bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of depth of response to predict progression‐free survival in relapsed or refractory multiple myeloma: Evaluation of results from 102 clinical trials
Authors: Mangal Naveen , Salem Ahmed Hamed , Menon Rajeev M. , Freise Kevin J. 
Published: April 2018

AbstractProgression‐free survival (PFS) is the standard endpoint for demonstration of clinical effectiveness of novel therapies in relapsed or refractory multiple myeloma (RRMM). However, the long evaluation times for PFS limits its usefulness in the development of new therapies. Therefore, the objective of this analysis was to determine the relationship between response rates and median PFS in RRMM. A database was systematically developed from 268 identified RRMM trials reported from 1999 to 2016. Evaluated covariates for the relationship between response rates and PFS included age, sex, drug class(es), and number of drug classes. One‐hundred two (102) trials involving 136 cohorts were included in the meta‐analysis, representing 13 322 patients in total. Regression analysis using response rates and median PFS indicated that the correlation between very good partial response (VGPR) or better and median PFS was higher (R2 = 0.63) than the separately analyzed correlations between clinical benefit, overall response, or complete response rate and median PFS (R2 = 0.47 – 0.52). Subsequent covariate analysis revealed that treatment with an immunomodulatory imide drug (IMiD) further improved the relationship (R2 = 0.69), with a longer median PFS at a given VGPR or better rate when at least 1 drug treatment was an IMiD. Number of drug classes was not found to alter this relationship. In conclusion, VGPR or better rate can be used to predict the median PFS, with adjustment for the additional PFS provided by an IMiD.
A numerical study on the occurrence of flowing wells in the discharge area of basins due to the upward hydraulic gradient induced wellbore flow
Authors: Zhang Zhi‐Yuan , Jiang Xiao‐Wei , Wang Xu‐Sheng , Wan Li , Wang Jun‐Zhi 
Published: April 2018

AbstractThe occurrence of flowing wells in basins has been found to be closely related to the discharge area with an upward hydraulic gradient. Unfortunately, previous studies on upward gradient induced wellbore flow with equaling total inflow (Qin) in the deep and total outflow (Qout) in the shallow could not explain the occurrence of flowing wells. By representing wells using the MNW2 Package imbedded in MODFLOW 2005, we obtain the exchange of groundwater between the aquifer and the well in the discharge area of 3D unit basins and identify three scenarios: Qin = Qout, Qin > Qout > 0 and Qin > Qout = 0. The relationship of Qin > Qout well explains why flowing wells only develop in a limited part of the discharge area. Sensitivity analysis shows that well location, water table undulation, and basin length–depth ratio do not change the profile of the ratio of cumulative flow rate in a flowing well to total inflow (Qv/Qin) versus the relative elevation in the inflow segment, zin*, but could significantly change the length of the inflow segment; well depth could change both the length of the inflow segment and the profile of Qv/Qin versus zin*. Based on the numerical results in homogeneous and isotropic basins with different basin length–depth ratios in the current study, the ratio of inflow in the lower half part of a flowing well to the total inflow is found to be at least 67% and could be close to 100%, indicating that water at the outlets of flowing wells with long open sections is mainly from the deep part of the well.
Chemostatic behaviour of major ions and contaminants in a semiarid spring and stream system near Los Alamos, NM, USA
Authors: Koger Jace M. , Newman Brent D. , Goering Timothy J. 
Published: April 2018

AbstractRecent studies have focused on the relationship between solute concentrations and discharge in streams, demonstrating that concentrations can vary little relative to changes in discharge (chemostatic behaviour). Chemostatic behaviour is dependent on catchment characteristics (e.g., lithology, geomorphology, and vegetation) and chemical characteristics of the solute (e.g., availability, reactivity, and mobility). An investigation of 3 springs and a stream near Los Alamos, NM, reveals that springs can behave in a chemostatic fashion as stream systems tend to do. Another unique finding of this study is that the anthropogenic contaminants barium and the high explosive RDX (hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine) can also behave chemostatically. The chemostatic behaviour of a contaminant has important implications for the residence time of contaminants in a system as well as having a major control on contaminant flux and mass transport. Redox (reduction–oxidation) and biogeochemically sensitive analytes (e.g., Fe, SO4, and NO3) display a combination of chemostatic and chemodynamic behaviour, showing the influence of temporally variable conditions on stream and spring chemistries.
Children's psycho‐spatial understanding of affect‐based time: The developmental trajectories of ego‐ and event‐moving perspectives
Authors: McAfee Ciara A. , Wyckoff Emily P. , Choe Katherine S. 
Published: April 2018

