bluuebunny/crossref_metadata_2025 huggingface dataset:
A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration
Authors: Sanche S , Sheehan N , Mesplède T , Wainberg MA , Li J , Nekka F
Published: May 2017

Preventing virological failure following HIV treatment remains a difficult task that is further complicated by the emergence of drug resistance. We have developed a mathematical model able to explain and predict HIV virological outcomes for various compounds and patients' drug intake patterns. Compared to current approaches, this model considers, altogether, drug penetration into lymph nodes, a refined adherence representation accounting for the propensity for long drug holidays, population pharmacokinetic and pharmacodynamic variability, drug interaction, and crossresistance. In silico results are consistent with clinical observations for treatment with efavirenz, efavirenz in association with tenofovir DF and emtricitabine, or boosted darunavir. Our findings indicate that limited lymph node drug penetration can account for a large proportion of cases of virological failure and drug resistance. Since a limited amount of information is required by the model, it can be of use in the process of drug discovery and to guide clinical treatment strategies.
Dissociated Agonist of Glucocorticoid Receptor or Prednisone for Active Rheumatoid Arthritis: Effects on P1NP and Osteocalcin Pharmacodynamics
Authors: Shoji S , Suzuki A , Conrado DJ , Peterson MC , Hey‐Hadavi J , McCabe D , Rojo R , Tammara BK
Published: May 2017

Fosdagrocorat (PF‐04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti‐inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment‐related changes in amino‐terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed‐effects longitudinal kinetic‐pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were −18, −22, and −22% (P1NP), and −7, −13, and −17% (OC), respectively. Changes with prednisone 5 and 10 mg were −15% and −18% (P1NP) and −10% and −17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%.
Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension
Authors: Krause A , Machacek M , Lott D , Hurst N , Bruderer S , Dingemanse J
Published: May 2017

Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long‐term data from 1,156 patients. PAH comedication did not affect exposure to selexipag, while exposure to its active metabolite ACT‐333679 was reduced by 30% when taken in combination, clinically not relevant in the context of individual dose up‐titration. Using log‐linear regression models linking model‐predicted steady‐state exposure to pharmacodynamics (PD), exposure to selexipag and ACT‐333679 showed some statistically significant, albeit not clinically relevant, effects on exercise capacity, laboratory values, and the occurrence of prostacyclin‐related adverse events, but not on vital signs or adverse events denoting hemorrhage. Using suitable modeling techniques, the GRIPHON study yielded clinically relevant data with limited burden of pharmacokinetics (PK) blood sampling, demonstrating that PK/PD modeling enables firm conclusions even with sparse PK and PD sampling.
Dynamical downscaling of East Asian winter monsoon changes with a regional ocean–atmosphere coupled model
Authors: Zou Liwei , Zhou Tianjun
Published: May 2017

This study investigated the impacts of regional air–sea coupling on the downscaling of historical and future winter climate changes under the Representative Concentration Pathway (RCP) 8.5 scenario over the Coordinated Regional Climate Downscaling Experiment (CORDEX) East Asia domain. Two sets of dynamical downscaling results were compared using a regional ocean–atmosphere coupled model (FROALS) and the corresponding atmosphere‐only regional climate model (RegCM3) at a horizontal resolution of 50 km. Driven by the reanalysis data, the inclusion of the local air–sea coupling process has little impact on the simulation of surface climate over most land regions of East Asia. However, driven by the global climate model, the cold SST anomalies simulated by FROALS were much larger than those driven by the reanalysis data, which favoured a stronger and northward extended low‐level anomalous anticyclone. The improved low‐level winter monsoon flow partly reduced the dry biases (cold biases) over the Yangtze River valley (north China and Mongolia) in RegCM3. Under the RCP8.5 scenario, a weakened Aleutian Low and relatively weak increase of northeasterly over the southern coast of China were found in the FROALS simulation, which were consistent with those from the driving global climate system model. However, the atmosphere‐only RCM exhibited extended regions with decreases in precipitation over east China, and a weaker surface warming over southern China. These projected changes in the atmosphere‐only RCM were followed by the evidently enhanced northerly flow in east China, which was mainly caused by the exaggerated decrease in sea‐level pressure over the western North Pacific as a result of strong responses to the local SST warming. Our results indicated that a regional air–sea coupled model could be a useful tool for the dynamical downscaling of present and future winter climate changes over East Asia.
Use of oxygen isotopes to differentiate between nitrous oxide produced by fungi or bacteria during denitrification
Authors: Rohe Lena , Well Reinhard , Lewicka‐Szczebak Dominika
Published: May 2017

Rationale

Fungal denitrifiers can contribute substantially to N2O emissions from arable soil and show a distinct site preference for N2O (SP(N2O)). This study sought to identify another process‐specific isotopic tool to improve precise identification of N2O of fungal origin by mass spectrometric analysis of the N2O produced.

