemia-reperfusion injury (HIRI) in rats.Wistar rats were randomly distributed into sham group (n = 18), ischemia-reperfusion (IR) group (n = 18), IR + NaHS group (n = 18) and IR + DL-propargylglycine (PAG) group (n = 18). The hepatic IR model was established by Pringle's hepatic vascular occlusion. At each of the indicated time points (1, 3 and 6 hours after IR), the serum levels of H(2)S and the hepatic CSE activity were measured. The serum levels of inflammatory factors, including TNF-α, IL-10 were determined by ELISA methods. The expression of apoptotic protein, TNF-α, in liver tissue was tested by Western blot assay, cell apoptosis was examined by TUNEL and the histological changes were examined in each group.The serum levels of H(2)S and CSE activity were significantly increased in group IR compared with group sham at all indicated time points (P0.05). The serum level of inflammatory factors (P0.01) and the hepatic expression of TNF-α protein (P0.05) were elevated obviously in group IR than that in group sham. Administration of NaHS could reduce the production of inflammatory factors in serum (P0.01), inhibit hepatic protein expression of TNF-α (P0.05) and attenuate the liver histological scores of IR injury (P0.05), whereas PAG aggravated them.The endogenous CSE/H(2)S system maybe involved in the pathogenesis of hepatic IR injury, which suggests that CSE/H(2)S system can protect liver from IR injury in rats by intervening in inflammatory reaction, attenuating the injury severity and inhibiting expression of apoptotic protein TNF-α.

To investigate whether endostatin, a potent antiangiogenic agent, synergizes with doxorubicin to suppress human hepatocellular carcinoma (HCC).An endostatin expression plasmid, Endo-cDNA3.1, was constructed and transfected into COS-1 cells. Human HCC cells of the line HepG2 and human umbilical vein endothelial cells of the line HUVEC were cultured and stimulated by the supernatant of the CoS-1 cells transfected with Endo-pcDNA3.1 and doxorubicin of different concentrations. MTT method was used to detect the proliferation of the cells. (How many) BALB/c mice were inoculated with HepG2 cells to establish HCC models, and then divided into 4 groups to undergo intratumoral injection of pcDNA3.1, End-pcDNA3.1, doxorubicin, or doxorubicin + Endo-pcDNA3.1. Other mice were used as untreated control group. Two weeks later 5 mice from each group were killed with the tumors taken out. Immunostaining was used to calculate the microvessel density and Western blotting was sued to detect the expression of endostatin, hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF).The proliferation of the HUVEC cells, but not that of the HepG2 cells, transfected with Endo-pcDNA3.1 + doxorubicin was inhibited. Doxorubicin dose-dependently inhibited the proliferation of both HUVEC and HepG2 cells. Endostatin was strongly expressed in the cells treated with Endo-pcDNA3.1 the tumor size of the Endo-pcDNA3.1 and doxorubicin groups were (1545 +/- 180) mm(3) and (953 +/- 250) mm(3) respectively, both significantly lower than that of the untreated and pcDNA3.1 groups [(2360 +/- 330) mm(3) and (2235 +/- 268) mm(3), respectively, all P0.01], and the tumor size of the Endo-pcDNA3.1 + doxorubicin group was (426 +/- 87) mm(3), significantly lower than any other groups (all P0.01). The number of microvessels of the Endo-pcDNA, doxorubicin, and doxorubicin + Endo-pcDNA3.1 groups were all significantly less than those of the pcDNA3.1 and untreated groups (P0.05 or P0.01). The expression of HIF-1alphawas downregulated in the Endo-pcDNA3.1 and Endo-pcDNA3.1 + doxorubicin groups, but not in the doxorubicin group. The VEGF expression was down-regulated in the Endo-pcDNA3.1, doxorubicin, and Endo-pcDNA3.1 + doxorubicin groups, especially in the latter.Endostatin gene therapy synergizes with doxorubicin to suppress HCC.

