bluuebunny/crossref_metadata_2025 huggingface dataset:
1,3-Butanediol attenuates hypertension and suppresses kidney injury in female rats
Authors: Ishimwe Jeanne A. , Garrett Michael R. , Sasser Jennifer M.
Published: June 2020

Thirty-seven million people in the United States are estimated to have chronic kidney disease (CKD). Hypertension (HTN) is the second leading risk factor for developing kidney disease. A recent study reported that increasing levels of β-hydroxybutyrate levels by administration of its precursor, 1,3-butanediol, decreased salt-induced HTN in male Dahl salt-sensitive (S) rats. The effect of 1,3-butanediol on hypertensive kidney disease in female rats or the absence of high salt has not been investigated. This study tested the hypothesis that 1,3-butanediol attenuates HTN and the progression of CKD in female S-SHR(11) rats. The S-SHR(11) strain is a congenic rat strain generated from genetic modification of the Dahl S rat, previously characterized as a model of accelerated renal disease. Rats received 1,3-butanediol (20% via drinking water) or control for 10 wk and were maintained on a 0.3% NaCl rodent diet ( n = 12–14 rats/group). Blood pressure was measured after 6 and 9 wk of treatment by tail-cuff plethysmography; after 10 wk, urine and tissues were collected. Activity of the treatment was confirmed by measuring plasma β-hydroxybutyrate levels, which were greater in the treated group. The 1,3-butanediol-treated group had lower systolic blood pressure, proteinuria, plasma creatinine, and renal fibrosis after 9 wk of treatment compared with controls. The treated group had significantly smaller spleens and increased the renal anti-inflammatory molecules interleukin-10 and granulocyte-macrophage colony-stimulating factor, suggesting reduced inflammation. The present data demonstrate that 1,3-butanediol lowers blood pressure and renal injury in female rats and could be a novel nutritional intervention for the treatment of CKD.
Bovine Dialyzable Leukocyte Extract IMMUNEPOTENT-CRP Induces Selective ROS-Dependent Apoptosis in T-Acute Lymphoblastic Leukemia Cell Lines
Authors: Lorenzo-Anota Helen Yarimet , Martínez-Torres Ana Carolina , Scott-Algara Daniel , Tamez-Guerra Reyes S. , Rodríguez-Padilla Cristina
Published: June 2020

Immunotherapies strengthen the immune system to fight multiple diseases such as infections, immunodeficiencies, and autoimmune diseases, and recently, they are being used as an adjuvant in cancer treatment. IMMUNEPOTENT-CRP (I-CRP) is an immunotherapy made of bovine dialyzable leukocyte extract (bDLE) that has chemoprotective and immunomodulatory effects in different cellular populations of the immune system and antitumor activity in different cancer cell lines. Our recent results suggest that the antineoplastic effect of I-CRP is due to the characteristics of cancer cells. To confirm, we evaluated whether the selectivity is due to cell lineage or characteristics of cancer cells, testing cytotoxicity in T-acute lymphoblastic leukemia cells and their cell death mechanism. Here, we assessed the effect of I-CRP on cell viability and cell death. To determine the mechanism of cell death, we tested cell cycle, mitochondrial and nuclear alterations, and caspases and reactive oxygen species (ROS) and their role in cell death mechanism. Our results show that I-CRP does not affect cell viability in noncancer cells and induces selective cytotoxicity in a dose-dependent manner in leukemic cell lines. I-CRP also induces mitochondrial damage through proapoptotic and antiapoptotic protein modulation (Bax and Bcl-2) and ROS production, nuclear alterations including DNA damage (γ-H2Ax), overexpression of p53, cell cycle arrest, and DNA degradation. I-CRP induced ROS-dependent apoptosis in leukemic cells. Overall, here, we show that I-CRP cytotoxicity is selective to leukemic cells, inducing ROS-dependent apoptosis. This research opens the door to further exploration of their role in the immune system and the cell death mechanism that could potentially work in conjunction with other therapies including hematological malignances.
A Mitomycin C-Sparing Novel Technique for Subscleral Trabeculectomy in Primary Congenital Glaucoma
Authors: Bor’i Ashraf , Al-Mosallamy Salah M. , Elsayed Tamer G. , El-Haig Wael M.
Published: June 2020

Purpose. To evaluate the safety and efficacy of a novel modified subscleral trabeculectomy technique in management of primary congenital glaucoma.Methods. This study included 25 infants diagnosed of having bilateral primary congenital glaucoma. For each patient, one eye was assigned to undergo subscleral trabeculectomy with trimming of the edges of the scleral bed (group I), while the contralateral eye underwent subscleral trabeculectomy with application of mitomycin C (0.4 mg/ml for 3 min) (group II). All the patients were followed up for a period of 14 ± 3 months (range 13–22 months).Results. 25 eyes were included in each group. Patients’ mean age was 2.5 ± 0.5 months (range 1.8–6.5 months). The mean preoperative intraocular pressure was 31 ± 4.9 mmHg and 32.1 ± 4.0 mmHg in group I and II, respectively. The mean postoperative intraocular pressure was 9.0 ± 1.0, 11.0 ± 3.2, 12.5 ± 0.9, 13.0 ± 2.9, and 15.5 ± 1.5 mm Hg in group I and was 10.3 ± 1.2, 12.0 ± 2.5, 13.5 ± 1.7, 15.0 ± 1.5, and 17.1 ± 2.8 mm Hg in group II at the first week and 1, 3, 6, and 12 months, respectively. There was no statistically significant difference between the mean intraocular pressure values recorded at both groups preoperatively and at each follow-up visit. Failure necessitating further surgical interventions was recorded in 4 eyes (16%) in group I as compared to 3 eyes (12%) in group II (P>0.05). Postoperative complications included mild hyphema, which occurred in one eye (4%) in group I and 2 eyes (8%) in group II, and shallow anterior chamber in 3 eyes (12%) in group I and in 2 eyes (8%) in group II. One eye (4%) in group I developed drawn-up pupil. Choroidal effusion developed in one eye (4%) at each group.Conclusion. Trimming the edges of the scleral bed adjacent to the sclera flap is a safe and effective surgical step which can be added to the subscleral trabeculectomy procedure to effectively control the intraocular pressure in patients with primary congenital glaucoma, sparing them the hazards associated with mitomycin C application.
Profiles of PD‐1, PD‐L1, PD‐L2 in Gastric Cancer and Their Relation with Mutation, Immune Infiltration, and Survival
Authors: Liu Jingwei , Li Hao , Sun Liping , Yuan Yuan , Xing Chengzhong
Published: June 2020

