bluuebunny/crossref_metadata_2025 huggingface dataset:
The L2 ∂¯-Cauchy problem on pseudoconvex domains and applications
Authors: Saber Sayed
Published: April 2017

Let [Formula: see text] be a complex manifold of dimension [Formula: see text] and [Formula: see text] be a weakly pseudoconvex domain with smooth boundary in [Formula: see text]. Let [Formula: see text] be a holomorphic line bundle over [Formula: see text] which is positive on a neighborhood of [Formula: see text]. Let [Formula: see text] be the [Formula: see text]-times tensor product of [Formula: see text] for positive integer [Formula: see text]. The purpose of this paper is to study the [Formula: see text]-problem with support conditions in [Formula: see text] for forms of type [Formula: see text], [Formula: see text] with values in [Formula: see text]. Applications to the [Formula: see text]-problem for smooth forms on boundaries of [Formula: see text] are given.
Hom-left symmetric algebroids
Authors: Peyghan E. , Nourmohammadifar L.
Published: April 2017

In this paper, we describe the construction of connections on hom-bundles and the pseudo-Riemannian structure on hom-Lie algebroids from an algebraic point of view. We study the representations of hom-Lie algebroids. We introduce the notion of a hom-left symmetric algebroid as a geometric generalization of a hom-left symmetric algebra. In addition using [Formula: see text]-operators, we construct some classes of hom-left symmetric algebroids. We show that there exists a phase space on a hom-left symmetric algebroid. Also, we prove that using phase spaces, we can construct hom-left symmetric algebroids.
On primitive normal elements over finite fields
Authors: Anju  , Sharma R. K.
Published: April 2017

Let [Formula: see text] be an extension of the field [Formula: see text] of degree [Formula: see text] where [Formula: see text] for some positive integer [Formula: see text] and prime [Formula: see text] In this paper, we establish a sufficient condition for the existence of a primitive element [Formula: see text] such that [Formula: see text] is also primitive as well as a primitive normal element [Formula: see text] of [Formula: see text] over [Formula: see text] such that [Formula: see text] is primitive.
Thermodynamic Investigation of Integrated Air Cycle Refrigeration Systems
Authors: Shoul Hamed , Ameri Mehran , Mohammadi S. M. Hojjat
Published: April 2017

An analysis of air cycle refrigeration (ACR) systems based on the first and second laws of thermodynamics has been carried out. Cooling the gas cooler outlet enhances the system efficiency, hence the use of integrated refrigeration systems (IRSs). The IRS consists of an ACR, an absorption chiller and a prime mover. The waste heat from the prime mover operates the absorption chiller, which provides additional cooling that is used to cool down the air exiting the gas cooler. LiBr-H2O and NH3-H2O are used as fluid pairs in absorption section. The prime mover can either be gas turbine or solid oxide fuel cell (SOFC). Results indicate that an IRS with NH3-H2O and two recuperators has a better first and second law efficiency compared to other considered systems. It is also concluded that the energy utilization factor and second law efficiency are higher for the system with SOFC as a prime mover.
Two Different Integration Methods for Weather Radar-Based Quantitative Precipitation Estimation
Authors: Ren Jing , Huang Yong , Guan Li , Zhou Jie
Published: April 2017

We discuss two different integration methods for radar-based quantitative precipitation estimation (QPE): the echo intensity integral and the rain intensity integral. Theoretical analyses and simulations were used to test differences between these two methods. Cumulative rainfall calculated by the echo intensity integral is usually greater than that from rain intensity integral. The difference of calculated precipitation using these two methods is generally smaller for stable precipitation systems and larger for unstable precipitation systems. If the echo intensity signal is sinusoidal, the discrepancy between the two methods is most significant. For stratiform and convective precipitation, the normalized error ranges from −0.138 to −0.15 and from −0.11 to −0.122, respectively. If the echo intensity signal is linear, the normalized error ranges from 0 to −0.13 and from 0 to −0.11, respectively. If the echo intensity signal is exponential, the normalized error ranges from 0 to −0.35 and from 0 to −0.30, respectively. When both the integration scheme and real radar data were used to estimate cumulative precipitation for one day, their spatial distributions were similar.
Effectiveness of Hypnosis in Combination with Conventional Techniques of Behavior Management in Anxiety/Pain Reduction during Dental Anesthetic Infiltration
Authors: Ramírez-Carrasco A. , Butrón-Téllez Girón C. , Sanchez-Armass O. , Pierdant-Pérez M.
Published: April 2017

Background and Objective. Anxiety/pain are experiences that make dental treatment difficult for children, especially during the time of anesthesia. Hypnosis is used in pediatric clinical situations to modify thinking, behavior, and perception as well as, recently, in dentistry; therefore the aim of this study was to evaluate the effectiveness of hypnosis combined with conventional behavior management techniques during infiltration anesthetic.Methods. Anxiety/pain were assessed with the FLACC scale during the anesthetic moment, as well as heart rate variability and skin conductance before and during the anesthetic moment, between the control and experimental group.Results. A marginal statistical difference (p=0.05) was found in the heart rate between baseline and anesthetic moment, being lower in the hypnosis group. No statistically significant differences were found with the FLACC scale or in the skin conductance (p>0.05).Conclusion. Hypnosis combined with conventional behavior management techniques decreases heart rate during anesthetic infiltration showing that there may be an improvement in anxiety/pain control through hypnotic therapy.
Rehabilitation Treatment and Progress of Traumatic Brain Injury Dysfunction
Authors: Dang Baoqi , Chen Wenli , He Weichun , Chen Gang
Published: April 2017

Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s. Behavioral problems, mood, cognition, particularly memory, attention, and executive function are commonly impaired by TBI. Spending to assist, TBI survivors with disabilities are estimated to be costly per year. Such impaired functional outcomes following TBI can be improved via various rehabilitative approaches. The objective of the present paper is to review the current rehabilitation treatment of traumatic brain injury in adults.
Prevalence and Associated Factors of Suicidal Ideation and Attempt among People Living with HIV/AIDS at Zewditu Memorial Hospital, Addis Ababa, Ethiopia: A Cross-Sectional Study
Authors: Gebremariam Etsay Hailu , Reta Mebratu Mitiku , Nasir Zebiba , Amdie Fisseha Zewdu
Published: April 2017

Background. Human Immune Deficiency Virus (HIV/AIDS) continues to be an underrecognized risk for suicidal ideation, suicidal attempt, and completion of suicide. Suicidal ideation and attempt in HIV/AIDS is not only a predictor of future attempted suicide and completed suicide.Methods. An institution based cross-sectional study was conducted among HIV-positive patients attending HIV care at Zewditu Memorial Hospital. Systematic random sampling technique was used to recruit 423 participants from April to May 2014. Composite International Diagnostic Interview was used to collect data. Multivariable logistic regression was computed to assess factors associated with suicidal ideation and attempt.Result. Suicidal ideation and suicidal attempt were found to be 22.5% and 13.9%, respectively. WHO clinical stage of HIV, not being on HAART, depression, family history of suicidal attempt, and perceived stigma were associated with suicidal ideation. WHO clinical stage, being female, not being on HAART, use of substance, and depression were associated with suicidal attempt.Conclusion. Early diagnosis and treatment of opportunistic infections, depression, and early initiation of ART need to be encouraged in HIV-positive adults. Furthermore, counseling on substance use and its consequences and early identification of HIV-positive people with family history of suicidal ideation have to be considered.
Immunoprofiling of Adult-Derived Human Liver Stem/Progenitor Cells: Impact of Hepatogenic Differentiation and Inflammation
Authors: El-Kehdy Hoda , Sargiacomo Camillo , Fayyad-Kazan Mohammad , Fayyad-Kazan Hussein , Lombard Catherine , Lagneaux Laurence , Sokal Etienne , Najar Mehdi , Najimi Mustapha
Published: April 2017

Adult-derived human liver stem/progenitor cells (ADHLSCs) are, nowadays, developed as therapeutic medicinal product for the treatment of liver defects. In this study, the impact of hepatogenic differentiation and inflammation priming on the ADHLSCs’ immune profile was assessed in vitro and compared to that of mature hepatocytes. The constitutive immunological profile of ADHLSCs was greatly different from that of hepatocytes. Differences in the expression of the stromal markers CD90 and CD105, adhesion molecules CD44 and CD49e, immunoregulatory molecules CD73 and HO-1, and NK ligands CD112 and CD155 were noted. While they globally preserved their immunological profile in comparison to undifferentiated counterparts, differentiated ADHLSCs showed a significant downregulation of CD200 expression as in hepatocytes. This was mainly induced by signals issued from EGF and OSM. On the other hand, the impact of inflammation was quite similar for all studied cell populations with an increased expression level of CD54 and CD106 and induction of that of CD40 and CD274. In conclusion, our immune profiling study suggests CD200 as a key factor in regulating the immunobiology of differentiated ADHLSCs. A better understanding of the molecular and physiological events related to such marker could help in designing the optimal conditions for an efficient therapeutic use of ADHLSCs.
The Methylation Status and Expression of Epstein-Barr Virus Early Genes BARF1 and BHRF1 in Epstein-Barr Virus-Associated Gastric Carcinomas
Authors: Li Jing , Liu Wen , Che Kui , Zhang Yan , Zhao Zhenzhen , Luo Bing
Published: April 2017

Epstein-Barr virus (EBV) is an important DNA virus which establishes latent infection in human malignancies. Expression of EBV-encoded genes in the associated tumors is strongly modulated by promoter CpG methylation of EBV genome. This study aimed to explore the methylation status of the promoters of EBV BamHI-A rightward frame 1 (BARF1) and BamHI-H rightward open reading frame 1 (BHRF1) and their influence on transcriptional expression, to further understand the roles of BARF1 and BHRF1 in the occurrence of EBV-associated cancer. We evaluated the methylation status of BARF1 and BHRF1 promoters in 43 EBV-associated gastric carcinoma (EBVaGC) tissues and EBV-positive cell lines. Their expressions were evaluated by real-time quantitative PCR. We found that the promoters of BARF1 and BHRF1 were methylated by varying degrees in different EBV-positive cell lines and were almost hypermethylated in all EBVaGC tissues. The methylation status of BARF1 and BHRF1 promoters were significantly reduced by 5-Aza-CdR along with the increasing gene expressions. Hypermethylation of Ap and Hp mediates the frequent silencing of BARF1 and BHRF1 in EBV-associated tumors, which could be reactivated by a demethylation agent, suggesting that promoter demethylation and activation is important for BARF1 and BHRF1 transcription and their further action.
The Role of Biologically Active Ingredients from Natural Drug Treatments for Arrhythmias in Different Mechanisms
Authors: Li Jie , Hu Dan , Song Xiaoli , Han Tao , Gao Yonghong , Xing Yanwei
Published: April 2017

