bluuebunny/crossref_metadata_2025 huggingface dataset:
UHPLC‐Q‐TOF MS‐Based Metabolic Analysis for the Therapeutic Efficacy of “Xuebijing Injection” against Sepsis‐Induced Acute Lung Injury
Authors: Shi Xuan , Chen Guannan , Wei Juan , Feng Di , Chen Yuanli , Zhou Huanping , Liu Meiyun , Lv Xin
Published: September 2018

“Xuebijing Injection” (XBJ) is a traditional Chinese medicine and has been wildly used in the treatment of sepsis in China. However, few studies have reported the use of XBJ in sepsis with acute lung injury (ALI). This study aimed to investigate the therapeutic efficacy of XBJ against sepsis‐induced ALI. Generally a total of 27 mice were equally randomized into three groups: a sham group was given saline before sham operation. A sepsis group received the cecal ligation and puncture (CLP) operation only. A sepsis+XBJ group, XBJ, was injected at 72, 48, and 24 h before CLP operation. The lung tissue was collected for UHPLC‐Q‐TOF/MS profiling analysis, biomarker identification, and pathway analysis. With the analysis of principal component analysis (PCA) and partial least squares discriminant analysis (PLS‐DA), forty‐five purine, amino acid, and sphingolipid metabolites in lung tissues were identified as potential biomarkers of sepsis‐induced ALI, among which 22 were reversed in the sepsis+XBJ group significantly. Conclusively, our results suggest that purine metabolic pathway, glutathione metabolic pathway, sphingomyelin metabolic pathway, arachidonic acid metabolic pathway, and phospholipid metabolic pathway may be the potential therapeutic pathways to overcome sepsis‐induced acute lung injury and we provided the potential mechanisms of protective effects of XBJ against ALI.
Key Substitution Attacks on Lattice Signature Schemes Based on SIS Problem
Authors: An Youngjoo , Lee Hyang-Sook , Lee Juhee , Lim Seongan
Published: September 2018

The notion of key substitution security on digital signatures in the multiuser setting has been proposed by Menezes and Smart in 2004. Along with the unforgeability of signature, the key substitution security is very important since it is a critical requirement for the nonrepudiation and the authentication of the signature. Lattice-based signature is a promising candidate for post-quantum cryptography, and the unforgeability of each scheme has been relatively well studied. In this paper, we present key substitution attacks on BLISS, Lyubashevsky’s signature scheme, and GPV and thus show that these signature schemes do not provide nonrepudiation. We also suggest how to avoid key substitution attack on these schemes.
Sovereign Credit Risk Assessment with Multiple Criteria Using an Outranking Method
Authors: de Lima Silva Diogo F. , Silva Julio Cezar Soares , Silva Lucimário G. O. , Ferreira Luciano , de Almeida-Filho Adiel T.
Published: September 2018

In view of the records of failures in rating agencies’ assessments for sorting countries’ quality of credit in degrees of default risk, this paper proposes a multicriteria sorting model using reference alternatives so as to allocate sovereign credit securities into three categories of risk. From a numerical application, what was observed from the results was a strong adherence of the model in relation to those of the agencies: Standard & Poor's and Moody's. Since the procedure used by the agencies is extremely subjective and often questioned, the contribution of this paper is to put forward the use of an objective and transparent methodology to sort these securities. Given the agencies’ conditions for undertaking the assessment, a complete similarity between the results obtained and the assignments of the agencies was not expected. Therefore, this difference arises from subjective factors that the agencies consider but the proposed model does not. Such subjective and questionable aspects have been partly responsible for the credibility of these credit agencies being diminished, especially after the 2007-2008 crisis.
Investigating Pathogenic and Hepatocarcinogenic Mechanisms from Normal Liver to HCC by Constructing Genetic and Epigenetic Networks via Big Genetic and Epigenetic Data Mining and Genome-Wide NGS Data Identification
Authors: Li Cheng-Wei , Chiu Yu-Kai , Chen Bor-Sen
Published: September 2018

The prevalence of hepatocellular carcinoma (HCC) is still high worldwide because liver diseases could develop into HCC. Recent reports indicate nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD&NASH) and primary biliary cirrhosis and primary sclerosing cholangitis (PBC&PSC) are significant of HCC. Therefore, understanding the cellular mechanisms of the pathogenesis and hepatocarcinogenesis from normal liver cells to HCC through NAFLD&NASH or PBC&PSC is a priority to prevent the progression of liver damage and reduce the risk of further complications. By the genetic and epigenetic data mining and the system identification through next-generation sequencing data and its corresponding DNA methylation profiles of liver cells in normal, NAFLD&NASH, PBC&PSC, and HCC patients, we identified the genome-wide real genetic and epigenetic networks (GENs) of normal, NAFLD&NASH, PBC&PSC, and HCC patients. In order to get valuable insight into these identified genome-wide GENs, we then applied a principal network projection method to extract the corresponding core GENs for normal liver cells, NAFLD&NASH, PBC&PSC, and HCC. By comparing the signal transduction pathways involved in the identified core GENs, we found that the hepatocarcinogenesis through NAFLD&NASH was induced through DNA methylation of HIST2H2BE, HSPB1, RPL30, and ALDOB and the regulation of miR-21 and miR-122, and the hepatocarcinogenesis through PBC&PSC was induced through DNA methylation of RPL23A, HIST2H2BE, TIMP1, IGF2, RPL30, and ALDOB and the regulation of miR-29a, miR-21, and miR-122. The genetic and epigenetic changes in the pathogenesis and hepatocarcinogenesis potentially serve as potential diagnostic biomarkers and/or therapeutic targets.
Preserved miR-361-3p Expression Is an Independent Prognostic Indicator of Favorable Survival in Cervical Cancer
Authors: Liu Shikai , Song Lili , Yao Hairong , Zhang Liang , Xu Dongkui , Li Qian , Li Ying
Published: September 2018