AbstractTime is closely linked to people's representation of spatial experience. Previous research showed that adults primed with positive affect judged that they were approaching the event (ego‐moving), whereas those primed with negative affect reported that the event was approaching them (event‐moving). The present research investigated the developmental sensitivity towards psycho‐spatial understanding by examining the role of positive and negative affect on children's perception of time. In Study 1, when tested in a within‐subjects design, 5‐, 7‐, and 9‐year‐olds as well as adults made ego‐moving judgments in response to an object of the positive event that was to happen in 2 days. However, by 9 years, children made adult‐like event‐moving responses to an object that stood for the negative affect. Five‐year‐olds continued to make ego‐moving judgments in the negative valence condition, whereas 7‐year‐olds' responses were in transition. Study 2 replicated the full developmental pattern found in Study 1, even when the positive and negative affect events were towards the identical object in the between‐subjects design and the time span was shortened to a few minutes. Implications of the affective spatiotemporal perception of time were further discussed in relation to the sense of agency.Highlights

We uncover the pattern of developmental sensitivity towards the psycho‐spatial embodiment of time, in relation to a positive or negative event.
Vignettes were used to ascertain participant's psycho‐spatial view of time in relation to valence; 9‐year‐olds had an adult‐like understanding.
Teaching children to use different psycho‐spatial agentic perspectives has the potential to help children at risk of anxiety and depression.
USP4 expression independently predicts favorable survival in lung adenocarcinoma
Authors: Zhong Ming , Jiang Qi , Jin Ronghui 
Published: April 2018

AbstractUbiquitin specific protease 4 (USP4) is a member of the USPs family, which catalyzes the cleavage of ubiquitin from a series of protein substrates, thereby modulating a number of cellular signaling pathways. In this study, we aimed to explore the expression profile of USP4 in lung adenocarcinoma (LUAD) using large patient cohorts in the Cancer Genome Atlas and the International Cancer Genome Consortium and to investigate its prognostic value and the possible mechanisms of its dysregulation. Results showed that USP4 was significantly downregulated in LUAD tissues (N = 514) compared with the normal controls (N = 59). The high USP4 expression group had significantly better overall survival (OS) and recurrence‐free survival (RFS). Multivariate analysis showed that preserved USP4 expression was an independent prognostic factor of favorable OS (HR: 0.574, 95%CI: 0.427–0.771, P < 0.001) and RFS (HR: 0.625, 95%CI: 0.444–0.880, P = 0.007) in LUAD. In comparison, although USP4 was downregulated in lung squamous cell carcinoma, its expression had no prognostic value in term of OS and RFS. By examining USP4 DNA copy number alterations (CNAs) (N = 511) and DNA methylation (N = 453) in LUAD, we found that DNA shallow deletion was frequent (–1, N = 239, 46.8%) and was associated with significantly decreased USP4 expression compared with the copy‐neutral (0) cases. The methylation status of some CpG sites in USP4 DNA was negatively correlated with USP4 expression. Based on these findings, we infer that USP4 expression might be a favorable biomarker in terms of OS and RFS in LUAD patients. DNA shallow deletion and hypermethylation might be two important mechanisms of decreased USP4 in these patients. © 2018 IUBMB Life, 70(7):670–677, 2018
Conventional and Microwave‐Activated the Synthesis of a Novel Series of Imidazoles, Pyrimidines, and Thiazoles Candidates
Authors: Selim Yasser , Abd El‐Azim Mohamed H. M. 
Published: April 2018