Arrhythmia is a disease that is caused by abnormal electrical activity in the heart rate or rhythm. It is the major cause of cardiovascular morbidity and mortality. Although several antiarrhythmic drugs have been used in clinic for decades, their application is often limited by their adverse effects. As a result, natural drugs, which have fewer side effects, are now being used to treat arrhythmias. We searched for all articles on the role of biologically active ingredients from natural drug treatments for arrhythmias in different mechanisms in PubMed. This study reviews 19 natural drug therapies, with 18 active ingredient therapies, such as alkaloids, flavonoids, saponins, quinones, and terpenes, and two kinds of traditional Chinese medicine compound (Wenxin-Keli and Shensongyangxin), all of which have been studied and reported as having antiarrhythmic effects. The primary focus is the proposed antiarrhythmic mechanism of each natural drug agent.Conclusion. We stress persistent vigilance on the part of the provider in discussing the use of natural drug agents to provide a solid theoretical foundation for further research on antiarrhythmia drugs.
MicroRNA Expression Signature in Human Calcific Aortic Valve Disease
Authors: Wang Hui , Shi Jing , Li Beibei , Zhou Qiulian , Kong Xiangqing , Bei Yihua
Published: April 2017

Altered microRNA (miRNA, miR) expression has been related to many disease processes; however, the miRNA expression signature in calcific aortic valve disease (CAVD) is unclear. In this study, microarrays were used to determine the miRNA expression signature of tissue samples from healthy individuals (n=4) and patients with CAVD (n=4). TargetScan, PITA, and microRNAorg 3-way databases were used to predict the potential target genes. DIANA-miRPath was used to incorporate the aberrant miRNAs into gene pathways. miRNA microarrays identified 92 differentially expressed miRNAs in CAVD tissues. The principal component analysis (PCA) of these samples and the unsupervised hierarchical clustering analysis based on the 92 aberrantly expressed miRNAs noted that miRNA expression could be categorized into two well-defined clusters that corresponded to healthy control and CAVD. Bioinformatic analysis showed the miRNA targets and potential molecular pathways. Collectively, our study reported the miRNA expression signature in CAVD and may provide potential therapeutic targets for CAVD.
Incidence and Risk Factors for Early Acute Kidney Injury in Nonsurgical Patients: A Cohort Study
Authors: Cely Javier Enrique , Mendoza Elkin José , Olivares Carlos Roberto , Sepúlveda Oscar Julián , Acosta Juan Sebastián , Barón Rafael Andrés , Diaztagle Juan José
Published: April 2017

Introduction. Detecting acute kidney injury (AKI) in the first days of hospitalization could prevent potentially fatal complications. However, epidemiological data are scarce, especially on nonsurgical patients.Objectives. To determine the incidence and risk factors associated with AKI within five days of hospitalization (EAKI).Methods. Prospective cohort of patients hospitalized in the Internal Medicine Department.Results. A total of 16% of 400 patients developed EAKI. The associated risk factors were prehospital treatment with nephrotoxic drugs (2.21 OR; 95% CI 1.12–4.36,p=0.022), chronic kidney disease (CKD) in stages 3 to 5 (3.56 OR; 95% CI 1.55–8.18,p<0.003), and venous thromboembolism (VTE) at admission (5.05 OR; 95% CI 1.59–16.0,p<0.006). The median length of hospital stay was higher among patients who developed EAKI (8 [IQR 5–14] versus 6 [IQR 4–10],p=0.008) and was associated with an increased requirement for dialysis (4.87 OR 95% CI 2.54 to 8.97,p<0.001) and in-hospital death (3.45 OR; 95% CI 2.18 to 5.48,p<0.001).Conclusions. The incidence of EAKI in nonsurgical patients is similar to the worldwide incidence of AKI. The risk factors included CKD from stage 3 onwards, prehospital treatment with nephrotoxic drugs, and VTE at admission. EAKI is associated with prolonged hospital stay, increased mortality rate, and dialysis requirement.
Consensus of Heterogeneous Multiagent Systems with Arbitrarily Bounded Communication Delay
Authors: Li Xue , Wu Huai , Yang Yikang
Published: April 2017

This paper focuses on the consensus problem of high‐order heterogeneous multiagent systems with arbitrarily bounded communication delays. Through the method of nonnegative matrices, we get a sufficient consensus condition for the systems with dynamically changing topology. The results of this paper show, even when there are arbitrarily bounded communication delays in the systems, all agents can reach a consensus no matter whether there are spanning trees for the corresponding communication graphs at any time.
Potential Hepatoprotective Role of Galectin-3 during HCV Infection in End-Stage Renal Disease Patients
Authors: Lukic Ruzica , Gajovic Nevena , Jovanovic Ivan , Jurisevic Milena , Mijailovic Zeljko , Maric Veljko , Popovska Jovicic Biljana , Arsenijevic Nebojsa
Published: April 2017