In this study, we aimed to assess the independent prognostic value of miR-361-3p in terms of overall survival (OS) and recurrence-free survival (RFS) in cervical cancer, as well as its possible regulative network. A retrospective analysis was performed by using data from the Cancer Genome Atlas-Cervical Cancer (TCGA-CESC). Results showed that decreased miR-361-3p expression was associated with lymphovascular invasion and poor responses to primary therapy. The patients with recurrence and the deceased cases had substantially lower miR-361-3p expression compared to their respective controls. By generating Kaplan-Meier curves of OS and RFS, we found that high miR-361-3p expression was associated with better survival outcome. More importantly, univariate and multivariate analysis confirmed that high miR-361-3p expression was an independent indicator of favorable OS (HR: 0.377, 95% CI: 0.233–0.608, p<0.001) and RFS (HR: 0.398, 95% CI: 0.192–0.825, p=0.013). By performing bioinformatic analysis, we identified 24 genes that were negatively correlated with miR-361-3p expression. Among the potential targeting genes, SOST, MTA1, TFRC, and YAP1 are involved in some important signaling pathways modulating cervical cancer cell invasion, migration, and drug sensitivity. Therefore, it is meaningful to verify the potential regulative effect of miR-361-3p on the expression of these genes in the future.
Spontaneously Diabetic Torii (SDT) Fatty Rat, a Novel Animal Model of Type 2 Diabetes Mellitus, Shows Blunted Circadian Rhythms and Melatonin Secretion
Authors: Sakimura Katsuya , Maekawa Tatsuya , Kume Shin-ichi , Ohta Takeshi
Published: September 2018

In patients with diabetes mellitus (DM), impairments of circadian rhythms, including the sleep–wake cycle, blood pressure, and plasma melatonin concentrations, are frequently observed. Animal models of DM are also reported to show aberrant circadian rhythms. However, the changes in the circadian rhythms of plasma soluble substances, including melatonin, in diabetic animals are controversial. In the present study, we investigated the circadian rhythms of spontaneous locomotor activity, metabolic parameters (plasma glucose, triglyceride, and total cholesterol), and plasma melatonin concentrations in Spontaneously Diabetic Torii (SDT) fatty rats, a novel animal model of type 2 DM. Although SDT fatty rats exhibited low locomotor activity in the dark phase, no phase shifts were observed. The circadian variations of plasma metabolic parameters were more apparent in the SDT fatty rats compared with control Sprague–Dawley (SD) rats. The circadian rhythms of plasma melatonin concentrations were significantly impaired in SDT fatty rats. To get an insight into the mechanism underlying the impaired melatonin secretion in SDT fatty rats, the expression of arylalkylamine N-acetyltransferase (Aanat) and acetylserotonin O-methyltransferase (Asmt) mRNA, which encode the rate-limiting enzymes for melatonin synthesis, was investigated in the pineal gland. There were no significant differences in Aanat and Asmt expression between the control SD and SDT fatty rats. These results suggest that SDT fatty rats show impaired circadian rhythms and dysregulated melatonin secretion.
The Antiosteoporosis Effects of Zhuanggu Guanjie Pill In Vitro and In Vivo
Authors: Chai Li-juan , Zhang Yue , Zhang Pan-yang , Bi Ya-nan , Yuan Xiao-mei , Li Yu-hong , Wang Yan-yan , Song Lei , Sun Li-kang , Zhou Kun
Published: September 2018

We investigated the beneficial effects and underlying mechanisms of Zhuanggu Guanjie (ZGGJ) pill in osteoporosis in vitro and in vivo. Bone marrow macrophages from 4–6-week-old mice were cultured in the presence of macrophage colony-stimulating factor (15 ng/mL) and receptor activator of nuclear factor-κB ligand (30 ng/mL). Osteoclast differentiation was determined by quantification of tartrate-resistant acid phosphatase activity. Gelatin zymography was used to detect the activity of matrix metalloproteinases in osteoclasts. Ovariectomized rats were administered orally with estradiol valerate or ZGGJ for 8 weeks. Blood was collected to measure serum indices. Tibiae were harvested to carry out bone microcomputed tomography scanning, histomorphological analysis, and bone strength determination. ZGGJ inhibited tartrate-resistant acid phosphatase activity, matrix metalloproteinase 9 expression, and bone resorption in vitro. At doses of 0.55, 1.1, and 2.2 g/kg, ZGGJ exerted significant osteoprotective effects including inhibition of bone turnover markers and improved tibia bone strength in ovariectomized rats. Microcomputed tomographic analysis showed that ZGGJ improved the trabecular architecture with increased connectivity density and trabecular thickness and decreased trabecular spacing. These results revealed that ZGGJ prevents bone loss induced by ovariectomy in rats and that inhibition of bone resorption is involved in the bone-protective effects of ZGGJ.
Characteristics and Changes over Time of Alcohol-Related Chronic Liver Diseases in Italy
Authors: Stroffolini Tommaso , Sagnelli Evangelista , Sagnelli Caterina , Morisco Filomena , Babudieri Sergio , Furlan Caterina , Pirisi Mario , Russello Maurizio , Smedile Antonina , Pisaturo Mariantonietta , Almasio Piero Luigi
Published: September 2018