A novel series of imidazoles, pyrimidines, and thiazoles were synthesized using microwave irradiation and conventional method from commercial available p‐aminobenzoic acid. Thus, one‐pot condensation of p‐aminobenzoic acid, urea, and chloroacetic acid have been provided two types of imidazole derivatives as separated mixture 2a and 2b. [3 + 2 + 1] Cyclocondensation of 2a, benzaldehyde, and urea/thiourea in acidic medium afforded imidazolo oxazine derivative 3 and Imidazolothiazine 4. Coupling of 2a with benzene diazonium salt gave the phenyldiazenyl imidazolidine 5. While the reaction of 2a, thiourea, and benzaldehyde in sodium ethoxide afforded imidazolothiazine 6. Oxidative cyclization of thiourea derivative 7 resulted a mixture of benzithiazole derivative 7a and oxathiazole derivative 7b. Cyclocondensation of 7a with phenylenediamine and 4‐methyl phenylenediamine furnished imidazole 8 and 9, respectively. Reaction of P‐aminobenzioc acid with potassium cyanate followed by Biginelli reaction with (acetyl acetone, ethyl acetoacetate, and diethyl malonate) and salicyladehyde in HCl tolerated pyrimidine derivatives 10a–c, respectively. In the same manner, the reactions and short reaction time make microwave technique one of the greenest methodology for synthesis of this class of heterocyclic system.
β2-Adrenoceptors inhibit neutrophil extracellular traps in human polymorphonuclear leukocytes
Authors: Marino Franca , Scanzano Angela , Pulze Laura , Pinoli Monica , Rasini Emanuela , Luini Alessandra , Bombelli Raffaella , Legnaro Massimiliano , de Eguileor Magda , Cosentino Marco 
Published: April 2018

Abstract
This study tests the hypothesis that in isolated human polymorphonuclear leukocytes (PMN) adrenergic ligands can affect neutrophil extracellular trap (NET) formation. We have previously shown that, in PMN, adrenaline (A), through the activation of adrenergic receptors (AR), reduces stimulus-dependent cell activation; we have, therefore, planned to investigate if AR are involved in NET production. PMN were obtained from venous blood of healthy subject. The ability of adrenergic ligands to affect reactive oxygen species (ROS) production, NET production, and cell migration was investigated in cells cultured under resting conditions or after activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP), LPS, or IL-8. Stimuli-induced NET production measured as ROS, microscopic evaluation, and elastase production was reverted by A and this effect was blocked by the selective β2–AR antagonist ICI-118,551. The stimulus-induced ROS generation and migration was prevented by A and by isoprenaline (ISO), and these effects were counteracted only by ICI-118,551 and not by the other two selective ligands for the β1 and β3–AR. Finally, the presence of the β–ARs on PMN was confirmed, by means of microscopy and flow cytometry. The data of the present study suggest that adrenergic compounds, through the interaction of mainly β2–AR, are able to affect neutrophil functions. These data are suggestive of a possible therapeutic role of β2–AR ligands (in addition to their classical use), promoting the possible therapeutic relevance of adrenergic system in the modulation of innate immunity proposing their possible use as anti-inflammatory drugs.
Adrenergic compounds modify NET production by human neutrophils and are able to affect other key functions of these cells.
Insight on the regulation of chemokine activities
Authors: Cecchinato Valentina , Uguccioni Mariagrazia 
Published: April 2018

Abstract
The activity of chemokines is regulated by several mechanisms that control the final cellular response. The present review discusses the complexity of the regulation of the chemokine system, and the novel findings describing how in persistent infections, the expression of chemokine receptors on the surface of T cells does not correlate with their homing potential. Thanks to the latest advances in our comprehension of the chemokine system, novel approaches targeting chemokines, chemokine receptors, or protein of their signaling pathway should be considered in order to achieve a personalized therapy.
Review focuses on the regulation of chemokine activities in health and disease.
Lipofection of plasmid DNA into human mast cell lines using lipid nanoparticles generated by microfluidic mixing
Authors: Duguay Brett A , Huang Kate Wei-Chen , Kulka Marianna 
Published: April 2018