Hepatitis C virus infection (HCV), one of the greatest causes of liver disease, is a frequent complication in patients with end-stage renal disease (ESRD) on dialysis. ESRD is defined as decreased glomerular filtration and also accompanied by impaired function of the immune system. Galectin-3 is aβ-galactoside-binding lectin, involved in various biological processes including pathogenesis of chronic renal disease. The aim of our study was to estimate disease severity in ESRD HCV+patients and analyze the serum concentrations of IL-1β, IL-4, IL-23, and IL-6; anti-HCV antibodies; and galectin-3. Also, we attempted to determine potential correlation between galectin-3 level and parameters of disease severity ALT and AST. Our results showed decreased levels of ALT and AST (p=0.00), demonstrating less liver destruction in ESRD HCV+patients in comparison to HCV+patients. Increased levels of IL-6 (p=0.03) implicate a hepatoprotective role of IL-6 in these patients. Also, level of galectin-3 (p=0.00) in the serum of ESRD HCV+patients was higher than that of HCV+patients. This alteration was accompanied with negative correlation between galectin-3 and AST and ALT, respectively (p=0.029;p=0.033). The presence of increased systemic levels of IL-6 and Gal-3 in ESRD HCV+patients may be an attempt to counteract or limit ongoing proinflammatory processes and to downregulate chronic inflammation, suggesting the new aspects of HCV infection in ESRD patients.
Geospatial Assessment of Cholera in a Rapidly Urbanizing Environment
Authors: Olanrewaju Olajumoke Esther , Adepoju Kayode Adewale
Published: April 2017

This study mapped out and investigated the spatial relationship between cholera incidences and environmental risk factors in the study area. The study area was stratified into eight zones. Water samples from each zone were collected and analyzed to determine the colony forming units. GIS layers including housing density, digitized roads, rivers, buildings, and cholera incidence data from hospital archives were also collected and analyzed using ArcGIS 10.1. It was observed that there was an association between the ERFs (p<0.001). Similarly, 18 out of the 44 waste dump sites, seven out of 18 markets, and two out of 36 abattoirs were found near the historical cholera cases. Similarly, 4 (21.1%) locations were traced to be predominantly close to rivers and waste dump site. All the historical cholera cases were found adjoining to roads and buildings. Highest CFU count was found in the wells and streams of areas with a cluster of all the environmental risk factors and high housing density. This study revealed that waste dump sites and market had the highest predisposing attribute while the least was abattoir. The uniqueness of the study lies in the combination of mapping and microbial analyses to identify and assess the pattern of cholera risk and also to provide clear information for development of strategies for environmental supervision.
Inhibition of miR‐302 Suppresses Hypoxia‐Reoxygenation‐Induced H9c2 Cardiomyocyte Death by Regulating Mcl‐1 Expression
Authors: Fang Yao-Ching , Yeh Chi-Hsiao
Published: April 2017

MicroRNAs play important roles in cell proliferation, differentiation, and apoptosis, and their expression influences cardiomyocyte apoptosis resulting from ischemia‐induced myocardial infarction. Here, we determined the role of miR expression in cardiomyocyte apoptosis during hypoxia and reoxygenation. The rat cardiomyocyte cell line H9c2 was incubated for 3 h in normal or hypoxia medium, followed by reoxygenation for 24 h and transfection with a miR‐302 mimic or antagomir. The effect of miR‐302 on myeloid leukemia cell‐differentiation protein‐1 (Mcl‐1) expression was determined by western blot, real‐time polymerase chain reaction, and luciferase reporter assays, with cell viability assays. We observed that miR‐302 expression was elevated by hypoxia/reoxygenation injury and increased further or decreased by transfection of the miR‐302 mimic or miR‐302 antagomir, respectively. Additionally, elevated miR‐302 levels increased apoptosis‐related protein levels and cardiomyocyte apoptosis, and luciferase reporter assays revealed miR‐302 binding to the Mcl‐1 mRNA 3′ untranslated region. Our findings suggested that miR‐302 overexpression aggravated hypoxia/reoxygenation‐mediated cardiomyocyte apoptosis by inhibiting antiapoptotic Mcl‐1 expression, thereby activating proapoptotic molecules. Furthermore, results indicating cardiomyocyte rescue from hypoxia/reoxygenation injury following treatment with miR‐302 antagomir suggested that miR‐302 inhibition might constitute a therapeutic strategy for protection against cardiomyocyte apoptosis during hypoxia/reoxygenation injury.
Obtuse Angle Prediction and Factor Evaluation for Image Reversible Data Hiding
Authors: Xiang Hongyin , Yuan Jinsha , Hou Sizu
Published: April 2017