Methods

Three pure bacterial and three fungal species were incubated under denitrifying conditions in treatments with natural abundance and stable isotope labelling to analyse the N2O produced. Combining different applications of isotope ratio mass spectrometry enabled us to estimate the oxygen (O) exchange accelerated by denitrifying enzymes and the ongoing microbial pathway in parallel. This experimental set‐up allowed the determination of δ18O(N2O) values and isotopic fractionation of O, as well as SP(N2O) values, as a perspective to differentiate between microbial denitrifiers.

Results

Oxygen exchange during N2O production was lower for bacteria than for fungi, differed between species, and depended also on incubation time. Apparent O isotopic fractionation during denitrification was in a similar range for bacteria and fungi, but application of the fractionation model indicated that different enzymes in bacteria and fungi were responsible for O exchange. This difference was associated with different isotopic fractionation for bacteria and fungi.

Conclusions

δ18O(N2O) values depend on isotopic fractionation and isotopic fractionation may differ between processes and organism groups. By comparing SP(N2O) values, O exchange and the isotopic signature of precursors, we propose here a novel tool for differentiating between different sources of N2O.
Large variability in CO2 and N2O emissions and in 15N site preference of N2O from reactions of nitrite with lignin and its derivatives at different pH
Authors: Wei Jing , Zhou Minghua , Vereecken Harry , Brüggemann Nicolas
Published: May 2017

Rationale

Chemodenitrification is an important N2O source in soil; however, knowledge about the production of CO2 and N2O from abiotic nitrite‐SOM reactions, especially the N2O isotopic signatures (intramolecular 15N site preference (SP), and δ15Nbulk and δ18O values), is quite limited at present.

Methods

N2O and CO2 emissions from chemical reactions of nitrite with lignin products were determined with gas chromatography, and their response surfaces as a function of pH from 3 to 6 and nitrite concentration from 0.1 to 0.5 mM were explored with polynomial regression. The intramolecular 15N distribution of N2O, as well as δ15Nbulk and δ18O values, were measured with an isotope ratio mass spectrometer coupled to an online pre‐concentration unit. The variability in N2O SP values was tested from pH 3 to 5, and for nitrite concentrations from 0.3 to 0.5 mM.

Results

Both CO2 and N2O emissions varied largely with pH and the structure of lignin products. The highest N2O emission occurred at pH 4–5 in 4‐hydroxy‐3,5‐dimethoxybenzaldehyde and 4‐hydroxy‐3,5‐dimethoxybenzoic acid treatments, and at pH 3 in the treatments with lignin, 4‐hydroxy‐3‐methoxybenzaldehyde, 4‐hydroxy‐3‐methoxybenzoic acid, 4‐hydroxybenzaldehyde, and 4‐hydroxybenzoic acid. A wide range of N2O SP values (11.9–37.4‰), which was pH dependent and not distinguishable from microbial pathways, was observed at pH 3–5. The δ15Nbulk and δ18O values of N2O were both in a similar range to that reported for fungal denitrification and bacterial denitrification.

Conclusions

These results present the first characterization of the isotopic composition of N2O from chemodenitrification in pure chemical assays. Chemical reactions of nitrite with lignin are pH‐dependent and associated with substantial CO2 and N2O emissions. The SP values of N2O derived from chemodenitrification were neither distinguishable from the biotic pathways nor remained stable with varying pH. Therefore, the use of N2O isotopic signatures for source partitioning is restricted when chemodenitrification is contributing significantly to N2O emission.
Propofol (2,6‐diisopropylphenol) is an applicable immersion anesthetic in the axolotl with potential uses in hemodynamic and neurophysiological experiments
Authors: Thygesen Mathias Møller , Rasmussen Mikkel Mylius , Madsen Jesper Guldsmed , Pedersen Michael , Lauridsen Henrik
Published: May 2017

The Mexican axolotl (Ambystoma mexicanum) is an important model species in regenerative biology. Traditionally, axolotls are anesthetized using benzocaine or MS‐222, both of which act to inhibit voltage gated sodium channels thereby preventing action potential propagation. In some neurophysiological experiments this is not desirable; therefore we tested propofol as an alternative anesthetic in the axolotl. We evaluated benzocaine, MS‐222, and propofol's cardiovascular effects, effects on action potential propagation in the spinal cord, and gross limb regenerative effects. We found that propofol is applicable as a general anesthetic in the axolotl allowing for neurophysiological experiments and yielding a stable anesthesia with significantly less cardiovascular effect than both benzocaine and MS‐222. Additionally, propofol did not affect gross limb regeneration. In conclusion we suggest the consideration of propofol as an alternative immersion anesthetic to benzocaine and MS‐222.
Radiation search operations using scene understanding with autonomous UAV and UGV
Authors: Christie Gordon , Shoemaker Adam , Kochersberger Kevin , Tokekar Pratap , McLean Lance , Leonessa Alexander
Published: May 2017