Abstract
Mast cells are important immune cells that have significant roles in mediating allergy and asthma. Therefore, studying the molecular mechanisms regulating these and other processes in mast cells is important to elucidate. Methods such as lipofection, transduction, and electroporation are often employed to dissect these mechanisms by disrupting gene expression in mast cell lines. However, as with other leukocytes, human mast cells (HMCs) are often refractory to the delivery of plasmids by lipofection. In this study, we investigated the utility of lipid nanoparticles (LNPs) containing the ionizable cationic lipids 1,2-dioleoyloxy-3-dimethylaminopropane, 1,2-dioleyloxy-3-dimethylaminopropane, or 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane for the delivery of plasmid DNA into HMC lines. Herein, we demonstrate for the first time the use of LNPs to achieve significant and reproducible levels of plasmid DNA transfection in HMC-1.2 and laboratory of allergic diseases 2 (LAD2) cells. These levels reached 53.2% and 16.0% in HMC-1.2 and LAD2 cells, respectively; and outperformed Lipofectamine 3000 in both cases. Moreover, cell viability in the transfected cells remained above 65% for all LNP conditions tested. Together, these observations illustrate the efficacy of this technique for mast cell researchers and further support the use of LNPs for nucleic acid delivery into leukocytes.
Method based on DNA-lipid nanoparticles successfully and reproducibly transfects human mast cell lines while yielding levels of transgene expression and cell viability superior to traditional lipofection techniques.
A surface plasmon resonance assay for characterisation and epitope mapping of anti‐GLP‐1 antibodies
Authors: Thomsen Lasse , Gurevich Leonid 
Published: April 2018

AbstractThe incretin hormone glucagon‐like peptide‐1 (GLP‐1) has been subject to substantial pharmaceutical research regarding the treatment of type 2 diabetes mellitus. However, quantification of GLP‐1 levels remains complicated due to the low circulation concentration and concurrent existence of numerous metabolites, homologous peptides, and potentially introduced GLP‐1 receptor agonists. Surface plasmon resonance (SPR) facilitates real‐time monitoring allowing a more detailed characterisation of the interaction compared with conventional enzyme‐linked immunosorbent assays (ELISA). In this paper, we describe the development of the first SPR assays for characterisation of anti‐GLP‐1 antibodies for ELISA purposes. Binding responses were obtained on covalently immobilised anti‐GLP‐1 antibodies at 12°C, 25°C, and 40°C and fitted to a biomolecular (1:1) interaction model showing association rates of 1.01 × 103 to 4.54 × 103 M−1 s−1 and dissociation rates of 3.56 × 10−5 to 1.56 × 10−3 s−1 leading to affinities of 35.2 to 344 nM, depending on the temperature. Determination of thermodynamic properties revealed an enthalpy driven interaction (ΔH < ΔS < 0) with higher affinities at lower temperatures due to the formation and stabilisation of hydrogen bonds within the binding site primarily composed of polar amino acids (ΔCp < 0). Pair‐wise epitope mapping was performed on captured anti‐GLP‐1 antibodies followed by subsequent interaction with GLP‐1 (7‐36) and other anti‐GLP‐1 antibodies. A global evaluation of every binding response led to an epitope map elucidating the potential of various anti‐GLP‐1 antibody pairs for sandwich ELISA and hence pinpointing the optimal antibody combinations. The SPR assays proved capable of providing vital information for ELISA development endorsing it as a useful optimisation tool.
Fragmentation pathways and differentiation of positional isomers of sorafenib and structural analogues by ESI‐IT‐MSn and ESI‐Q‐TOF‐MS/MS coupled with DFT calculations
Authors: Yu Dandan , Liang Xianrui 
Published: April 2018