A pixel‐based pixel‐value‐ordering (PPVO) has been used for reversible data hiding to generate large embedding capacity and high‐fidelity marked images. The original PPVO invented an effective prediction strategy in pixel‐by‐pixel manner. This paper extends PPVO and proposes an obtuse angle prediction (OAP) scheme, in which each pixel is predicted by context pixels with better distribution. Moreover, for evaluating prediction power, a mathematical model is constructed and three factors, including the context vector dimension, the maximum prediction angle, and the current pixel location, are analyzed in detail. Experimental results declare that the proposed OAP approach can achieve higher PSNR values than PPVO and some other state‐of‐the‐art methods, especially in the moderate and large payload sizes.
Atorvastatin-Diltiazem Combination Induced Rhabdomyolysis Leading to Diagnosis of Hypothyroidism
Authors: Ehelepola N. D. B. , Sathkumara S. M. B. Y. , Bandara H. M. P. A. G. S. , Kalupahana K. L. R.
Published: April 2017

Statins and hypothyroidism, independently, can rarely cause rhabdomyolysis. The combination of them especially with concurrent intake of drugs such as diltiazem increases the risk of rhabdomyolysis. Hashimoto’s encephalopathy is a rare condition associated with Hashimoto’s thyroiditis and some patients with that can present with a stroke like picture. An elderly male who has been on atorvastatin for three years and on diltiazem for a week presented with sudden onset inability to walk and confusion. On examination muscle tenderness was noticed and creatine kinase levels indicated rhabdomyolysis which we attributed to atorvastatin. Patient developed a seizure and myoclonus of masseters. Considering this, his confusion and his neutrophilia and high C-reactive protein levels, empirical antibiotics with dexamethasone were started and the patient responded to that. His cerebrospinal fluid and blood culture reports that arrived later did not show sepsis. After going home also his CK (creatine kinase) levels remained high; TSH (thyroid-stimulating hormone) level test was done and hypothyroidism was diagnosed. His antithyroid peroxidase antibody levels were also very high. We retrospectively think he had Hashimoto’s encephalopathy as well. His lipid profile and TSH and CK values returned to normal in that order after a few months of levothyroxine therapy.
Interactions of Nitrogen Source and Rate and Weed Removal Timing Relative to Nitrogen Content in Corn and Weeds and Corn Grain Yield
Authors: Knight Alexandra M. , Everman Wesley J. , Jordan David L. , Heiniger Ronnie W. , Smyth T. Jot
Published: April 2017

Adequate fertility combined with effective weed management is important in maximizing corn (Zea mays L.) grain yield. Corn uptake of nitrogen (N) is dependent upon many factors including weed species and density and the rate and formulation of applied N fertilizer. Understanding interactions among corn, applied N, and weeds is important in developing management strategies. Field studies were conducted in North Carolina to compare corn and weed responses to urea ammonium nitrate (UAN), sulfur-coated urea (SCU), and composted poultry litter (CPL) when a mixture of Palmer amaranth (Amaranthus palmeri S. Wats.) and large crabgrass (Digitaria sanguinalis L.) was removed with herbicides at heights of 8 or 16 cm. These respective removal timings corresponded with 22 and 28 days after corn planting or V2 and V3 stages of growth, respectively. Differences in N content in above-ground biomass of corn were noted early in the season due to weed interference but did not translate into differences in corn grain yield. Interactions of N source and N rate were noted for corn grain yield but these factors did not interact with timing of weed control. These results underscore that timely implementation of control tactics regardless of N fertility management is important to protect corn grain yield.
Acquired MET Y1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non–Small Cell Lung Cancer
Authors: Li Anna , Yang Jin-ji , Zhang Xu-chao , Zhang Zhou , Su Jian , Gou Lan-ying , Bai Yu , Zhou Qing , Yang Zhenfan , Han-Zhang Han , Zhong Wen-Zhao , Chuai Shannon , Zhang Qi , Xie Zhi , Gao Hongfei , Chen Huajun , Wang Zhen , Wang Zheng , Yang Xue-ning , Wang Bin-chao , Gan Bin , Chen Zhi-hong , Jiang Ben-yuan , Wu Si-pei , Liu Si-yang , Xu Chong-rui , Wu Yi-long
Published: April 2017

Purpose: MET amplification, responsible for 20% of acquired resistance to EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non–small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs–induced resistance remains elusive.

Experimental Design: We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasmas ctDNA samples to detect and quantify genetic alterations.

Results: We identified 2 newly acquired MET mutations, Y1248H and D1246N, in 2 patients and further confirmed their resistance against type I MET-TKIs in silco, in vitro, and in vivo. Interestingly, NIH3T3 cells harboring either mutation exhibited responses to type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKI resistance mechanism.

Conclusions: Our study provides insight into the diversity of mechanisms underlying MET-TKI–induced resistance and highlights the potential of sequential use of MET-TKIs. Clin Cancer Res; 23(16); 4929–37. ©2017 AACR.
A Novel Galectin-1 Inhibitor Discovered through One-Bead Two-Compound Library Potentiates the Antitumor Effects of Paclitaxel in vivo
Authors: Shih Tsung-Chieh , Liu Ruiwu , Fung Gabriel , Bhardwaj Gaurav , Ghosh Paramita M. , Lam Kit S.
Published: April 2017