Autonomously searching for hazardous radiation sources requires the ability of the aerial and ground systems to understand the scene they are scouting. In this paper, we present systems, algorithms, and experiments to perform radiation search using unmanned aerial vehicles (UAV) and unmanned ground vehicles (UGV) by employing semantic scene segmentation. The aerial data are used to identify radiological points of interest, generate an orthophoto along with a digital elevation model (DEM) of the scene, and perform semantic segmentation to assign a category (e.g., road, grass) to each pixel in the orthophoto. We perform semantic segmentation by training a model on a dataset of images we collected and annotated, using the model to perform inference on images of the test area unseen to the model, and then refining the results with the DEM to better reason about category predictions at each pixel. We then use all of these outputs to plan a path for a UGV carrying a LiDAR to map the environment and avoid obstacles not present during the flight, and a radiation detector to collect more precise radiation measurements from the ground. Results of the analysis for each scenario tested favorably. We also note that our approach is general and has the potential to work for a variety of different sensing tasks.
Online covariance estimation for novelty‐based visual obstacle detection
Authors: Ross Patrick , English Andrew , Ball David
Published: May 2017

Robust obstacle detection remains a challenge for mobile robots traversing outdoor field environments. Obstacle detection systems that combine multiple cues can potentially overcome deficiencies in individual cues. A key challenge in designing multi‐sensor obstacle detection systems is to automatically and appropriately combine these cues in an unsupervised manner. This paper presents a method for obstacle detection, which continuously adapts its obstacle definition and the weighting of each cue for the current conditions. The key contribution of this paper is a method for online covariance estimation for Parzen windows probability density estimation, which in this application determines the relative importance of each descriptor dimension. By iteratively estimating the covariance using small subsets of the available data, the proposed method is capable of converging to an approximate solution order of magnitude faster than standard optimizers, making it suitable for use online. The application of this covariance estimation method to our novelty‐based obstacle detection system improves obstacle detection precision and reduces learning duration after environmental transitions. It also removes all environment‐specific parameters from the method, and allows the descriptor to contain arbitrary data without time‐consuming hand‐tuning.
Bias and inference from misspecified mixed‐effect models in stepped wedge trial analysis
Authors: Thompson Jennifer A. , Fielding Katherine L. , Davey Calum , Aiken Alexander M. , Hargreaves James R. , Hayes Richard J.
Published: May 2017

Many stepped wedge trials (SWTs) are analysed by using a mixed‐effect model with a random intercept and fixed effects for the intervention and time periods (referred to here as the standard model). However, it is not known whether this model is robust to misspecification.

We simulated SWTs with three groups of clusters and two time periods; one group received the intervention during the first period and two groups in the second period. We simulated period and intervention effects that were either common‐to‐all or varied‐between clusters. Data were analysed with the standard model or with additional random effects for period effect or intervention effect. In a second simulation study, we explored the weight given to within‐cluster comparisons by simulating a larger intervention effect in the group of the trial that experienced both the control and intervention conditions and applying the three analysis models described previously.

Across 500 simulations, we computed bias and confidence interval coverage of the estimated intervention effect.

We found up to 50% bias in intervention effect estimates when period or intervention effects varied between clusters and were treated as fixed effects in the analysis. All misspecified models showed undercoverage of 95% confidence intervals, particularly the standard model. A large weight was given to within‐cluster comparisons in the standard model.

In the SWTs simulated here, mixed‐effect models were highly sensitive to departures from the model assumptions, which can be explained by the high dependence on within‐cluster comparisons. Trialists should consider including a random effect for time period in their SWT analysis model. © 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.
A Versatile Scanning Photocurrent Mapping System to Characterize Optoelectronic Devices based on 2D Materials
Authors: Reuter Christoph , Frisenda Riccardo , Lin Der‐Yuh , Ko Tsung‐Shine , Perez de Lara David , Castellanos‐Gomez Andres
Published: May 2017

The investigation of optoelectronic devices based on 2D materials and their heterostructures is a very active area of investigation with both fundamental and applied aspects involved. Here, a description of a home‐built scanning photocurrent microscope is presented, which is designed and developed to perform electronic transport and optical measurements of 2D‐materials‐based devices. The complete system is rather inexpensive (<10 000 €) and it can be easily replicated in any laboratory. To illustrate the setup, current–voltage characteristics are measured, in the dark and under global illumination, of an ultrathin p–n junction formed by the stacking of an n‐doped few‐layer MoS2 flake onto a p‐type MoS2 flake. Scanning photocurrent maps are then acquired, and by mapping the short‐circuit current generated in the device under local illumination, it is found that at zero bias, the photocurrent is generated mostly in the region of overlap between the n‐type and p‐type flakes.
Competing‐risks model in screening for pre‐eclampsia in twin pregnancy according to maternal factors and biomarkers at 11–13 weeks' gestation
Authors: Francisco C. , Wright D. , Benkő Z. , Syngelaki A. , Nicolaides K. H.
Published: May 2017

Objective

To develop a model for screening for pre‐eclampsia (PE) in twin pregnancies based on maternal demographic characteristics and medical history and biomarkers at 11–13 weeks' gestation.