AbstractSorafenib is an orally active multikinase inhibitor for the treatment of renal cell carcinoma. A series of sorafenib structural analogues were investigated in this work for their gas‐phase fragmentation behaviors using electrospray ionization ion trap mass spectrometry and quadrupole time‐of‐flight mass spectrometry in the positive mode. The possible fragmentation pathways were proposed based on ESI‐MS/MS data and theoretical calculation. Different from the typical α‐cleavage of amide, consecutive reactions that involved elimination of H2O and CH3NC were observed for 2‐pyridinecarboxamide derivatives, which were followed by the formation of a stabilized 7‐membered ring carbocation by loss of CO. Two possible protonation sites occurred at carbonyl oxygen atoms for aryl‐urea derivatives and the α‐cleavage of urea was the main fragmentation pathways, which was followed by the formation of stable benzo [d] oxazole ring characteristic to aryl‐urea derivatives. The relative abundance of characteristic fragment ions and the energy‐resolved breakdown curves were used to distinguish the 4 sets of positional isomers of sorafenib and analogues. The methodology and results of the present work would contribute to the chemical structure identification of other structural analogues and the potential impurities presented in active pharmaceutical ingredients and drug formulations.
Integrating flipped drain and power gating techniques for efficient FinFET logic circuits
Authors: Dadoria Ajay Kumar , Khare Kavita , Gupta T.K. , Panwar Uday 
Published: April 2018

AbstractPower dissipation is a main attention for designing complementary metal oxide semiconductor Very Large Scale Integration (VLSI) circuits in deep sub‐micron technology. Constant field device scaling leads to high transistor density, reduction in power supply, lower threshold voltage, and reduction in oxide thickness. This gives rise to short channel effects and increases the leakage currents causing power dissipation. In this paper, based on literature survey, new flipped drain gating (FDG) technique is proposed for mitigation of leakage currents; further FDG technique is integrated with power gating technique which makes power dissipation lower than FDG. Proposed techniques are integrated with FinFET technology and applied on Logic Gates and bench mark circuits on HSPICE simulator. Simulation is carried out at 27°C temperature by using 20 to 7‐nm Berkley Predictive Technology Module. Simulation results at 10‐MHz frequency shows maximum saving in leakage power using FDG technique at input vector 01 as 80.35% compared with conventional drain gating for EXOR logic. Similarly, FDG technique saves maximum dynamic power of 25.98% when compared with conventional drain gating for AND logic.
Process Monitoring of Laser Beam Melting
Authors: Hagedorn Yves , Pastors Felix 
Published: April 2018

AbstractPowder bed laser melting (PBLM) is increasingly applied for series production in automotive, medicine and aerospace. Main drivers are extended design capabilities and steadily decreasing production costs. Nevertheless, process stability remains one central challenge for general industrial implementation. This challenge may be tackled by extensive process control, based on coaxial thermal emissivity sensing or high‐speed imaging. Towards this, the present work provides a first insight into the correlation of sensor data, applied process parameters and part properties.
A Great Year for the Industrial Laser Business in the USA
Authors: Belforte David A. 
Published: April 2018

AbstractThe global industrial laser business in 2017 experienced a record year in terms of revenues, topping the 4.3 billion dollars mark. From the end of the Great Recession (officially June 2009), according to Industrial Laser Solutions (ILS), market revenues grew at a 14.95 % CAGR for a 250 % increase over end of recession values (Fig. 1). Leading this charge were fiber laser revenues which rose at an exceptional 37.38 % CAGR to more than $2 B in 2017.
Perennial biomass production from marginal land in the Upper Mississippi River Basin
Authors: Feng Qingyu , Chaubey Indrajeet , Cibin Raj , Engel Bernard , Sudheer K.P. , Volenec Jeffrey , Omani Nina 
Published: April 2018

AbstractMarginal land is considered promising for biomass production. However, understanding on biomass crop growth and total biofuel production from this land type is very limited. This study evaluated potential production of switchgrass (Panicum virgatum) and Miscanthus (Miscanthus × giganteus) on marginal lands in the Upper Mississippi River Basin. A soil and water assessment tool model with detailed representation of marginal lands and their suitability for growth of the 2 grasses was setup. Marginal land was defined as cropland and grassland with land capability class from 3 to 8. All marginal lands were included as new land covers in the land use map and were preserved when HRUs were defined. The soil and water assessment tool model was calibrated for flow at 13 sites within the Upper Mississippi River Basin region at monthly scale. The predicted biomass by growing switchgrass and Miscanthus on marginal lands in the study area can produce up to 37% of the 132 × 109 L biofuel goal set by the 2010 Energy Independence and Security Act in the USA. The simulated flow was lower when marginal lands were converted to grow perennial bioenergy crops. The results from this study improved our understanding on growth of perennial crops on marginal land and their contributions to biofuel development.