Background. Although multiple types of cancers demonstrated favorable outcome after immunotherapy of PD‐1/PD‐L1 blockade, the specific regulatory mechanism of PD genes in gastric cancer (GC) remains largely unknown. Materials and Methods. Expression of RNA, copy number variants, and clinical parameters of GC individuals from TCGA were analyzed. Coexpressed genes for PD‐1, PD‐L1, and PD‐L2 were selected by correlation analysis and confirmed by STRING. Gene Ontology and KEGG pathway analyses were performed by clusterProfiler. The influence of PD‐1/PD‐L1/PD‐L2 on immune cell infiltration was investigated by MCP‐counter. Results. PD‐L2 demonstrated significant relation with clinical stage of GC (P = 0.043). Survival analysis showed that PD‐1 expression was correlated with better prognosis of GC patients (HR = 0.70, P = 0.031), but PD‐L2 expression was related with worse survival (HR = 1.42, P = 0.032). Mutation of PIK3CA could alter the level of PD‐1, PD‐L1, and PD‐L2 (P < 0.001), and TP53 mutation demonstrated significant correlation with PD‐L1 (P = 0.015) and PD‐L2 (P = 0.014) expression. Enrichment analysis of PD‐1/PD‐L1/PD‐L2 coexpressed genes indicated a biological process of mononuclear cell proliferation, leukocyte cell‐cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1 and Th2, cell differentiation of Th17, and hematopoietic cell landscape. As for immune infiltration analysis, PD‐1 was mainly related with cytotoxic lymphocytes and endothelial cells; PD‐L1 were associated with monocytic lineage; PD‐L2 showed significant correlation with myeloid dendritic cells. Conclusion. PD‐1 expression showed association with better prognosis of GC, and PD‐L2 expression was related with worse survival. Mutations of PIK3CA and TP53 significantly correlated with PD‐1/PD‐L1/PD‐L2 axis. PD‐1/PD‐L1/PD‐L2 coexpressed genes demonstrated enrichment in mononuclear cell proliferation, leukocyte cell‐cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1, Th2, and Th17.
Minimum-Fuel Ascent of Hypersonic Vehicle considering Control Constraint Using the Improved Pigeon-Inspired Optimization Algorithm
Authors: He Jiahao , Liu Yanbin , Li Shuanglin , Tang Yue
Published: June 2020

Trajectory optimization problem for hypersonic vehicles has long been recognized as a difficult problem. This paper brings control constraints into the trajectory optimization to make the optimal trajectory meet the requirements of control performance. The strong nonlinear characteristic of the ascent phase aerodynamics makes the trajectory optimization problem difficult to be solved by the optimal control theory. A trajectory optimization algorithm based on the improved pigeon-inspired optimization (PIO) algorithm is proposed to solve the complex trajectory optimization problem under multiple constraints. To overcome the obstacle of premature convergence and deceptiveness, the evolutionary strategy of qubit in quantum evolutionary algorithm (QEA) is introduced into the PIO to maintain population diversity and judge the optimal solution. To handle constraints, the penalty function is used to construct the fitness function. The optimal ascent trajectory is obtained by utilizing the improved PIO algorithm. Then, the trajectory inverse algorithm is used to verify the feasibility of the optimal trajectory to ensure that a feasible optimal trajectory is obtained. The comparison results show that the proposed algorithm outperforms particle swarm optimization (PSO) and standard PIO on trajectory optimization. Meanwhile, the simulation result shows that the performance of the optimal ascent trajectory with control constraints is improved and the trajectory is feasible. Therefore, the method is potentially feasible for solving the ascent trajectory optimization problem under control constraint for hypersonic vehicles.
5α,6α-Epoxyphytosterols and 5α,6α-Epoxycholesterol Increase Nitrosative Stress and Inflammatory Cytokine Production in Rats on Low-Cholesterol Diet
Authors: Wielkoszyński Tomasz , Zalejska-Fiolka Jolanta , Strzelczyk Joanna K. , Owczarek Aleksander J. , Cholewka Armand , Kokoszczyk Katarzyna , Stanek Agata
Published: June 2020