Introduction. To evaluate the characteristics of alcohol-related chronic liver disease (CLD) in Italy and their potential changes over time. Patients and Methods. Subjects with CLD were enrolled in two national surveys performed in 2001 and in 2014 in Italy. The two surveys prospectively recruited patients aged ≥ 18 years referring to more than 80 Italian liver units scattered all over the country using similar clinical approach, analytical methods, and threshold of risky alcohol intake definition (≥ 3 units/day in men and ≥ 2 units/day in women). Results. Out of 12,256 enrolled subjects, 2,717 (22.2%) reported a risky alcohol intake. Of them, anti-HCV positive was observed in 48.3% of subjects. The overall sex ratio (M/F) was 3.1, decreasing from 3.8 in 2001 to 1.3 in 2014. Women were significantly older than men (58.9 versus 53.1 years; p<0.01) and an increasing ageing over time was observed in both sexes. The proportion of subjects with liver cirrhosis increased over time in both sexes, and decompensated stage (Child B or C) was detected in 55.9% of cases in 2001 and 46.0% in 2014. Conclusions. Risky alcohol intake plays a role in more than one-fifth of CLD in Italy, with a shift over time towards an older age and a more severe liver disease stage. These data put alcohol back in the spotlight with an important role in CLD in the years to come in Italy.
A Novel Curcumin-Galactomannoside Complex Delivery System Improves Hepatic Function Markers in Chronic Alcoholics: A Double-Blinded, randomized, Placebo-Controlled Study
Authors: T. Krishnareddy Naveen , Thomas Jestin V. , Nair Saritha S. , N. Mulakal Johannah , Maliakel Balu P. , Krishnakumar I. M.
Published: September 2018

Considering the recent interest in free (unconjugated) curcuminoids delivery, the present study investigated the efficacy of a novel food-grade free-curcuminoids delivery system (curcumin-galactomannoside complex; CGM) in improving the hepatic function markers (inflammation and oxidative stress) in chronic alcoholics. The double-blinded, placebo-controlled study randomized 48 subjects with elevated serum transaminases and gamma-glutamyl transferase (GGT) levels, who were allocated to two groups (n=24) and to receive either placebo or CGM at (250 mg × 2)/day for 8 weeks. While liver function markers (transaminases and GGT) in the placebo group showed an increase (~ 9.5%), CGM group indicated a significant decrease in transaminases (31%) and GGT (29%) from the baseline levels. The beneficial effect of CGM was also clear from the significant increase (p <0.001) in endogenous antioxidants (GSH, SOD, and GPx) and decrease in inflammatory markers (IL-6 and CRP) levels (p <0.001) as compared to both the baseline and placebo group. To summarize, the nutritional intervention of CGM-curcumin was found to offer a significant hepatoprotective effect to attenuate the alcohol induced alterations to hepatic function markers. The Indian Medical Council and Drug Controller General of India approved Clinical Trial Registry No.CTRI/2018/03/012385.
Factors Affecting Unmet Need of Family Planning Among Married Tharu Women of Dang District, Nepal
Authors: Bhusal Chet Kant , Bhattarai Sigma
Published: September 2018

Background. Increase in population plays a decisive role in providing universal access to reproductive health; however, there is very limited evidence about the reason of unmet need among marginalized and tribal communities such as Tharus. This study aimed to determine the factors affecting unmet need of family planning among married Tharu women of Dang, Nepal. Methods. Community-based cross-sectional household survey among 650 married Tharu women of age group 15-49 in October 2015 to April 2016 was conducted in Dang district, Nepal. Randomly 3 wards were selected from each Tulsipur municipality, Hekuli Village Development Committee, and Pawan Nagar VDC. Results. The mean age and parity were 30±7.31 and 2±0.69, respectively. Out of 650 women, 47% were using contraceptives. Westoff model was used for calculating total unmet need which is 49%, where unmet need for limiting and spacing was 27% and 22%, respectively. Hence after combining the current users and total unmet need, total demand for family planning was 96%. After adjustment, significant relation was observed between number of living sons ≥ 1 and unmet need of family planning (OR= 0.4; CI=0.2-0.8, p=0.01 ), similarly for women education; lower secondary level (OR=0.3; CI=0.1-0.6, p=0.01) and secondary (OR=0.1; CI=0.03-0.4, p=0.01); husband education, lower secondary level (OR=0.3; CI=0.1-0.6, p=0.01) and secondary (OR=0.4; CI= 0.2-0.9, p=0.04); and husband occupation, wage labor (OR=0.6; CI=0.4-0.99, p=0.05). In addition, having very good knowledge about method was also significantly associated (OR=0.49; CI= 0.2-0.97, p= 0.04). Conclusion. Unmet need of family planning was significantly higher among less than secondary educated women. It is also predisposed by spouse education, partner’s occupation, and number of living sons. This study concerns the need for all stake holders to focus on strategic behavior communication program regarding reproductive health.
Improved Convolutional Neural Network for Chinese Sentiment Analysis in Fog Computing
Authors: Chen Haoping , Du Lukun , Lu Yueming , Gao Hui
Published: September 2018