Methods

This was a screening study in twin pregnancies at 11–13 weeks' gestation. Bayes theorem was used to combine the a‐priori risk from maternal factors with various combinations of uterine artery pulsatility index (UtA‐PI), mean arterial pressure (MAP), serum pregnancy‐associated plasma protein‐A (PAPP‐A) and placental growth factor (PlGF) multiples of the median (MoM) values. The performance of screening for PE requiring delivery at < 32, < 37 and < 42 weeks' gestation was estimated in 1100 twin pregnancies and 35 948 singleton pregnancies with complete data on UtA‐PI, MAP, PlGF and PAPP‐A.

Results

In twin pregnancies that developed PE, the values of MAP and UtA‐PI were increased and the values of PlGF and PAPP‐A were decreased. The distributions of log10 MoM values of biomarkers with gestational age at delivery were similar to those that were previously reported in singleton pregnancies and it was therefore assumed that the same model could be used for both singleton and twin pregnancies. The performance of screening for PE by maternal factors was improved by the addition of MAP, UtA‐PI and PlGF; there was no further improvement with the addition of PAPP‐A. In a mixed population of singleton and twin pregnancies, combined screening by maternal factors, MAP, UtA‐PI and PlGF and risk cut‐off of 1 in 75 for PE at < 37 weeks, the detection rate of PE at < 32, < 37 and < 42 weeks in singleton pregnancies was 91%, 77% and 57%, respectively, at a screen‐positive rate (SPR) of 13%; the respective rates for twin pregnancies were 100%, 99% and 97%, at a SPR of 75%.

Conclusion

First‐trimester combined screening for PE in singleton pregnancies can be adapted for screening in twins, leading to detection of nearly all affected cases but at a high SPR. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta‐analysis
Authors: Srebniak M. I. , Joosten M. , Knapen M. F. C. M. , Arends L. R. , Polak M. , van Veen S. , Go A. T. J. I. , Van Opstal D.
Published: May 2017

Objective

To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for unbalanced structural chromosomal aberrations, with the aim of determining whether high‐resolution testing for submicroscopic aberrations is beneficial in a general pregnant population.

Methods

EMBASE, PubMed, Web of Science and CENTRAL databases were searched systematically on 3 June 2016 for all relevant articles on the prevalence of pathogenic submicroscopic copy number variants (CNVs) in fetuses referred for prenatal invasive testing because of advanced maternal age (AMA) or parental anxiety (ANX). Relevant full‐text articles were analyzed and the prevalence of submicroscopic CNVs was calculated based on the extracted data. Meta‐analysis was conducted in a pooled cohort of 10 614 fetuses based on the 10 largest studies (n > 300) of a total of 19 that were relevant.

Results

Pooled estimate analysis indicated that 0.84% (95% CI, 0.55–1.30%) of fetuses that had invasive testing because of AMA/ANX carried a pathogenic clinically significant submicroscopic aberration. The onset/penetrance of submicroscopic findings was studied in 10 314 fetuses reported in eight papers that presented aberrant cases with all necessary details to allow assessment of the findings. The pooled estimates resulting from meta‐analysis of the data indicated that an early‐onset syndromic disorder was detected in 0.37% (95% CI, 0.27–0.52%) of cases, a susceptibility CNV was found in 0.30% (95% CI, 0.14–0.67%) and late‐onset diseases were reported in 0.11% (95% CI, 0.05%–0.21%). The prevalence of early‐onset syndromic disorders caused by a submicroscopic aberration was calculated to be 1:270. When the risk for submicroscopic aberrations is added to the individual risk for microscopic chromosomal aberrations, all pregnant women have a risk of higher than 1 in 180 for a relevant chromosomal aberration, and pregnant women under 36 years of age have a higher risk for submicroscopic pathogenic aberrations than for Down syndrome.

Conclusion

This systematic review shows that a significant proportion of fetuses in a general pregnant population carry a submicroscopic pathogenic CNV. Based on these figures, all women should be informed on their individual risk for all pathogenic chromosomal aberrations and not only for common trisomies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Decreased endothelial function and increased subclinical heart failure in women several years after pre‐eclampsia
Authors: Breetveld N. M. , Ghossein‐Doha C. , van Neer J. , Sengers M. J. J. M. , Geerts L. , van Kuijk S. M. J. , van Dijk A. P. , van der Vlugt M. J. , Heidema W. M. , Brunner‐La Rocca H. P. , Scholten R. R. , Spaanderman M. E. A.
Published: May 2017

Objectives

Pre‐eclampsia (PE) is associated with both postpartum endothelial dysfunction and asymptomatic structural heart alterations consistent with heart failure Stage B (HF‐B). In this study, we assessed the relationship between endothelial function, measured by flow‐mediated dilation (FMD), and HF‐B in women with a history of PE.