Objective. Oxidized cholesterol derivatives are compounds with proven atherogenic and mutagenic effects. However, little is known about the effect of oxidized plant sterol derivatives (oxyphytosterols), whose structure is similar to the one of oxycholesterols. Our previous studies indicate that they have a similar profile of action, e.g., both exacerbate disorder of lipid metabolism and oxidative stress in experimental animals. The aim of the present study was to assess the effect of epoxycholesterol and epoxyphytosterols (mainly sitosterol) on the severity of nitrosative stress and the concentration of selected proinflammatory cytokines in blood and liver tissue of rats on a low-cholesterol diet.Material and Methods. Forty-five male Wistar rats were fed with feed containing 5α,6α-epoxyphytosterols (ES group,n: 15), 5α,6α-epoxycholesterol (ECh group,n: 15), and oxysterol-free feed (C group,n: 15) for 90 days (daily dose of oxysterols: 10 mg/kg). At the end of the experiment, nitrotyrosine, TNF-α, IL-1β, IL-6, and lipid metabolism parameters were determined in blood serum. Furthermore, nitrotyrosine, TNF-α, cholesterol, and triglyceride content were determined in liver homogenates.Results. Serum nitrotyrosine, IL-1β, and TNF-αconcentrations as well as TNF-αcontent in the liver were significantly higher in both groups exposed to oxysterols (ECh and ES groups) as compared to the C group. The serum IL-6 level and nitrotyrosine content in the liver were significantly higher in the ECh group, as compared to the C and ES groups. There was evidence to support the dyslipidemic effect of studied compounds.Conclusions. The results indicate that oxidized plant sterols have a similar toxicity profile to that of oxycholesterols, including nitrosative stress induction, proinflammatory effect, and impaired lipid metabolism.
Pipeline Lifting Mechanics Research of Horizontal Directional Drilling
Authors: Guo Zhengwei , Xie Shuai , Ren Liancheng , Yinchun Gong , Dong Chaoqun
Published: June 2020

During lifting pipeline of horizontal directional drilling (HDD), the rotation angle of pipeline is determined by such parameters as the location of lifting point, axial force, and length of pipeline. The continuous beam theory is used to analyze the mechanical behaviour of pipeline during lifting construction, and the mechanical model of pipeline during lifting construction process is established. The analysis results show that the lifting height of gondola 1 varies linearly with the length of pipeline. The lifting height of gondola 2 varies linearly with axial force and pipe gravity. The longer the spanning pipeline is, the higher the lifting height is. The lifting height of gondola 2 varies curve trend with the axial force and pipe stiffness. When the length of pipeline is small, the lifting height of gondola 2 is approximately 0.
miR-155-5p Implicates in the Pathogenesis of Renal Fibrosis via Targeting SOCS1 and SOCS6
Authors: Zhang Wanfen , Li Xiaoping , Tang Yushang , Chen Cheng , Jing Ran , Liu Tongqiang
Published: June 2020

Renal fibrosis is associated with the reduction in the functional renal parenchyma and in most cases progresses to end-stage kidney failure, a devastating condition that requires lifelong dialysis or kidney transplantation. However, due to the extreme complexity in the pathogenesis of renal fibrosis and our limited knowledge, therapeutic options for renal fibrosis in the clinical setting are still scarce and often ineffective. Hence, further studies on the molecular mechanisms underlying renal fibrosis are compellingly needed. Multiple miRNAs have demonstrated to participate in kidney diseases in a TGF-β dependent or independent manner, but there is very little known about miR-155-5p on renal fibrosis. In the present study, we firstly explored the expression level and functions of miR-155-5p in the setting of renal fibrosis. Our research revealed that miR-155-5p is highly expressed in kidney tissues from patients and unilateral ureteral obstruction (UUO) rat models, and miR-155-5p knockdown significantly blocks renal fibrosis both in vivo and in vitro. In mechanism, our data demonstrate that miR-155-5p promotes renal fibrosis by increasing the phosphorylated activation of STAT3 via targeting SOCS1/6. Altogether, our findings highlight a miR-155-5p/SOCS/STAT3 axis in the pathogenesis of renal fibrosis, which may provide promising therapeutic targets for clinical prevention of this disease.
Feature Selection and Model Fusion Approach for Predicting Urban Macro Travel Time
Authors: Li D. D. , Yu D. X. , Qu Z. J. , Yu S. H.
Published: June 2020

With the rapid growth of car ownership, traffic congestion has become one of the most serious social problems. For us, accurate real-time travel time predictions are especially important for easing traffic congestion, enabling traffic control and management, and traffic guidance. In this paper, we propose a method to predict urban road travel time by combining XGBoost and LightGBM machine learning models. In order to obtain a relatively complete data set, we mine the GPS data of Beijing and combine them with the weather feature to consider the obtained 14 features as candidate features. By processing and analyzing the data set, we discussed in detail the correlation between each feature and the travel time and the importance of each feature in the model prediction results. Finally, the 10 important features screened by the LightGBM and XGBoost models were used as key features. We use the full feature set and the key feature set as input to the model to explore the effect of different feature combinations on the prediction accuracy of the model and then compare the prediction results of the proposed fusion model with a single model. The results show that the proposed fusion model has great advantages to urban travel time prediction.
Prognostic Value of C-Reactive Protein to Albumin Ratio in Glioblastoma Multiforme Patients Treated with Concurrent Radiotherapy and Temozolomide
Authors: Topkan Erkan , Besen Ali A. , Mertsoylu Huseyin , Kucuk Ahmet , Pehlivan Berrin , Selek Ugur
Published: June 2020