To investigate the effects of oxymatrine on protecting the liver against ischemia-reperfusion injury (IRI) and explore the mechanism thereof.Thirty male Wistar rats were randomly divided into 3 equal groups: IRI group (2 ml normal saline was injected into the dorsal vein of penis, 30 min later laparotomy was performed, arterial clamp was used to grip the hepatic artery and portal vein for 30 minutes and then removed, the vessels were reperfused for 90 min, and 4 ml blood was collected from the aorta; parts of the liver were resected); oxymatrine group (oxymatrine 40 mg/kg was injected into the dorsal vein of penis, and the other procedures were the same as in the IRI group); and sham operation group (2 ml normal saline was injected into the dorsal vein of penis, laparotomy was performed, 150 min after the injection 4 ml blood was collected from the aorta and parts of the liver were resected). The levels of alanine transaminase (ALT) and aspartate transaminase (AST) were detected. The liver tissues underwent HE staining and TUNEL staining for pathological examination. Suspension of single hepatocytes was prepared to observe the ratio of apoptotic cells and cell cycles by flow cytometry (FCM). Western blotting was used to examine the Fas protein expression.The AST and ALT levels of the IRI group were 1326 U/L +/- 211 U/L and 768 U/L +/- 175 U/L respectively, significantly higher than those of the sham operation group (112 U/L +/- 53 U/L and 55 U/L +/- 17 U/L, both P0.05) and those of the oxymatrine group (513 U/L +/- 96 U/L and 352 U/L +/- 72 U/L respectively, both P0.01). The liver cells of the sham operation group were normal, those of the IRI group showed remarkable edema and cytoplasm degeneration. TUNEL staining showed remarkably more apoptotic cells in the IRI group. FCM showed that the apoptotic rate of hepatocytes was 42.8% +/- 5.2% in the IRI group, significantly higher than in the oxymatrine group (8.8% +/- 1.8%, P0.01), and that the ratio of hepatocytes in G(0)/G(1) stage of the IRI group was 99.2% +/- 1.8%, significantly higher than that of the sham operation group (77.0% +/- 2.1%), and that of the oxymatrine group (87.6% +/- 2.8%) (both P0.05); the ratio of hepatocytes in the S stage of the IRI group was 0.52% +/- 0.25%, significantly lower than those of the sham operation group (23.94% +/- 1.84%) and oxymatrine group (12.42% +/- 0.46%) (both P0.01). The Fas protein expression was significantly highly in the IRI group than in the oxymatrine group.Remarkably reducing the IRI of hepatocytes, oxymatrine has potential to protect the liver against IRI during surgical intervention.

To investigate the synergistic effects of antisense HIF-1alpha gene therapy combined with B7-1-mediated immunotherapy on cancer treatment.Antisense HIF-1alpha and B7-1 expression vector were constructed. Lymphoma cells EL-4 were injected subcutaneously into C57BL/6 mice and transplanted lymphomas were established. The mice received either antisense HIF-1alpha, B7-1, or a combinational agent, complexed with DOTAP cationic liposomes. The tumor growth in the mice was monitored. Expression of HIF-1alpha, B7-1 and VEGF were detected by immunohistochemistry and Western blotting. The tumor blood vessels were immunostained with CD31- antibodies and the tumor vascular density was assessed by light microscopy.Gene transfer of plasmid expressing the encoded antisense HIF-1alpha inhibited VEGF expression and reduced vascular density in the tumors, eradicated tumors in diameter smaller than 0.1 cm and only retarded the growth of larger tumors. Whereas combination of antisense HIF-1alpha gene therapy and B7-1 immunotherapy eradicated all tumors in diameter of 0.4 cm.Antisense HIF-1alpha blocks tumor hypoxia pathway by downregulating VEGF expression, reduction of vascular density and enhances B7-1-mediated immunotherapy. Strategies that target HIF-1 may have therapeutic potential in cancer treatment and are worthy of further studying.

To explore the effect of von Hippel-Lindau(VHL) gene on growth of EL-4 solid tumors in vivo.C57BL/6 mice model of solid tumors was established by subcutaneous injection of EL-4 lymphoma cells. Mice were randomly divided into two groups as treatment group (n=6) and control group (n=6) when tumor diameter increased to 0.1 cm and 0.4 cm respectively. Plasmid pcDNA3-VHL was injected into solid tumor in treatment group, empty pcDNA3 vector in control group. The growth of tumor was observed. Immunohistochemistry and Western blot analysis were used to examine the transgenic expression of VHL, hypoxia inducible factor-1alpha (HIF)-1alpha, bcl-2 and VEGF. Microvessel density (MVD) and apoptosis index (AI) of tumors were also detected.VHL gene transfer eradicated tumors with small size (0.1 cm diameter), but it only retarded the growth of large tumors (0.4 cm diameter). VHL was overexpressed, the expression levels of VEGF, HIF-1alpha and bcl-2 were reduced in treatment group compared with those in the control group. The level of MVD was significantly lower in treatment group (P0.05), but AI was higher in treatment group compared with those in the control group (P0.01).VHL gene therapy can inhibit the growth of EL-4 solid tumor in vivo.