Fog computing extends the concept of cloud computing to the edge of network to relieve performance bottleneck and minimize data analytics latency at the central server of a cloud. It uses edge nodes directly to perform data input and data analysis. In public opinion analysis system, edge nodes that collect opinions from users are responsible for some data filtering jobs including sentiment analysis. Therefore, it is crucial to find suitable algorithm that is lightweight in operation and accurate in predictive performance. In this paper, we focus on Chinese sentiment analysis job in fog computing environment and propose a non‐task‐specific method called Channel Transformation Based Convolutional Neural Network (CTBCNN) for Chinese sentiment classification, which uses a new structure called channel transformation based (CTB) convolutional layer to enhance the ability of automatic feature extraction and applies global average pooling layer to prevent overfitting. Through experiments and analysis, we show that our method do achieve competitive accuracy and it is convenient to apply this method to different cases in operation.
Reduced Incidence and Better Liver Disease Outcomes among Chronic HCV Infected Patients Who Consume Cannabis
Authors: Adejumo Adeyinka Charles , Adegbala Oluwole Muyiwa , Adejumo Kelechi Lauretta , Bukong Terence Ndonyi
Published: September 2018

Background and Aim. The effect of cannabis use on chronic liver disease (CLD) from Hepatitis C Virus (HCV) infection, the most common cause of CLD, has been controversial. Here, we investigated the impact of cannabis use on the prevalence of CLD among HCV infected individuals. Methods. We analyzed hospital discharge records of adults (age ≥ 18 years) with a positive HCV diagnosis. We evaluated records from 2007 to 2014 of the Nationwide Inpatient Sample (NIS). We excluded records with other causes of chronic liver diseases (alcohol, hemochromatosis, NAFLD, PBC, HBV, etc.). Of the 188,333 records, we matched cannabis users to nonusers on 1:1 ratio (4,728:4,728), using a propensity-based matching system, with a stringent algorithm. We then used conditional regression models with generalized estimating equations to measure the adjusted prevalence rate ratio (aPRR) for having liver cirrhosis (and its complications), carcinoma, mortality, discharge disposition, and the adjusted mean ratio (aMR) of total hospital cost and length of stay (LOS) [SAS 9.4]. Results. Our study revealed that cannabis users (CUs) had decreased prevalence of liver cirrhosis (aPRR: 0.81[0.72-0.91]), unfavorable discharge disposition (0.87[0.78-0.96]), and lower total health care cost ($39,642[36,220-43,387] versus $45,566[$42,244-$49,150]), compared to noncannabis users (NCUs). However, there was no difference among CUs and NCUs on the incidence of liver carcinoma (0.79[0.55-1.13]), in-hospital mortality (0.84[0.60-1.17]), and LOS (5.58[5.10-6.09] versus 5.66[5.25-6.01]). Among CUs, dependent cannabis use was associated with lower prevalence of liver cirrhosis, compared to nondependent use (0.62[0.41-0.93]). Conclusions. Our findings suggest that cannabis use is associated with decreased incidence of liver cirrhosis, but no change in mortality nor LOS among HCV patients. These novel observations warrant further molecular mechanistic studies.
Synthesis and Photo- and Ionochromic and Spectral-Luminescent Properties of 5-Phenylpyrazolidin-3-one Azomethine Imines
Authors: Bren Vladimir A. , Dubonosov Alexander D. , Popova Oksana S. , Revinskii Yurii V. , Tikhomirova Karina S. , Minkin Vladimir I.
Published: September 2018

Photochromic 5-phenylpyrazolidin-3-one-based azomethine imines containing 2-((1H-imidazol-2-yl)methylene) 1, 2-(pyridin-2-ylmethylene) 2, 2-(quinolin-2-ylmethylene) 3, and 2-((8-hydroxyquinolin-2-yl)methylene) 4 substituents were synthesized. All the compounds exist in the ring-opened O forms. Under irradiation with light of 365 nm, compounds 1–4 undergo thermally reversible isomerization into ring-closed bicyclic diaziridine isomers C. Azomethine imines 1–3 exhibit properties of ion-active molecular “off-on” switches of fluorescence when interacting with F− or AcO− anions. Compound 4 represents a bifunctional chemosensor demonstrating a colorimetric “naked-eye” effect for Ni2+ cation and complete fluorescence quenching in the presence of H+, F−, and CN− ions.
Experimental Study on the Concrete with Compound Admixture of Iron Tailings and Slag Powder under Low Cement Clinker System
Authors: Wu Ruidong , Liu Juanhong
Published: September 2018

In order to study the performance of concrete with compound admixture of iron tailings and slag powder under low cement clinker system, the mixture ratio of different iron tailings powder and slag powder was designed to prepare C30 and C50 concrete. The workability, strength, carbonation depth, chloride diffusion coefficient, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and X‐ray diffraction (XRD) of concrete were measured, respectively. The test results show that iron tailings powder is beneficial to improve the workability, and the strength of concrete decreases with the increase of iron tailings powder content, while the carbonation depth and chloride diffusion coefficient increase with the increase of iron tailings powder content. Under low cement clinker system, the iron tailings powder should not be used alone (below 70% of mineral admixture). When the ratio of iron tailings to slag powder is 1 : 1, the strength, carbonation depth, chloride ion permeation coefficient, and the microstructure of concrete are roughly the same to that of concrete with single slag powder. So, the iron tailings powder can replace S95 grade slag powder in the same quantity. Iron tailings powder does not take part in hydration reaction, but it can improve particle gradation, reach close accumulation, and increase the quantity of central grains.
2D Semimodel of Full‐Section Anchorage in Thick Soft Rock Roadway
Authors: Lyu Xianzhou , Zhao Zenghui , Ma Qing , Wang Xiaojie , Gao Xiaojie
Published: September 2018