Objective. We investigated the prognostic impact of C-reactive protein to albumin ratio (CRP/Alb) on the survival outcomes of newly diagnosed glioblastoma multiforme (GBM) patients treated with radiotherapy (RT) and concurrent plus adjuvant temozolomide (TMZ). Methods. The pretreatment CRP and Alb records of GBM patients who underwent RT and concurrent plus adjuvant TMZ were retrospectively analyzed. The CRP/Alb was calculated by dividing serum CRP level by serum Alb level obtained prior to RT. The availability of significant cutoff value for CRP/Alb that interacts with survival was assessed with the receiver-operating characteristic (ROC) curve analysis. The primary endpoint was the association between the CRP/Alb and the overall survival (OS). Results. A total of 153 patients were analyzed. At a median follow-up of 14.7 months, median and 5-year OS rates were 16.2 months (95% CI: 12.5–19.7) and 9.5%, respectively, for the entire cohort. The ROC curve analysis identified a significant cutoff value at 0.75 point (area under the curve: 74.9%; sensitivity: 70.9%; specificity: 67.7%; P<0.001) for CRP/Alb that interacts with OS and grouped the patients into two: CRP/Alb <0.75 (n = 61) and ≥0.75 (n = 92), respectively. Survival comparisons revealed that the CRP/Alb <0.75 was associated with a significantly superior median (22.5 versus 15.7 months; P<0.001) and 5-year (20% versus 0%) rates than the CRP/Alb ≥0.75, which retained its independent significance in multivariate analysis (P<0.001). Conclusion. Present results suggested the pretreatment CRP/Alb as a significant and independent inflammation-based index which can be utilized for further prognostic lamination of GBM patients.
Sensor Type, Axis, and Position-Based Fusion and Feature Selection for Multimodal Human Daily Activity Recognition in Wearable Body Sensor Networks
Authors: Badawi Abeer A. , Al-Kabbany Ahmad , Shaban Heba A.
Published: June 2020

This research addresses the challenge of recognizing human daily activities using surface electromyography (sEMG) and wearable inertial sensors. Effective and efficient recognition in this context has emerged as a cornerstone in robust remote health monitoring systems, among other applications. We propose a novel pipeline that can attain state-of-the-art recognition accuracies on a recent-and-standard dataset—the Human Gait Database (HuGaDB). Using wearable gyroscopes, accelerometers, and electromyography sensors placed on the thigh, shin, and foot, we developed an approach that jointly performs sensor fusion and feature selection. Being done jointly, the proposed pipeline empowers the learned model to benefit from the interaction of features that might have been dropped otherwise. Using statistical and time-based features from heterogeneous signals of the aforementioned sensor types, our approach attains a mean accuracy of 99.8%, which is the highest accuracy on HuGaDB in the literature. This research underlines the potential of incorporating EMG signals especially when fusion and selection are done simultaneously. Meanwhile, it is valid even with simple off-the-shelf feature selection methods such the Sequential Feature Selection family of algorithms. Moreover, through extensive simulations, we show that the left thigh is a key placement for attaining high accuracies. With one inertial sensor on that single placement alone, we were able to achieve a mean accuracy of 98.4%. The presented in-depth comparative analysis shows the influence that every sensor type, position, and placement can have on the attained recognition accuracies—a tool that can facilitate the development of robust systems, customized to specific scenarios and real-life applications.
Protection of Lycopene against Embryonic Anomalies and Yolk Sac Placental Vasculogenic Disorders Induced by Nicotine Exposure
Authors: Park Seul Gi , Lin Chunmei , Gwon Lee Wha , Lee Jong-Geol , Baek In-Jeoung , Lee Beom Jun , Nam Sang-Yoon
Published: June 2020

Identification of a new agent from natural products for the protection of embryonic anomalies is potentially valuable. To investigate the protective effect exerted by lycopene against nicotine‐induced malformations, mouse embryos in embryonic day 8.5 with yolk sac placentas were cocultured with 1 mM nicotine and/or lycopene (1 × 10−6, 1 × 10−5 μM) for 48 h. The morphological defects and apoptotic cell deaths in the embryo and yolk sac placenta of the nicotine group were significantly increased. Exposure to nicotine resulted in reduced superoxide dismutase (SOD) activity and cytoplasmic SOD and cytoplasmic glutathione peroxidase mRNA levels, but increased lipid peroxidation level in embryos. Moreover, treatment with nicotine resulted in aggravated expressions of the mRNA or protein level of antiapoptotic (BCL2‐associated X protein, B‐cell lymphoma‐extralarge, and caspase 3), anti‐inflammatory (nuclear factor kappa‐light‐chain‐enhancer of activated B cells and tumor necrosis factor‐alpha), and vasculogenic (vascular endothelial growth factor‐alpha, insulin‐like growth factor‐1, alpha smooth muscle actin, transforming growth factor‐beta 1, and hypoxia inducible factor‐1 alpha) factors in the embryo and yolk sac placenta. However, all the parameters were significantly improved by treatment with lycopene, as compared to the nicotine group. These findings indicate the potential of lycopene as a protective agent against embryonic anomalies and yolk sac vasculogenic and placenta‐forming defects induced by nicotine through modulations of oxidative, apoptotic, vasculogenic, and inflammatory activities.
Maximum Principle for Near-Optimality of Mean-Field FBSDEs
Authors: Li Ruijing , Hu Chaozhu
Published: June 2020

The present paper concerns with a near-optimal control problem for systems governed by mean-field forward-backward stochastic differential equations (FBSDEs) with mixed initial-terminal conditions. Utilizing Ekeland’s variational principle as well as the reduction method, the necessary and sufficient near-optimality conditions are established in the form of Pontryagin’s type. The results are obtained under restriction on the convexity of the control domain. As an application, a linear-quadratic stochastic control problem is solved explicitly.
Levosimendan Protects against Doxorubicin‐Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway
Authors: Li Ling-Li , Wei Li , Zhang Ning , Wei Wen-Ying , Hu Can , Deng Wei , Tang Qi-Zhu
Published: June 2020