Through the one-bead two-compound (OB2C) ultra–high-throughput screening method, we discovered a new small-molecule compound LLS2 that can kill a variety of cancer cells. Pull-down assay and LC/MS-MS indicated that galectin-1 is the target protein of LLS2. Galectin-1 is known to be involved in the regulation of proliferation, apoptosis, cell cycle, and angiogenesis. Binding of LLS2 to galectin-1 decreased membrane-associated H-Ras and K-Ras and contributed to the suppression of pErk pathway. Importantly, combination of LLS2 with paclitaxel (a very important clinical chemotherapeutic agent) was found to exhibit synergistic activity against several human cancer cell lines (ovarian cancer, pancreatic cancer, and breast cancer cells) in vitro. Furthermore, in vivo therapeutic study indicated that combination treatment with paclitaxel and LLS2 significantly inhibits the growth of ovarian cancer xenografts in athymic mice. Our results presented here indicate that the OB2C combinatorial technology is a highly efficient drug screening platform, and LLS2 discovered through this method can be further optimized for anticancer drug development. Mol Cancer Ther; 16(7); 1212–23. ©2017 AACR.
Novel Indole-based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through p38 Mitogen-Activated Protein Kinase Activation
Authors: Manuel-Manresa Pilar , Korrodi-Gregório Luís , Hernando Elsa , Villanueva Alberto , Martínez-García David , Rodilla Ananda M. , Ramos Ricard , Fardilha Margarida , Moya Juan , Quesada Roberto , Soto-Cerrato Vanessa , Pérez-Tomás Ricardo
Published: April 2017

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer. Mol Cancer Ther; 16(7); 1224–35. ©2017 AACR.
Intrapartum Ultrasound to Differentiate Flexion and Deflexion in Occipitoposterior Rotation
Authors: Bellussi Federica , Ghi Tullio , Youssef Aly , Cataneo Ilaria , Salsi Ginevra , Simonazzi Giuliana , Pilu Gianluigi
Published: April 2017

Objective: To evaluate the ability of intrapartum ultrasound to differentiate occipitoposterior (OP) rotation with normal flexion of the head from deflexion, to compare the accuracy of ultrasound with the digital examination, and to assess the outcome of labor according to the type of presentation. Patients and Methods: A retrospective study of patients with abnormal labor because of either prolongation and/or abnormal cardiotocography and OP rotation who underwent intrapartum sonography. Results: Normal flexion was inferred in 36/42 cases by a longitudinal sonographic view of the fetal face demonstrating the chin approaching the chest. In the remaining 6, deflexion was diagnosed by visualizing the chin separate and distant from the chest. In 3 of these cases, the orbits were at the same level of the pubis suggesting brow presentation. In the remaining 3 cases, the orbits were above the pubis, and sinciput presentation was inferred. Head deflexion was diagnosed more accurately with ultrasound than clinically and always required a cesarean section versus 36% of cases with OP flexed presentation (p = 0.0052). Conclusions: Fetuses with abnormal labor and OP rotation had deflexed presentations in 14% of cases and were never delivered vaginally. Sonography was far more accurate than the digital examination.
Survival of Cervical Cancer Patients Presenting with Occult Supraclavicular Metastases Detected by FDG-Positron Emission Tomography/CT: Impact of Disease Extent and Treatment
Authors: Ioffe Yevgeniya J. , Massad Leslie Stewart , Powell Matthew A. , Hagemann Andrea R. , Mutch David G. , Thaker Premal H. , Schwarz Julie K. , Grigsby Perry W.
Published: April 2017

Aims: The study aimed to do the following: (1) describe progression free survival (PFS) and overall survival (OS) of women with cervical cancer presenting with occult supraclavicular lymph node (SCLN) metastases, identified by positron emission tomography CT (PET-CT) and (2) compare OS of patients with isolated SCLN metastases to that of patients with SCLN and extranodal metastatic disease. Methods: Patients were identified retrospectively. Treatment intent was abstracted. PFS and OS in the high-dose chemo-radiotherapy (RT), palliative RT, and supportive treatment groups, as well as OS of patients with SCLN metastases only vs. SCLN and extranodal metastases were calculated. Results: Fourteen patients received high-dose chemo-RT, 32 received palliative RT, and 6 received supportive care (n = 52). Median PFS was 3 months in high-dose chemo-RT group and 1 month in palliative RT (p = ns). Median OS was 12 months in high-dose chemo-RT group, 7 months in palliative RT group, and 2 months in palliative care group (p = 0.05). OS was significantly different between patients with isolated SCLN disease vs. SCLN and extranodal disease, that is, 10.5 vs. 3 months (p = 0.009, χ2 = 6.9). Conclusions: In this limited analysis, median OS of cervical cancer patients with PET/CT-positive SCLN metastases was the longest when treated with high-dose chemo-RT. Patients with SCLN and extranodal metastases experienced significantly shorter OS, as compared to patients with SCLN only disease.
Expression of the ERBB Family of Ligands and Receptors in Gastric Cancer
Authors: Byeon Sun-ju , Lee Hye Seung , Kim Min-A , Lee Byung Lan , Kim Woo Ho
Published: April 2017