This paper focuses on the reinforcement effect of full‐face anchorage in thick soft rock roadway. A 2D semimodel of full‐face anchorage in roadway with thick surrounding soft rock was proposed firstly by transforming the confinement effect of the excavation face in the longitudinal direction as the virtual internal support force at the circumferential surface. Then, based on the theory of elasticity, the theoretical model of the coupling effect between surrounding rock and anchoring system was established, and the analytical solutions of stress and displacement were obtained employing superposition principle. Finally, the theoretical solution was verified by numerical simulation, and the distribution laws of stress release‐anchor stock‐surrounding rock coupling were analyzed in detail considering stress release. Results demonstrated that the stress field of the surrounding rock diverse widely with different stress release coefficients. With the increasing of stress release coefficient, the radial stress of the surrounding rock decreases, while the tangential stress increases. The supporting role of the bolt is mainly reflected in improving the radial stress of the anchorage zone. However, it has little effect on the tangential stress. What is more, the anchoring effect is more significant to soft rock stress than hard rock. In addition, the prestress of rock bolt has a certain matching relation with the bolt parameters, the surrounding rock parameters, and the initial stress. This study laid a theoretical foundation for further analysis of the interaction between surrounding rock and bolt supporting in plastic zone.
Methylation-dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1-mutant Gliomas
Authors: Unruh Dusten , Mirkov Snezana , Wray Brian , Drumm Michael , Lamano Jonathan , Li Yuping D. , Haider Qazi F. , Javier Rodrigo , McCortney Kathleen , Saratsis Amanda , Scholtens Denise M. , Sarkaria Jann N. , James C. David , Horbinski Craig
Published: September 2018

Purpose:

Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in patients with IDH1mut glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas.

Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways.

Results:

A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P = 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P = 0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin.

Conclusions:

These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas.
Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes
Authors: Payton Marc , Cheung Hung-Kam , Ninniri Maria Stefania S. , Marinaccio Christian , Wayne William C. , Hanestad Kelly , Crispino John D. , Juan Gloria , Coxon Angela
Published: September 2018

Aurora kinase A and B have essential and non-overlapping roles in mitosis, with elevated expression in a subset of human cancers, including acute myeloid leukemia (AML). In this study, pan-aurora kinase inhibitor (AKI) AMG 900 distinguishes itself as an anti-leukemic agent that is more uniformly potent against a panel of AML cell lines than are isoform-selective AKIs and classic AML drugs. AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis. AMG 900 and aurora-B–selective inhibitor AZD1152-hQPA showed comparable cellular effects on AML lines that do not harbor a FLT3-ITD mutation. AMG 900 was active against P-glycoprotein–expressing AML cells resistant to AZD1152-hQPA and was effective at inducing expression of megakaryocyte-lineage markers (CD41, CD42) on human CHRF-288-11 cells and mouse Jak2V617F cells. In MOLM-13 cells, inhibition of p-histone H3 by AMG 900 was associated with polyploidy, extra centrosomes, accumulation of p53 protein, apoptosis, and cleavage of Bcl-2 protein. Co-administration of cytarabine (Ara-C) with AMG 900 potentiated cell killing in a subset of AML lines, with evidence of attenuated polyploidization. AMG 900 inhibited the proliferation of primary human bone marrow cells in culture, with a better proliferation recovery profile relative to classic antimitotic drug docetaxel. In vivo, AMG 900 significantly reduced tumor burden in a systemic MOLM-13 xenograft model where we demonstrate the utility of 3′-deoxy-3′-18F-fluorothymidine [18F]FLT positron emission tomographic (PET)–CT imaging to measure the antiproliferative effects of AMG 900 in skeletal tissues in mice.
Inhibiting Integrin β8 to Differentiate and Radiosensitize Glioblastoma-Initiating Cells
Authors: Malric Laure , Monferran Sylvie , Delmas Caroline , Arnauduc Florent , Dahan Perrine , Boyrie Sabrina , Deshors Pauline , Lubrano Vincent , Da Mota Dina Ferreira , Gilhodes Julia , Filleron Thomas , Siegfried Aurore , Evrard Solène , Kowalski-Chauvel Aline , Moyal Elizabeth Cohen-Jonathan , Toulas Christine , Lemarié Anthony
Published: September 2018

Glioblastomas (GB) are malignant brain tumors with poor prognosis despite treatment with surgery and radio/chemotherapy. These tumors are defined by an important cellular heterogeneity and notably contain a subpopulation of GB-initiating cells (GIC), which contribute to tumor aggressiveness, resistance, and recurrence. Some integrins are specifically expressed by GICs and could be actionable targets to improve GB treatment. Here, integrin β8 (ITGB8) was identified as a potential selective target in this highly tumorigenic GIC subpopulation. Using several patient-derived primocultures, it was demonstrated that ITGB8 is overexpressed in GICs compared with their differentiated progeny. Furthermore, ITGB8 is also overexpressed in GB, and its overexpression is correlated with poor prognosis and with the expression of several other classic stem cell markers. Moreover, inhibiting ITGB8 diminished several main GIC characteristics and features, including self-renewal ability, stemness, migration potential, and tumor formation capacity. Blockade of ITGB8 significantly impaired GIC cell viability via apoptosis induction. Finally, the combination of radiotherapy and ITGB8 targeting radiosensitized GICs through postmitotic cell death.