Background and Aims. Myocyte apoptosis plays a critical role in the development of doxorubicin‐ (DOX‐) induced cardiotoxicity. In addition to its cardiotonic effect, laboratory evidence indicates that levosimendan can inhibit apoptosis, but its role in DOX‐induced cardiac injury remains unclear. Therefore, the present study is aimed at exploring whether levosimendan could attenuate DOX‐induced cardiotoxicity. Methods. Levosimendan (1 mg/kg) was administered to mice through oral gavage once daily for 4 weeks, and the mice were also subjected to an intraperitoneal injection of DOX (5 mg/kg) or saline, once a week for 4 weeks, to create a chronic model of DOX‐induced cardiotoxicity. A morphological examination and biochemical analysis were used to evaluate the effects of levosimendan. H9C2 cells were used to verify the protective role of levosimendan in vitro. And an Akt inhibitor was utilized to verify the cardioprotection of levosimendan. Results. Levosimendan reduced the cardiac dysfunction and attenuated the myocardial apoptosis induced by DOX in vivo and in vitro. Levosimendan also inhibited the activation of phosphatase and tensin homolog (PTEN) and upregulated P‐Akt expression both in vivo and in vitro. And inhibition of Akt abolished the cardioprotection of levosimendan in vitro. Conclusion. Levosimendan may protect against DOX‐induced cardiotoxicity via modulation of the PTEN/Akt signaling pathway.
Application of Artificial Intelligence for the Estimation of Concrete and Reinforcement Consumption in the Construction of Integral Bridges
Authors: Beljkaš Željka , Knežević Miloš , Rutešić Snežana , Ivanišević Nenad
Published: June 2020

Estimation of basic material consumption in civil engineering is very important in the initial phases of project implementation. Its importance is reflected in the impact of material quantities on forming the prices of individual positions, hence on forming the total cost of construction. The construction companies use the estimate of material quantity, among other things, as a base to make a bid on the market. The precision of the offer, taking into account the overall conditions of the business realization, directly influences the profit that the company can make on a specific project. In the early stages of project implementation, there are not enough available data, especially when it comes to the data needed to estimate material consumption, and therefore, the accuracy of material consumption estimation in the early stages of project realization is smaller. The paper presents the research on the use of artificial intelligence for the estimation of concrete and reinforcement consumption and the selection of optimal models for estimation. The estimation model was developed by using artificial neural networks. The best artificial neural network model showed high accuracy in material consumption estimation expressed as the mean absolute percentage error, 8.56% for concrete consumption estimate and 17.31% for reinforcement consumption estimate.
Conventional Echocardiography and Two-Dimensional Speckle Tracking in Healthy Sevoflurane-Anesthetized Dogs Undergoing Continuous Rate Infusion of Nalbuphine
Authors: Marques Marcel G. , Marques Ana Elisa G. W. , de Siqueira Carlos E. , de Sousa Élen A. P. , Ribeiro Yan S. , Floriano Beatriz P. , Ferreira Wagner L. , Santos Paulo S. P.
Published: June 2020

Nalbuphine is an agonist-antagonist opioid with adequate analgesic properties and few depressant effects on the respiratory system. However, there are no detailed reports available on cardiovascular effects of nalbuphine in dogs. The aim of this study was to assess the effects of a continuous rate infusion (CRI) of nalbuphine on left ventricular systolic and diastolic function of healthy sevoflurane-anesthetized dogs. Eighteen mixed-breed bitches aged 1–4 years and weighing 9.9 ± 3.8 kg were used. Dogs were randomly assigned to one of two groups: nalbuphine (GN, n = 9) and control (GC, n = 9). Anesthesia was induced and maintained with sevoflurane (2V%) followed by an intravenous (IV) bolus of nalbuphine (0.3 mg/kg) or 0.9% NaCl at equal volume and then CRI of nalbuphine (0.4 mg/kg/h) or 0.9% NaCl at an equal infusion rate. Echocardiographic and hemodynamic variables were determined at baseline and 20, 40, 60, and 80 minutes following start of CRI. No differences were found between groups for left ventricular systolic and diastolic variables obtained through conventional echocardiography and two-dimensional speckle tracking. Likewise, hemodynamic variables did not differ between groups. The E′/A′ ratio significantly increased at 20 minutes compared to baseline only in GN. Nalbuphine given at a CRI does not influence left ventricular systolic and diastolic function in healthy sevoflurane-anesthetized dogs.
Inhibition of HIV‐1 Protease by Carpobrotus edulis (L.)
Authors: Omoruyi Beauty E. , Ighodaro David I. , Afolayan Anthony J. , Bradley Graeme
Published: June 2020