Objective: Gastric cancer (GC) is the second most common cancer and the third leading cause of cancer-related death in Korea. Alterations in the ERBB (homology to the erythroblastoma viral gene product, v-erbB) receptor family and ERBB-related signaling pathways are frequently observed in GC. However, the roles of the ERBB receptors and their ligands in GC are not well established. Methods: We evaluated the expression levels of various ERBB receptor ligands (i.e., heparin-binding epidermal growth factor-like growth factor [HBEGF], transforming growth factor-α [TGFA], amphiregulin [AREG], epiregulin [EREG], epidermal growth factor [EGF], and betacellulin [BTC]) and 3 ERBB family receptors (i.e., epidermal growth factor receptor [EGFR], human EGFR2 [HER2], and ERBB3) in 313 cases of GC using immunohistochemistry, fluorescence in situ hybridization, and mRNA in situ hybridization. Results: A high expression of EGFR, HER2, and ERBB3 was observed in 30, 32, and 27 cases, respectively. A high expression of HBEGF, TGFA, AREG, EREG, EGF, and BTC was observed in 91, 97, 151, 74, 26, and 37 cases, respectively. A high expression of TGFA was associated with better survival, while a high expression of BTC was associated with worse survival. These results were confirmed using Cox proportional hazards analysis. HBEGF, TGFA, AREG, tumor-node-metastasis classification, Lauren's classification, and ERBB3 were significant survival parameters in multivariate analysis. Conclusion: Among the ERBB family receptors and ligands examined, 3 ligands (i.e., TGFA, HBEGF, and AREG) and ERBB3 had a prognostic impact.
Metastatic Pituitary Carcinoma to Cervical Lymph Node: Diagnosis by Fine Needle Aspiration and Review of the Literature
Authors: Wang Huiying , Liang Jiancong , Yong William H. , Sullivan Peggy
Published: April 2017

Background: Pituitary carcinomas are rare neoplasms whose designation requires demonstration of metastatic disease. No specific morphologic features can reliably distinguish pituitary carcinomas from pituitary adenomas, rendering the diagnosis particularly challenging. Furthermore, as reports of pituitary carcinoma on fine needle aspiration (FNA) biopsy are exceedingly rare in the literature, the cytological features of pituitary carcinoma are poorly characterized. Case Report: Here we describe a case of pituitary carcinoma in a 67-year-old woman with history of recurrent adrenocorticotropic hormone (ACTH)-producing pituitary adenoma who presented with a persistent left cervical nodule for 2 years. Ultrasound-guided FNA of the nodule consisted of loosely cohesive clusters of epithelioid cells with marked cytologic atypia, intermediate to large nuclei, relatively irregular nuclear contour, coarse granular chromatin, prominent nucleoli, and delicate finely granular cytoplasm. Immunohistochemical stains performed on the cell block revealed positivity for synaptophysin, chromogranin and ACTH with an increased Ki-67 proliferation index (approximately 25%). Review of the patient's previously resected pituitary tumor showed similar cytomorphologic features. Conclusion: Given the similar cytologic features of pituitary carcinomas compared to other neuroendocrine tumors, it is important to obtain a complete clinical history and maintain a high index of suspicion in order to make a correct diagnosis of pituitary carcinoma on FNA.
68Gallium DOTANOC-PET Imaging in Lung Carcinoids: Impact on Patients' Management
Authors: Lamarca Angela , Pritchard D. Mark , Westwood Thomas , Papaxoinis Georgios , Nonaka Daisuke , Vinjamuri Sobhan , Valle Juan W. , Manoharan Prakash , Mansoor Wasat
Published: April 2017

Background:68Gallium DOTA-PET imaging is preferable to standard somatostatin receptor scintigraphy where available; however, its role in the management of lung carcinoid tumours (LC) remains unclear. Methods: All consecutive patients with histologically confirmed LC from two ENETS Centres of Excellence were identified retrospectively. The primary objective was to assess the impact of 68Ga-DOTANOC-PET on clinical management in patients with LC. Results: Of 166 patients screened, 46 were eligible: 52% female, median age 57 years (range 21-86); type of LC: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (4%), typical (44%), atypical (35%), not reported (17%); stage: localised (63%), locally advanced (13%), and metastatic (17%) (7% unknown). A total of 47 68Ga-DOTANOCs were performed with the following rationale: LC diagnosis confirmation (4; 9%), primary tumour identification (2; 4%), post-surgical assessment (19; 40%), staging (patients with known LC present at time of 68Ga-DOTANOC) (19; 40%), and consideration of peptide receptor radionuclide therapy (3; 7%). Twenty-seven (57%) scans showed evidence of non-physiological uptake: median maximum standardised uptake value 7.2 (range 1.42-53). 68Ga-DOTANOC provided additional information in 37% (95% CI 22-51) of patients and impacted on management in 26% (95% CI 12-41); 9 patients (21%) were identified to have occult sites of metastases. Out of the 19 patients with post-surgical 68Ga-DOTANOC, 3 (16%) were identified to have distant metastases. There were no differences in the rate of practice changing 68Ga-DOTANOC results by type of LC (p value 0.5). Conclusions: Our results support the role of 68Ga-DOTANOC for optimising the management of patients with LC, including post-surgical re-staging due to the potential for identifying occult metastases.
Aortic–Brachial Arterial Stiffness Gradient and Cardiovascular Risk in the Community
Authors: Niiranen Teemu J. , Kalesan Bindu , Larson Martin G. , Hamburg Naomi M. , Benjamin Emelia J. , Mitchell Gary F. , Vasan Ramachandran S.
Published: April 2017