Implications:

This study identifies ITGB8 as a new selective marker for GICs and as a promising therapeutic target in combination with chemo/radiotherapy for the treatment of highly aggressive brain tumors.
Comparing Therapeutic Efficacy and Safety of Epoetin Beta and Epoetin Alfa in the Treatment of Anemia in End-Stage Renal Disease Hemodialysis Patients
Authors: Azmandian Jalal , Abbasi Mohammad Reza , Pourfarziani Vahid , Nasiri Amir Ahmad , Ossareh Shahrzad , Ezzatzadegan Jahromi Shahrokh , Sanadgol Hooshang , Amini Somayeh , Shahvaroughi Farahani Arshia
Published: September 2018

Background: Anemia is one of the most prevalent complications in patients with chronic kidney disease, which is believed to be caused by the insufficient synthesis of erythropoietin by the kidney. This phase III study aimed to compare the efficacy and safety of CinnaPoietin® (epoetin beta, CinnaGen) with Eprex® (epoetin alfa, Janssen Cilag) in the treatment of anemia in ESRD hemodialysis patients. Methods: In this randomized, active-controlled, double-blind, parallel, and non-inferiority trial, patients were randomized to receive either CinnaPoietin® or Eprex® for a 26-week period. The primary endpoints of this study were to assess the mean hemoglobin (Hb) change during the last 4 weeks of treatment from baseline along with the evaluation of the mean weekly epoetin dosage per kilogram of body weight that was necessary to maintain the Hb level within 10–12 g/dL during the last 4 weeks of treatment. As the secondary objective, safety was assessed along with other efficacy endpoints. Results: A total of 156 patients were included in this clinical trial. There was no statistically significant difference between treatment groups regarding the mean Hb change (p = 0.21). In addition, the mean weekly epoetin dosage per kg of body weight for maintaining the Hb level within 10–12 g/dL showed no statistically significant difference between treatment arms (p = 0.63). Moreover, both products had comparable safety profiles. However, the incidence of Hb levels above 13 g/dL was significantly lower in the CinnaPoietin® group. Conclusion: CinnaPoietin® was proved to be non-inferior to Eprex® in the treatment of anemia in ESRD hemodialysis patients. The trial was registered in Clinicaltrials.gov (NCT03408639).
Plasmapheresis Therapy in Kidney Transplant Rejection
Authors: Xie Pan , Tao Min , Peng Kanfu , Zhao Hongwen , Zhang Keqin , Sheng Yuxiu , Ankawi Ghada , Ronco Claudio
Published: September 2018

Kidney transplantation (KT) is considered an optimal treatment strategy for end-stage renal disease. But human leukocyte antigen-sensitized, ABO-incompatible and antibody-mediated rejection might be the alarming hurdles in KT. Therapeutic plasma exchange is the mainstay of the antibody reduction therapy for reducing autoantibody more effectively. Even in the treatment for highly sensitized patients, it has played an indispensable role. However, clinicians should tailor therapies to individual patient’s needs and multimodal treatment will bring better outcomes. Early diagnosis and precise treatment would reduce morbidity, mortality, and economic costs.
Elevated Plasma Active Matrix Metalloproteinase-9 Level Is Associated With Coronary Artery In-Stent Restenosis
Authors: Jones Gregory T. , Kay I. Patrick , Chu J.W.S. , Wilkins G.T. , Phillips L.V. , McCormick M. , van Rij A.M. , Williams M.J.A.
Published: September 2018

Objective—

This study aimed to determine whether the plasma levels of matrix metalloproteinase-9 (MMP-9) or tissue inhibitor of metalloproteinases-1 (TIMP-1) were altered in patients with a history of symptomatic in-stent restenosis (ISR).

Methods and Results—

A group of 158 patients with a history of ISR were compared with 128 symptom-free patients. Plasma samples and a detailed risk factor history were collected. Plasma samples were analyzed for pro–MMP-9 and latent MMP-9 and active MMP-9, latent MMP-3, and TIMP-1. Several variables were associated with ISR, including index coronary disease extent and severity (number of diseased vessels and American College of Cardiology/American Heart Association lesion classification), number, diameter, and total length of stent(s) inserted, and plasma high-density lipoprotein cholesterol. Plasma active MMP-9 (odds ratio, 1.96; 95% CI, 1.43 to 2.69) showed independent risk association with ISR. Patients with multiple sites of ISR had significantly higher levels of active MMP-9 compared with patients with only a single ISR lesion or no ISR.