Carpobrotus edulis (L.) is a plant commonly found in the Eastern Cape Province of South Africa and is used for the general treatment of infections relating to the human immunodeficiency virus (HIV). HIV‐1 protease plays an important role during HIV replication and maturation to its infectious form, and therefore inhibition of the enzyme is one of the main focus areas in drug development. The inhibitory effect of a water extract of C. edulis leaves against HIV‐1 protease activity was determined using the SensoLyte® 520 HIV‐1 protease assay fluorimetric kit and employing a HiLyte Fluor™488/QXL™520 fluorescence resonance energy transfer (FRET) peptide. Cytotoxicity of the extract towards HeLa Chang cell lines was determined using an in vitro MTT assay, and the phytochemical profile of the extract was determined with FT‐IR and LC‐MS. HIV‐1 protease activity was inhibited 83.06% (IC50 1.6 mg/ml) (p < 0.0001) by the pepstatin A inhibitor control. Treatment with all C. edulis extract concentrations (16, 1.6, 0.16, and 0.016 mg/ml) inhibited HIV‐1 protease activity significantly (p < 0.0001) in a typical dose response manner. With regards to cytotoxicity, the negative controls containing untreated HeLa Chang cells exhibited high formazan formation rates in contrast with the positive controls, containing curcumin, which reduced formazan formation significantly (p < 0.001), exhibiting cytotoxicity towards the cells. There was no significant (p > 0.05) difference in the formazan formation rates between the negative controls and 1, 0.5, 0.125, 0.065, 0.031, and 0.015 mg/ml plant extract, confirming no toxicity of C. edulis extracts towards HeLa Chang cells. Major functional phytochemical compounds identified included alcohols, phenols, alkanes, amines, carboxylic acids, and esters. LC‐ESI‐TOF/MS analysis revealed the putative identities of main compounds present in the aqueous leaves extract, including some that contribute to its anti‐HIV‐1 protease action.
Correlation and Path Coefficient Analysis of Yield and Yield Components of Quality Protein Maize (Zea mays L.) Hybrids at Jimma, Western Ethiopia
Authors: Aman Jemal , Bantte Kassahun , Alamerew Sentayehu , Sbhatu Desta Berhe
Published: June 2020

Maize is one of the most important staple food crops in many parts of Ethiopia. However, it is not used extensively due to its poor nutritional quality and low productivity. It lacks two essential amino acids, namely, lysine and tryptophan. Knowledge of the interrelationships of grain yield and its various causal (contributory) components is very helpful to improve the efficiency of breeding programs using appropriate selection indices. This article reports the findings of a study conducted to determine the nature of relationships of grain yield and its contributing components and to identify those components with significant effects on yield with the intention of using them as selection criteria using path coefficient analysis (PCA). Therefore, PCA has shown that yield per hectare had a significant and positive phenotypic correlation with plant height, ear height, number of kernels per row, and 100-grain weight. Moreover, PCA had a significant and positive genotypic correlation with days to 50% tasseling, plant height, ear height, and 100-grain weight. The highest direct positive effect on yield per hectare was exhibited by ear height. The findings of this study showed that most genotypes are early maturing and are suitable for areas with short rainy seasons and prone to drought.
Metastasis-Specific Gene Expression in Autochthonous and Allograft Mouse Mammary Tumor Models: Stratification and Identification of Targetable Signatures
Authors: Ross Christina , Szczepanek Karol , Lee Maxwell , Yang Howard , Peer Cody J. , Kindrick Jessica , Shankarappa Priya , Lin Zhi-Wei , Sanford Jack D. , Figg William D. , Hunter Kent W.
Published: June 2020

Breast cancer metastasis is a leading cause of cancer-related death of women in the United States. A hurdle in advancing metastasis-targeted intervention is the phenotypic heterogeneity between primary and secondary lesions. To identify metastasis-specific gene expression profiles we performed RNA-sequencing of breast cancer mouse models; analyzing metastases from models of various drivers and routes. We contrasted the models and identified common, targetable signatures. Allograft models exhibited more mesenchymal-like gene expression than genetically engineered mouse models (GEMM), and primary culturing of GEMM-derived metastatic tissue induced mesenchymal-like gene expression. In addition, metastasis-specific transcriptomes differed between tail vein and orthotopic injection of the same cell line. Gene expression common to models of spontaneous metastasis included sildenafil response and nicotine degradation pathways. Strikingly, in vivo sildenafil treatment significantly reduced metastasis by 54%, while nicotine significantly increased metastasis by 46%. These data suggest that (i) actionable metastasis-specific pathways can be readily identified, (ii) already available drugs may have great potential to alleviate metastatic incidence, and (iii) metastasis may be influenced greatly by lifestyle choices such as the choice to consume nicotine products. In summary, while mouse models of breast cancer metastasis vary in ways that must not be ignored, there are shared features that can be identified and potentially targeted therapeutically.

Implications:

The data we present here exposes critical variances between preclinical models of metastatic breast cancer and identifies targetable pathways integral to metastatic spread.

Visual Overview:

http://mcr.aacrjournals.org/content/molcanres/18/9/1278/F1.large.jpg.
Single-Cell Transcriptomics Analysis Identifies Nuclear Protein 1 as a Regulator of Docetaxel Resistance in Prostate Cancer Cells
Authors: Schnepp Patricia M. , Shelley Greg , Dai Jinlu , Wakim Nicole , Jiang Hui , Mizokami Atsushi , Keller Evan T.
Published: June 2020

The majority of patients with prostate cancer treated with docetaxel develop resistance to it. To better understand the mechanism behind the acquisition of resistance, we conducted single-cell RNA-sequencing (scRNA-seq) of docetaxel-sensitive and -resistant variants of DU145 and PC3 prostate cancer cell lines. Overall, sensitive and resistant cells clustered separately. Differential gene expression analysis between resistant and sensitive cells revealed 182 differentially expressed genes common to both prostate cancer cell lines. A subset of these genes gave a gene expression profile in the resistant transcriptome-like–sensitive cells similar to the resistant cells. Exploration for functional gene pathways identified 218 common pathways between the two cell lines. Protein ubiquitination was the most differentially regulated pathway and was enriched in the resistant cells. Transcriptional regulator analysis identified 321 potential regulators across both cell lines. One of the top regulators identified was nuclear protein 1 (NUPR1). In contrast to the single-cell analysis, bulk analysis of the cells did not reveal NUPR1 as a promising candidate. Knockdown and overexpression of NUPR1 in the prostate cancer cells demonstrated that NUPR1 confers docetaxel resistance in both cell lines. Collectively, these data demonstrate the utility of scRNA-seq to identify regulators of drug resistance. Furthermore, NUPR1 was identified as a mediator of prostate cancer drug resistance, which provides the rationale to explore NUPR1 and its target genes for reversal of docetaxel resistance.