Methods

This was an observational study in which 67 formerly pre‐eclamptic women (≥ 4 years postpartum) and 37 healthy parous controls were assessed ultrasonographically for cardiac function and geometry, as well as for endothelial function by means of brachial artery FMD. HF‐B was diagnosed as left ventricular hypertrophy (left ventricular mass index (LVMi) > 95 g/m2), concentric remodeling (relative wall thickness > 0.42 and LVMi ≤ 95 g/m2), mild systolic dysfunction (left ventricular ejection fraction > 40% and < 55%) or asymptomatic valvular disease. Cardiovascular and metabolic syndrome variables were compared between women with history of PE and controls, as well as between those in the formerly pre‐eclamptic group who had HF Stage A, HF‐B or no HF. Logistic regression analysis was performed to assess the associations of FMD with PE, metabolic syndrome risk factors and obstetric parameters.

Results

The prevalence of HF‐B amongst formerly pre‐eclamptic women was three‐fold higher than that observed for controls (25% vs 8%, P < 0.05), while FMD was lower in formerly pre‐eclamptic women compared with controls (6.12% vs 8.22%, P < 0.01); history of PE remained associated independently with lower FMD after adjusting for metabolic syndrome risk factors and obstetric parameters (β, –1.88; 95% CI, −3.59 to −0.18). However, HF‐B did not relate to low FMD in formerly pre‐eclamptic women.

Conclusions

Years after pregnancy, formerly pre‐ eclamptic women have lower FMD and have HF‐B more often compared with healthy parous controls. Nonetheless, HF‐B was not related to reduced FMD. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Quantified discordant placental echogenicity in twin anemia–polycythemia sequence (TAPS) and middle cerebral artery peak systolic velocity
Authors: Bamberg C. , Diemert A. , Glosemeyer P. , Hecher K.
Published: May 2017

Objective

To quantify sonographic placental echogenicity in twin anemia–polycythemia sequence (TAPS) and to correlate it with middle cerebral artery peak systolic velocity (MCA‐PSV) measurements.

Methods

We performed a retrospective search for consecutive TAPS cases between 16 and 36 weeks of gestation (MCA‐PSV > 1.5 multiples of the median (MoM) in the anemic donor and < 1.0 MoM in the polycythemic recipient) in our database of monochorionic twin gestations from January 2007 until December 2016. In cases for which ultrasound images showing the donor's and the recipient's part of the placenta were available, echogenicity for both twins was quantified by image processing. MCA‐PSV Doppler values of both fetuses were correlated to their respective placental echogenicity. Placental thickness of both twins was also measured.

Results

Of 756 cases with MCA‐PSV measurements identified from the database, 36 (4.8%) had TAPS; of these, 23 had TAPS combined with twin–twin transfusion syndrome and 13 showed isolated TAPS. Placental echogenicity could be quantified in 28 pregnancies. Mean ± SD placental echogenicity of donor twins was significantly higher than that of recipients (138.7 ± 22.8 vs 77.9 ± 37.0; P < 0.0001). Furthermore, a significant positive correlation was found between placental echogenicity and MCA‐PSV MoM (R = 0.67, P < 0.0001). Mean placental thickness of donor twins (n = 20) was significantly higher than that of recipients (49.3 mm ± 13.4 vs 25.4 mm ± 10.1; P < 0.0001).

Conclusions

Echogenicity of the placental share in recipient and donor twins with TAPS correlates with MCA‐PSV values. Quantification of sonographic placental echogenicity may help to determine the severity of TAPS in monochorionic twins. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
An analysis of the kinetics of molecular response during the first trimester of treatment with nilotinib in newly diagnosed chronic myeloid leukemia patients in chronic phase
Authors: Steegmann Juan Luis , Colomer Dolors , Gómez-Casares Maria-Teresa , García-Gutiérrez Valentín , Ortí Guillermo , Ramírez-Payer Angel , Olavarria Eduardo , Vall-llovera Ferrán , Giraldo Pilar , Conde Eulogio , Vallansot Rolando , López-Lorenzo Jose Luis , Palomera Luis , Álvarez-Larrán Alberto , Conesa Venancio , Bautista Guiomar , Casas Laura , Giles Frank , Hochhaus Andreas , Casado-Montero Luis Felipe
Published: May 2017

Purpose

This study was aimed to analyze the association of very early molecular response to nilotinib with the achievement of deep molecular response (MR4) at 18 months. We hypothesized that the BCR-ABL1 levels during the first 3 months of therapy, and the kinetics of their descent in this period, could be predictive of deep molecular response thereafter.

Methods

This substudy of the ENEST1st trial included 60 patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib, and BCR-ABL1IS levels were measured using GUS as the control gene. The analysis included seven time points during the first trimester of treatment (baseline and fortnightly thereafter).