Conclusion—

Plasma active MMP-9 levels may be a useful independent predictor of bare metal stent ISR.
Coronary Endothelial Dysfunction Is Associated With Elevated Serum PCSK9 Levels in People With HIV Independent of Low‐Density Lipoprotein Cholesterol
Authors: Leucker Thorsten M. , Weiss Robert G. , Schär Michael , Bonanno Gabriele , Mathews Lena , Jones Steven R. , Brown Todd T. , Moore Richard , Afework Yohannes , Gerstenblith Gary , Hays Allison G.
Published: September 2018

Background

HIV
+ people are at increased risk of coronary artery disease, but the responsible mechanisms are incompletely understood. Proprotein convertase subtilisin/kexin type 9 (
PCSK
9) is traditionally recognized for its importance in cholesterol metabolism; however, recent data suggest an additional, low‐density lipoprotein receptor–independent adverse effect on endothelial cell inflammation and function. We tested the hypotheses that
PCSK
9 levels are increased and that abnormal coronary endothelial function is related to
PCSK
9 serum levels in
HIV
+ individuals.

Methods and Results

Forty‐eight
HIV
+ participants receiving antiretroviral therapy with suppressed viral replication, without coronary artery disease, and 15 age‐ and low‐density lipoprotein cholesterol–matched healthy
HIV−
subjects underwent magnetic resonance imaging to measure coronary endothelial function, quantified as percentage change in coronary artery cross‐sectional area during isometric handgrip exercise, an endothelial‐dependent stressor; and blood was obtained for serum
PCSK
9 and systemic vascular biomarkers. Data are presented as mean±SD. Mean serum
PCSK
9 was 65% higher in the
HIV
+ subjects (302±146 ng/
mL
) than in the
HIV
− controls (183±52 ng/
mL
,
P
<0.0001). Coronary endothelial function was significantly reduced in the
HIV
+ versus
HIV
− subjects (percentage change in coronary artery cross‐sectional area, 2.9±9.6% versus 11.1±3.7%;
P
<0.0001) and inversely related to
PCSK
9 (
R
=−0.51,
P
<0.0001). Markers of endothelial activation and injury, P‐selectin and thrombomodulin, were also significantly increased in the
HIV
+ subjects; and P‐selectin was directly correlated with serum
PCSK
9 (
R
=0.31,
P
=0.0144).

Conclusions

Serum
PCSK
9 levels are increased in treated
HIV
+ individuals and are associated with abnormal coronary endothelial function, an established measure of vascular health.
Translating Critical Design: Agonism in Engineering Education
Authors: Malazita James W.
Published: September 2018

Speculative and Critical Design (SCD) methods can produce provocative artifacts that help audiences recognize the political worlds in which all designed objects participate. Similarly, SCD can be leveraged in educational settings to help design students engage with social and political theory through their design work. SCD practices, however, are rarely seen outside of arts and creative design spaces, which limits any potential political impact they may have. This article traces the integration of SCD practices into “the hard case” of engineering education—a space with radically different, and at times oppositional, intellectual, and political traditions than creative design. I argue that the SCD platforms must reflexively account for and bridge radical epistemological differences among design disciplines, including those disciplines that may have an innate aversion to “political” content, if they are to have transformational impact outside of art and creative design worlds.
Navigating Colonial Power: Challenging Precedents and the Limitation of Local Elites
Authors: Siddiqui Sohaira
Published: September 2018

In 1869, the British allowed Muslims to sit as judges on the High Court. This article explores the legal opinions of the first Muslim judge to be appointed to the High Court, Syed Mahmood. Straddling two competing worlds – that of Cambridge University and that of his native India – Justice Mahmood both legitimated and resisted colonial judicial power. In this essay I will demonstrate how British judges interpreted points of Islamic law within an English legal framework, and how these interpretations contradicted their translated texts of Islamic law, yet became the foundation of legal precedents established through the doctrine of stare decisis. Despite participating within the British colonial judiciary, Mahmood challenged these precedents, demonstrating his ability to navigate the paradoxes of colonial power to secure for himself a legitimate platform from which he could argue his juridical interventions. The efficacy of these challenges, however, ultimately was restrained by the institutions and structures of the colonial jural project.
Family Reunification between Static EU Citizens and Third Country Nationals
Authors: Berneri Chiara
Published: September 2018

According to the available data, the number of refugees worldwide has recently exceeded 50 million people. Europe in particular has become the place to which immigrants direct themselves in search of a better life. Numerous have been the efforts at EU level to introduce new legal channels of immigration. Within these efforts, family reunification has not been thoroughly explored by the EU as a tangible way to provide an alternative legal pathway to asylum.

The scope of this work is to link family reunification between static EU citizens and third country nationals to the current European immigration background in order to appreciate it as a way to channel safe immigration. This article will first give an overview of where we stand today in terms of the protection of this kind of family looking at data and case law. It will then focus on the reasons why a further enhancement of this tool is desirable and how it can be achieved in a concrete fashion. In particular, it will argue that a broader reading of the concept of emotional dependency, within the broader application of Zambrano, should be applied to further benefit families involved in the current refugee crisis.
On *-d- > -l- and *-š- > -l- in Western New Iranian
Authors: Asatrian Garnik , Hakobian Gohar
Published: September 2018

The *-d- > -l- and *-š- > -l- changes in New Iranian are usually regarded as Eastern Iranian phonetic features. However, a thorough study of the Western New Iranian lexicon, particularly that of the dialects located geographically at a great distance from Eastern Iranian linguistic domain, unveiled a considerable number of lexemes, definitely genuine forms, with the same characteristics. The paper presents a comprehensive corpus of all lexical units in WNIran. in which these phonetic peculiarities are manifested.
Zingela (Asparagaceae, Scilloideae), a distinct new urgineoid genus from KwaZulu-Natal, South Africa
Authors: CROUCH NEIL R. , MARTÍNEZ-AZORÍN MARIO , CRESPO MANUEL B. , PINTER MICHAEL , ALONSO-VARGAS MARÍA Á.
Published: September 2018