Implications:

Using single-cell sequencing of prostate cancer, we show that NUPR1 plays a role in docetaxel resistance.
Bacterial SOS Genes mucAB/umuDC Promote Mouse Tumors by Activating Oncogenes Nedd9/Aurkb via a miR-145 Sponge
Authors: Tanooka Hiroshi , Inoue Ayako , Takahashi Ryou-u , Tatsumi Kouichi , Fujikawa Kazuo , Nagao Tetsuji , Ishiai Masamichi , Chiwaki Fumiko , Aoyagi Kazuhiko , Sasaki Hiroki , Ochiya Takahiro
Published: June 2020

The mechanism of cancer induction involves an aberrant expression of oncogenes whose functions can be controlled by RNAi with miRNA. Even foreign bacterial RNA may interfere with the expression of oncogenes. Here we show that bacterial plasmid mucAB and its Escherichia coli genomic homolog umuDC, carrying homologies that match the mouse anti-miR-145, sequestered the miR-145 function in mouse BALB 3T3 cells in a tetracycline (Tet)-inducible manner, activated oncogene Nedd9 and its downstream Aurkb, and further enhanced microcolony formation and cellular transformation as well as the short fragments of the bacterial gene containing the anti-miR-145 sequence. Furthermore, mucAB transgenic mice showed a 1.7-fold elevated tumor incidence compared with wild-type mice after treatments with 3-methylcolanthrene. However, the mutation frequency in intestinal stem cells of the mucAB transgenic mice was unchanged after treatment with X-rays or ethyl-nitrosourea, indicating that the target of mucAB/umuDC is the promotion stage in carcinogenesis.

Implications:

Foreign bacterial genes can exert oncogenic activity via RNAi, if endogenously expressed.

Visual Overview:

http://mcr.aacrjournals.org/content/molcanres/18/9/1271/F1.large.jpg.
Multiple Myeloma Presenting in Patients Younger than 50 Years of Age: A Single Institution Experience
Authors: Duek Adrian , Trakhtenbrot Luba , Avigdor Abraham , Nagler Arnon , Leiba Merav
Published: June 2020

Introduction: Multiple myeloma (MM) is uncommon in persons younger than 50 years of age. The presenting features in this age group are unclear. Methods: We analyzed a cohort of patients <50 years of age with MM treated in our center. Results: Twenty-three patients at a median age of 41.5 years (range 27–49) were analyzed. Patients presented at International Staging System (ISS) I–II (79%), had high frequency of bone lytic lesions (89%), extramedullary disease (26%), light-chain myeloma (45%), and translocation t(11;14) (68%). The subpopulation of patients carrying t(11;14) were younger (p = 0.025). This subgroup had higher bone marrow infiltration of plasma cells (75 vs. 47.5%), higher incidence of proteinuria (2.9 vs. 0.19 g/day), and poorer response to therapy: 85.7% of patients achieving complete/very good partial remission after induction therapy did not have t(11;14). A trend toward inferior progression-free survival (PFS) was observed in patients with t(11; 14) compared to patients without this translocation (median PFS 18 and 36 months, respectively). Discussion/Conclusion: Translocation t(11; 14) seems to be more prevalent in young myeloma patients. Young myeloma patients and especially those who harbor translocation t(11; 14) may represent a distinct clinical entity that confers a poor outcome.
2020 European Thyroid Association Clinical Practice Guideline for the Use of Image-Guided Ablation in Benign Thyroid Nodules
Authors: Papini Enrico , Monpeyssen Hervé , Frasoldati Andrea , Hegedüs Laszlo
Published: June 2020

Standard therapeutic approaches for benign thyroid lesions that warrant intervention are surgery for cold and either surgery or radioiodine for autonomously functioning thyroid nodules (AFTN). Image-guided thermal ablation (TA) procedures are increasingly proposed as therapy options for selected clinical conditions. Due to mounting scientific evidence and widening availability, ETA considered it appropriate to develop guidelines for the use of TA in adult patients. TA procedures are well tolerated, but a dedicated training of the operators is required and information on possible complications needs to be shared with the patients. The following factors should be considered when weighing between observation, surgery, and TA for benign thyroid nodules. In solid non-hyperfunctioning nodules, TA induces a decrease in thyroid nodule volume, paralleled by improvement in symptoms. Nodule re-growth is possible over time and may necessitate repeat treatment, or surgery, in a dialogue with the patient. In AFTN, radioactive iodine is the first-line treatment, but TA may be considered in young patients with small AFTN due to higher probability of restoring normal thyroid function and avoidance of irradiation. In cystic nodules, ethanol ablation (EA) is the most effective and least expensive treatment. TA may be considered for cystic lesions that relapse after EA or have a significant residual solid component following drainage and EA. TA should be restricted to benign lesions that cause symptoms or cosmetic concern. Presently, laser and radiofrequency ablation are the most thoroughly assessed techniques, with similar satisfactory clinical results. Microwaves and high-intensity focused ultrasound therapy options remain to be fully evaluated.
Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels
Authors: Wang Zhe , Chen Han , Bartz Traci M. , Bielak Lawrence F. , Chasman Daniel I. , Feitosa Mary F. , Franceschini Nora , Guo Xiuqing , Lim Elise , Noordam Raymond , Richard Melissa A. , Wang Heming , Cade Brian , Cupples L. Adrienne , de Vries Paul S. , Giulanini Franco , Lee Jiwon , Lemaitre Rozenn N. , Martin Lisa W. , Reiner Alex P. , Rich Stephen S. , Schreiner Pamela J. , Sidney Stephen , Sitlani Colleen M. , Smith Jennifer A. , Willems van Dijk Ko , Yao Jie , Zhao Wei , Fornage Myriam , Kardia Sharon L.R. , Kooperberg Charles , Liu Ching-Ti , Mook-Kanamori Dennis O. , Province Michael A. , Psaty Bruce M. , Redline Susan , Ridker Paul M. , Rotter Jerome I. , Boerwinkle Eric , Morrison Alanna C. ,   on behalf of the CHARGE Gene-Lifestyle Interactions Working Group
Published: June 2020