A recent study reported that the aortic–brachial arterial stiffness gradient, defined as carotid–radial/carotid–femoral pulse wave velocity (PWV ratio), predicts all-cause mortality better than carotid–femoral pulse wave velocity (CFPWV) alone in dialysis patients. However, the prognostic significance of PWV ratio for cardiovascular disease (CVD) in the community remains unclear. Accordingly, we assessed the correlates and prognostic value of the PWV ratio in 2114 Framingham Heart Study participants (60±10 years; 56% women) free of overt CVD. Mean PWV ratio decreased from 1.36±0.19 in participants aged <40 years to 0.73±0.21 in those aged ≥80 years. In multivariable linear regression, older age, male sex, higher body mass index, diabetes mellitus, lower high-density lipoprotein cholesterol, higher mean arterial pressure, and higher heart rate were associated with lower PWV ratio (
P
<0.001 for all). During a median follow-up of 12.6 years, 248 first CVD events occurred. In Cox regression models adjusted for standard CVD risk factors, 1-SD changes in CFPWV (hazard ratio, 1.33; 95% confidence interval, 1.10–1.61) and PWV ratio (hazard ratio, 1.32; 95% confidence interval, 1.09–1.59) were associated with similar CVD risks. Models that included conventional CVD risk factors plus CFPWV or PWV ratio gave the same C statistics (C=0.783). Although PWV ratio has been reported to provide incremental predictive value over CFPWV in dialysis patients, we could not replicate these findings in our community-based sample. Our findings suggest that the prognostic significance of PWV ratio may vary based on baseline CVD risk, and CFPWV should remain the criterion standard for assessing vascular stiffness in the community.
Brain Renin–Angiotensin System
Authors: van Thiel Bibi S. , Góes Martini Alexandre , te Riet Luuk , Severs David , Uijl Estrellita , Garrelds Ingrid M. , Leijten Frank P.J. , van der Pluijm Ingrid , Essers Jeroen , Qadri Fatimunnisa , Alenina Natalia , Bader Michael , Paulis Ludovit , Rajkovicova Romana , Domenig Oliver , Poglitsch Marko , Danser A.H. Jan
Published: April 2017

Because of the presence of the blood–brain barrier, brain renin–angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I–generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt–treated mice, and Ang II–infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 μL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.
Pregnancy Reprograms Large-Conductance Ca
2+
-Activated K
+
Channel in Uterine Arteries
Authors: Hu Xiang-Qun , Dasgupta Chiranjib , Chen Man , Xiao Daliao , Huang Xiaohui , Han Limin , Yang Shumei , Xu Zhice , Zhang Lubo
Published: April 2017

The large-conductance Ca
2+
-activated K
+
(BK
Ca
) channel is of critical importance in pregnancy-mediated increase in uterine artery vasodilation and blood flow. The present study tested the hypothesis that active DNA demethylation plays a key role in pregnancy-induced reprogramming and upregulation of BK
Ca
channel β1 subunit (BKβ1) in uterine arteries. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep. Pregnancy significantly increased the expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) in uterine arteries. A half-palindromic estrogen response element was identified at the TET1 promoter, and estrogen treatment increased TET1 promoter activity and TET1 expression in uterine arteries. In accordance, pregnancy and steroid hormone treatment resulted in demethylation of BKβ1 promoter by increasing 5-hydroxymethylcytosine and decreasing 5-methylcytosine at the CpG in the Sp1
-380
binding site that is of critical importance in the regulation of the promoter activity and BKβ1 expression. Inhibition of TET1 with fumarate significantly decreased BKβ1 expression in uterine arteries of pregnant animals and blocked steroid hormone–induced upregulation of BKβ1. Functionally, fumarate treatment inhibited pregnancy and steroid hormone–induced increases in BK
Ca
channel current density and BK
Ca
channel–mediated relaxations. In addition, fumarate blocked pregnancy and steroid hormone–induced decrease in pressure-dependent myogenic tone of the uterine artery. The results demonstrate a novel mechanism of estrogen-mediated active DNA demethylation in reprogramming of BK
Ca
channel expression and function in the adaption of uterine circulation during pregnancy.
Following Glaziou’s footsteps: rediscovery and updated description of three species of Behuria Cham. (Melastomataceae) from the Atlantic Forest (Brazil)
Authors: BOCHORNY THUANE , BACCI LUCAS F. , GOLDENBERG RENATO
Published: April 2017

This study was carried out in the state of Rio de Janeiro and led to the rediscovery of three endemic and threatened species of Behuria (Melastomataceae). The type specimens for these species were collected by the French botanist A.F.M. Glaziou. Behuria corymbosa and Behuria glazioviana were collected for the last time 127 years ago by him, in 1889. Behuria mourae was collected twice after the type; the last collection dates from about 72 years ago. In order to find the exact localities where Glaziou collected these three species we studied the labels of the type specimens, Glaziou’s notebooks and letters, looking for tracks that would lead us to places that he visited. We also consulted documents from a local library and gathered information from local people. Here we present updated descriptions, comments, photos and conservation assessments for each species.