Results

The rates of MMR at 12 months, and of MR4 at 18 months (primary variable of the study), were 70 and 41%, respectively, similar to those obtained in the core study. BCR-ABL1IS ≤10% was achieved at 1, 1.5, 2 and 3 months in 50, 70, 83 and 93% of the patients, respectively. The observed shape of the BCR-ABL1IS descent was biphasic, with a faster slope during the first trimester and a median halving time (HT) of 11 days, the shortest reported in the literature. An HT ≤13 days was predictive of MMR at 12 months and MR4 at 18 months.

Conclusions

The association of a shorter HT with response provides a rationale for exploring very early kinetics patterns in all patients treated with potent TKIs such as nilotinib.
Damage to the microbial cell membrane during pyrolytic sugar utilization and strategies for increasing resistance
Authors: Jin Tao , Rover Marjorie R , Petersen Elspeth M , Chi Zhanyou , Smith Ryan G , Brown Robert C , Wen Zhiyou , Jarboe Laura R
Published: May 2017

Lignocellulosic biomass is an appealing feedstock for the production of biorenewable fuels and chemicals, and thermochemical processing is a promising method for depolymerizing it into sugars. However, trace compounds in this pyrolytic sugar syrup are inhibitory to microbial biocatalysts. This study demonstrates that hydrophobic inhibitors damage the cell membrane of ethanologenic Escherichia coli KO11+lgk. Adaptive evolution was employed to identify design strategies for improving pyrolytic sugar tolerance and utilization. Characterization of the resulting evolved strain indicates that increased resistance to the membrane-damaging effects of the pyrolytic sugars can be attributed to a glutamine to leucine mutation at position 29 of carbon storage regulator CsrA. This single amino acid change is sufficient for decreasing EPS protein production and increasing membrane integrity when exposed to pyrolytic sugars.
Prevailing-frequency approximation of the coupling ray theory along the SH and SV reference rays in a heterogeneous generally anisotropic medium which is approximately uniaxial
Authors: Bulant Petr , Klimeš Luděk
Published: May 2017

The behaviour of the actual polarization of an electromagnetic wave or elastic S–wave is described by the coupling ray theory, which represents the generalization of both the zero–order isotropic and anisotropic ray theories and provides continuous transition between them. The coupling ray theory is usually applied to anisotropic common reference rays, but it is more accurate if it is applied to reference rays which are closer to the actual wave paths. In a generally anisotropic or bianisotropic medium, the actual wave paths may be approximated by the anisotropic–ray–theory rays if these rays behave reasonably. In an approximately uniaxial (approximately transversely isotropic) anisotropic medium, we can define and trace the SH (ordinary) and SV (extraordinary) reference rays, and use them as reference rays for the prevailing–frequency approximation of the coupling ray theory. In both cases, i.e. for the anisotropic–ray–theory rays or the SH and SV reference rays, we have two sets of reference rays. We thus obtain two arrivals along each reference ray of the first set and have to select the correct one. Analogously, we obtain two arrivals along each reference ray of the second set and have to select the correct one. In this paper, we suggest the way of selecting the correct arrivals. We then demonstrate the accuracy of the resulting prevailing–frequency approximation of the coupling ray theory using elastic S waves along the SH and SV reference rays in four different approximately uniaxial (approximately transversely isotropic) velocity models.
Oral Administration of Ethanolamine Glycerophospholipid Containing a High Level of Plasmalogen Improves Memory Impairment in Amyloid β‐Infused Rats
Authors: Yamashita Shinji , Hashimoto Michio , Haque Abdul Md. , Nakagawa Kiyotaka , Kinoshita Mikio , Shido Osamu , Miyazawa Teruo
Published: May 2017

Ethanolamine plasmalogen (PlsEtn), a major phospholipid in neuronal membranes [60–90 mol% of ethanolamine glycerophospholipid (EtnGpl)], is specifically decreased in brains from patients with Alzheimer's disease (AD). The present study investigated how PlsEtn administration affects cognitive deficits and lipid composition in an animal model of AD. AD model rats were infused with amyloid‐β (Aβ) into the cerebral ventricle and divided into three groups. Control, Egg, and Ascidian groups were then orally administered vehicle, egg yolk EtnGpl (260 μmol as EtnGpl/kg BW/day; 10 μmol as PlsEtn/kg BW/day), or ascidian viscera EtnGpl (260 μmol as EtnGpl/kg BW/day; 209 μmol as PlsEtn/kg BW/day), respectively. After 4 weeks of dosing, Aβ‐infused rats were tested for learning ability in an 8‐arm radial maze. The administration of ascidian viscera EtnGpl improved both reference and working memory‐related learning abilities. In lipid analysis, the Ascidian group showed higher levels of PlsEtn species in the plasma, erythrocytes, and liver when compared to other groups. In addition, although there were no differences at levels of total plasmalogen including choline plasmalogen, the Ascidian group had significantly higher levels of 18:0ol/22:6‐PlsEtn in the cerebral cortex. These levels of 18:0ol/22:6‐PlsEtn in the cerebral cortex were correlated with working memory‐related learning ability. Moreover, 18:0ol/22:6‐PlsEtn levels in the cerebral cortex showed positive correlations with those in the erythrocytes and liver. In summary, dietary PlsEtn, especially that with 22:6n‐3 (docosahexaenoic acid, DHA), may ameliorate learning deficiencies in AD by altering lipid composition in the brain.
Sex-oriented research on dioecious crops of Indian subcontinent: an updated review
Authors: Sarkar Sutanu , Banerjee Joydeep , Gantait Saikat
Published: May 2017