Background:

Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

Methods:

In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

Results:

We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (
PCSK9
,
LPA
,
LPL
,
LIPG
,
ANGPTL4
,
APOB
,
APOC3
, and
CD300LG
) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (
P
=6.65×10
−6
for the interaction test) and replicated at nominal significance level (
P
=0.013) in
SMC5
.

Conclusions:

In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
Inflammation and Circulating Natriuretic Peptide Levels
Authors: Fish-Trotter Hannah , Ferguson Jane F. , Patel Nirav , Arora Pankaj , Allen Norrina B. , Bachmann Katherine N. , Daniels Lori B. , Reilly Muredach P. , Lima Joao A.C. , Wang Thomas J. , Gupta Deepak K.
Published: June 2020

Background:

NPs (natriuretic peptides) are cardiac-derived hormones that promote natriuresis, diuresis, and vasodilation. Preclinical evidence suggests that nonhemodynamic triggers for NP release exist, with a few studies implicating inflammatory stimuli. We examined the association between inflammation and NP levels in humans.

Methods:

The associations between inflammation and NP levels were examined in 3 independent studies. First, in 5481 MESA (Multi-Ethnic Study of Atherosclerosis) participants, the cross-sectional (exam 1) and longitudinal (exams 1 to 3) associations between circulating IL6 (interleukin-6) and NT-proBNP (N terminal pro B-type natriuretic peptide) levels were examined in multivariable-adjusted models. Second, in a prospective study of 115 healthy individuals, changes in NP levels were quantified following exposure to lipopolysaccharide as an inflammatory stimulus. Third, in 13 435 hospitalized patients, the association between acute inflammatory conditions and circulating NP levels was assessed using multivariable-adjusted models.

Results:

At the baseline MESA exam, each 1-unit higher natural log IL6 was associated with 16% higher NT-proBNP level ([95% CI, 10%–22%];
P
=0.002). Each 1-unit higher baseline natural log IL6 level also associated with 6% higher NT-proBNP level ([95% CI, 1%–11%];
P
=0.02) at 4-year follow-up. In the lipopolysaccharide study, median NT-proBNP levels rose from 21 pg/mL pre-lipopolysaccharide to 54 pg/mL post-lipopolysaccharide,
P
<0.001. In the hospitalized patient study, acute inflammatory conditions were associated with 36% higher NP levels ([95% CI, 17%–60%];
P
<0.001).

Conclusions:

Inflammation appears to be associated with NP release. Interpretation of NP levels should therefore take into account inflammatory conditions.
Blood Pressure and Angiogenic Markers in Pregnancy
Authors: Birukov Anna , Herse Florian , Nielsen Julie H. , Kyhl Henriette B. , Golic Michaela , Kräker Kristin , Haase Nadine , Busjahn Andreas , Bruun Signe , Jensen Boye L. , Müller Dominik N. , Jensen Tina Kold , Christesen Henrik T. , Andersen Marianne Skovsager , Jørgensen Jan Stener , Dechend Ralf , Andersen Louise Bjørkholt
Published: June 2020

Pregnancy-induced hypertension is a severe pregnancy complication, increasing risk of long-term cardiovascular disease in mothers and offspring. We hypothesized that maternal blood pressure in pregnancy associated with offspring blood pressure; that the associations were sex-specific; and that maternal circulating placental angiogenic markers (PlGF [placental growth factor] and sFlt-1 [soluble fms-like tyrosine kinase-1]) mediated this relationship. We analyzed data from 2434 women and 2217 children from the Odense Child Cohort, a prospective Danish cohort study. Offspring blood pressure trajectory from 4 months to 5 years was highly associated to maternal first, second, and third trimester blood pressure, and mean blood pressure in pregnancy, independent of maternal and offspring covariates. There were offspring sex-specific associations: Girls from mothers in the highest quartile of first and third trimester blood pressure had significantly higher systolic blood pressure at 5 years than the rest of the cohort (mean difference±SEM: 1.81±0.59 and 2.11±0.59 mm Hg, respectively, all
P
<0.01); whereas boys had significantly higher diastolic blood pressure at 5 years (mean difference±SEM: 1.11±0.45 and 1.03±0.45, respectively, all
P
<0.05). Concentrations of PlGF at gestational week 28 correlated inversely to maternal gestational blood pressure trajectory, independent of the diagnosis of pregnancy-induced hypertension, adjusted β coefficients (95% CI) for predicting systolic blood pressure (SBP): −3.18 (−4.66 to −1.70) mm Hg, for predicting diastolic blood pressure (DBP): −2.48 (−3.57 to −1.40) mm Hg. In conclusion, maternal gestational blood pressure predicted offspring blood pressure trajectory until 5 years in a sex-differential manner. Furthermore, subtle alterations in blood pressure in early pregnancy preceded hypertension or preeclampsia, and PlGF was a mediator of cardiovascular health in pregnancy.