In the course of resolving the identity of plants usually named ‘Drimia indica’ from KwaZulu-Natal Province, South Africa, molecular and morphological data revealed the identity of more than one taxon carrying this name. Our studies support the establishment of a new urgineoid genus, Zingela gen. nov., to accommodate a species (Z. pooleyorum) collected and illustrated some 50 years ago, but never validly published. We here provide data on its morphology, ecology, and distribution.
Phylogenetic relationships of the Balkan Moitessieriidae (Caenogastropoda: Truncatelloidea)
Authors: HOFMAN SEBASTIAN , RYSIEWSKA ALEKSANDRA , OSIKOWSKI ARTUR , GREGO JOZEF , SKET BORIS , PREVORČNIK SIMONA , ZAGMAJSTER MAJA , FALNIOWSKI ANDRZEJ
Published: September 2018

The family Moitessieriidae includes minute dioecious gastropods exclusively inhabiting subterranean waters, including thermal ones. Only empty shells were collected in most species, the vast majority of them are described from their gross shell morphology alone. Several visits to a site are usually required to obtain at least some living individuals. High variability in shell morphology and the lack of diagnostic features, coupled with anticipated high levels of endemism, has resulted in a long list of nominal moitessierid species. Type specimens stored as empty shells omit unambiguous identification and delimitation of species boundaries. Due to inaccessibility of cave animals and consequent lack of material suitable for molecular analysis, the phylogenetic relationships, as well as the taxonomy of the family at genus/species level, are far from being understood. The anatomy of the family is also poorly known and provided only for a few taxa. The distinctness of the Moitessieriidae has sometimes been questioned, and their monophyly not proved. Twelve species of the Balkan Moitessieriidae are considered: two species of Paladilhiopsis, two species of Bythiospeum, six species of Iglica, Costellina turrita and Lanzaia bosnica. The shell morphology of each species, as well as the reproductive system of Paladilhiopsis and Iglica, were analysed. DNA sequences of nuclear histone H3, ribosomal 18S, ribosomal 28S and mitochondrial cytochrome oxidase subunit I (COI) were applied to infer phylogenetic relationships among the taxa. The sequences of Bythiospeum from GenBank have been used to infer relationships between Bythiospeum and Paladilhiopsis that were recently synonymized. Paladilhiopsis and Iglica are distinct, but closely related genera, as is the genus Bythiospeum, which does not occur in the Balkans. Its relationships with both former taxa remain unresolved. The Moitessieriidae are clearly distinct from all other families of the Truncatelloidea, however, their monophyly remains doubtful.
Association of the North Atlantic Surface Turbulent Heat Fluxes with Midlatitude Cyclones
Authors: Tilinina Natalia , Gavrikov Alexander , Gulev Sergey K.
Published: September 2018

Atmospheric mechanisms leading to the formation of very strong turbulent air–sea heat fluxes in the North Atlantic are analyzed using the National Centers for Environmental Prediction (NCEP) Climate Forecast System Reanalysis (CFSR) for the winter periods from 1979 to 2010. Surface turbulent flux extremes were quantified by considering both absolute and relative extremeness of these fluxes. For all cases of very strong surface turbulent fluxes, regional composites of the associated atmospheric conditions were built using reanalysis output. These composites clearly demonstrate a critical role of the cyclone–anticyclone interaction zone in forming very strong surface fluxes. The implied importance of cyclones followed by anticyclones in generation of surface air–sea heat flux extremes was demonstrated by the analysis of case studies. We further used the results of numerical cyclone tracking to identify extratropical cyclones associated with air–sea flux events of different intensities and to quantify the life cycle characteristics of these cyclones. Analysis of frequency distribution of surface heat fluxes has shown that extreme fluxes over the North Atlantic are associated with less than 30% of winter cyclones and that this association occurs mostly during the initial stage of their life cycle. Analysis of life cycle characteristics of these cyclones shows, in turn, that they are considerably more intense than most North Atlantic cyclones and are characterized by rapid deepening and slower propagation. We argue that variability of the North American high is a key factor controlling atmospheric conditions favorable for the occurrence of high turbulent air–sea heat fluxes in the North Atlantic mid- and subpolar latitudes.
Parental Perception and Participation in Genetic Testing Among Children With Autism Spectrum Disorders
Authors: Harrington John W. , Emuren Leonard , Restaino Kathryn , Schrier Vergano Samantha
Published: September 2018

The purpose of this study was to determine the factors associated with genetic testing in children with autism spectrum disorders (ASDs) and understand parental involvement in the decision to test using survey data of parents of children with ASD. Evaluation by a geneticist was associated with genetic testing by more than 39 times compared to evaluation by a nongeneticist (95% CI = 9.15-168.81). Those offered testing by the physicians were more than 6 times more likely to be tested than those not offered testing (95% CI = 1.66-24.61). Financial concerns, not being offered testing, and lack of awareness were the most consistent reasons for not testing given by participants. A physician’s recommendation for testing and an evaluation by a geneticist were the most important factors associated with genetic testing in children with ASD. Educating primary care physicians and nongenetic specialists can potentially improve genetic testing among children with ASD.