A number of dioecious species are grown across India and some of those plants play a crucial role in the agro-based economy of the country. The diagnosis of sex is very difficult in the dioecious plant prior flowering wherein sex identification at the seedling stage is of great importance to breeders as well as farmers for crop improvement or production purpose. A comprehensive approach of sex determination comprising morphological, biochemical, cytological and molecular attributes is a must required for gender differentiation in dioecious plant species. In the present review, we highlighted the economical, medicinal as well as industrial importance of most of the dioecious species extensively grown in Indian subcontinent. In addition to that, the cytogenetic, genetic as well as molecular information in connection to their sex determination were critically discussed in this review.
Effect of gene order in DNA constructs on gene expression upon integration into plant genome
Authors: Aydın Akbudak M. , Srivastava Vibha
Published: May 2017

Several plant biotechnology applications are based on the expression of multiple genes located on a single transformation vector. The principles of stable expression of foreign genes in plant cells include integration of full-length gene fragments consisting of promoter and transcription terminator sequences, and avoiding converging orientation of the gene transcriptional direction. Therefore, investigators usually generate constructs in which genes are assembled in the same orientation. However, no specific information is available on the effect of the order in which genes should be assembled in the construct to support optimum expression of each gene upon integration in the genome. While many factors, including genomic position and the integration structure, could affect gene expression, the investigators judiciously design DNA constructs to avoid glitches. However, the gene order in a multigene assembly remains an open question. This study addressed the effect of gene order in the DNA construct on gene expression in rice using a simple design of two genes placed in two possible orders with respect to the genomic context. Transgenic rice lines containing green fluorescent protein (GFP) and β-glucuronidase (GUS) genes in two distinct orders were developed by Cre-lox-mediated site-specific integration. Gene expression analysis of transgenic lines showed that both genes were expressed at similar levels in either orientation, and different transgenic lines expressed each gene within 1–2× range. Thus, no significant effect of the gene order on gene expression was found in the transformed rice lines containing precise site-specific integrations and stable gene expression in plant cells could be obtained with altered gene orders. Therefore, gene orientation and integration structures are more important factors governing gene expression than gene orders in the genomic context.
An Evaluation of the Effectiveness of the Australian Army’s Aboriginal Community Assistance Program from a Military Participant Perspective
Authors: Briggs Joanne , Archer F. , Spencer C.
Published: May 2017

Study/Objective

Evaluating the effectiveness of the Army Aboriginal Community Assistance Programs (AACAPs) from a military participant perspective provides the objective of this research. The study will identify areas of concern and provide guidance on current military policy, doctrine and protocol.

Background

Army Aboriginal Community Assistance Programs (AACAPs) represent a co-operative initiative between the Australian Army and Australian Government, that delivers complex support for Disaster Relief and Humanitarian Assistance (HA/DR) to improve the health and well-being of indigenous communities. Since 1997, the Army has conducted a number of AACAPs in remote Indigenous communities within continental Australia. No previous evaluations of these programs exist.

Methods

A ‘Quality Improvement’ study underpins this evaluation. Shewhart’s “Plan, Do, Study, Act” Model provides the guiding framework for the study. Allen’s Logic Model exemplifies the most appropriate framework to articulate the program needs and objectives, and to delineate the processes inherent in the program for this evaluation. The Center for Disease Control (CDC) evaluation model for public health programs, provides the evaluation standards to examine the delivery of health care to the deployed force in an austere environment. Part 1 of the study will be a desktop examination of current military policy, doctrine and protocol relating to AACAP. Part 2 will overlay personal experience from military participants in the AACAPs through a semi-structured interview, to enable deployed health personnel the opportunity to comment on their experiences. Analysis will comprise quantitative and qualitative method, specifically descriptive statistics and thematic analysis respectively. Army has approved all required governance, and ethics approval will be sought from Monash University.

Results

This is a proposed study, no results are available.

Conclusion

The benefit of this research will be gaining new knowledge with context of a humanitarian focused military task, through the lens of quality improvement to build capacity and enhance capability.
Kompetenzorientierte Psychiatrische Pflege
Authors: König Nadine , Schädle-Deininger Hilde
Published: May 2017

Zusammenfassung. Die Orientierung der Psychiatrischen Pflege an Kompetenzen, Fähigkeiten, Fertigkeiten und Ressourcen von psychisch erkrankten Menschen ist nichts Neues. Dies jedoch konsequent zur Grundlage des alltäglichen Handelns unter partnerschaftlichen Beteiligung von Betroffenen zu machen, erfordert theoretische Verknüpfungen und individuelle Lösungen.
Selbstvernachlässigung bei alten Menschen
Authors: Buneta Thomas
Published: May 2017

Zusammenfassung. Glückwunsch, Frau Gogl! Herzlichen Dank für Ihren wertvollen Beitrag zu einem Thema, das Pflegende wohl eher nicht lieben. Clever, akribisch, vorausschauend und vor allem leidenschaftlich sind Sie ans Werk gegangen. Selten habe ich mich in einem Buch so wohl gefühlt. Ehrlich gesagt, scheute ich mich vor dem Lese-Auftakt. Bei meinen Erfahrungen mit Selbstvernachlässigung im Beruf bekam ich schon vor der ersten Seite Juckreiz.
Does Perfectionism Predict Depression, Anxiety, Stress, and Life	Satisfaction After Controlling for Neuroticism?
Authors: Smith Martin M. , Saklofske Donald H. , Yan Gonggu , Sherry Simon B.
Published: May 2017

Abstract. Neuroticism overlaps substantially with several perfectionism dimensions, depression, anxiety, stress, and life satisfaction. Accordingly, research testing whether perfectionism dimensions explain unique variance in these outcomes beyond neuroticism is needed. Research on cultural differences in perfectionism is also scarce. And it is especially unclear whether the link between perfectionism and psychological distress differs across individualistic and collectivistic cultures. Our study addressed these important gaps in knowledge. A sample of undergraduates from a traditionally individualistic culture (Canada; N = 449) and a traditionally collectivistic culture (China; N = 585) completed measures of self-oriented perfectionism, personal standards, socially prescribed perfectionism, concern over mistakes, doubts about actions, depression, anxiety, stress, and satisfaction with life. To test the incremental validity of perfectionism dimensions beyond neuroticism, as well as to test potential moderating effects of culture, four hierarchical regression analyses with interactions were conducted. Results supported the explanatory power of concern over mistakes and doubts about actions, beyond neuroticism and culture, in the prediction of depression, anxiety, and stress. As the first study to explore the incremental validity of perfectionism dimensions across undergraduates from traditionally individualistic and collectivistic cultures, our research both extends and clarifies understanding of the predictive power of perfectionism in important ways.
Antenna Towers Attract Additional Lightning Strikes
Authors: Witman Sarah
Published: May 2017

Atmospheric scientists evaluate the influence of human-made structures on lightning data.
Scientists Predict Active Hurricane Season
Authors: Wendel JoAnna
Published: May 2017

A combination of warm sea surface temperatures and a weak or absent El Niño may create conditions conducive to tropical storm formation.
CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion
Authors: Shing Jennifer C , Lindquist Lonn D , Borgese Nica , Bram Richard J
Published: May 2017

Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions, along with WRB and TRC40, to mediate tail-anchored (TA) protein insertion into the ER membrane. Physiologic roles for CAML include endocytic trafficking, intracellular calcium signaling, and the survival and proliferation of specialized immune cells, recently attributed to its requirement for TA protein insertion. To identify a possible role for CAML in cancer cells, we generated Eμ-Myc transgenic mice that carry a tamoxifen-inducible deletion allele of Caml. In multiple B-cell lymphoma cell lines derived from these mice, homozygous loss of Caml activated apoptosis. Cell death was blocked by Bcl-2/Bcl-xL overexpression; however, rescue from apoptosis was insufficient to restore proliferation. Tumors established from an Eμ-Myc lymphoma cell line completely regressed after tamoxifen administration, suggesting that CAML is also required for these cancer cells to survive and grow in vivo. Cell cycle analyses of Caml-deleted lymphoma cells revealed an arrest in G2/M, accompanied by low expression of the mitotic marker, phospho-histone H3 (Ser10). Surprisingly, lymphoma cell viability did not depend on the domain of CAML required for its interaction with TRC40. Furthermore, a small protein fragment consisting of the C-terminal 111 amino acid residues of CAML, encompassing the WRB-binding domain, was sufficient to rescue growth and survival of Caml-deleted lymphoma cells. Critically, this minimal region of CAML did not restore TA protein insertion in knockout cells. Taken together, these data reveal an essential role for CAML in supporting survival and mitotic progression in Myc-driven lymphomas that is independent of its TA protein insertion function.
The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling
Authors: Nappo G , Handle F , Santer F R , McNeill R V , Seed R I , Collins A T , Morrone G , Culig Z , Maitland N J , Erb H H H
Published: May 2017

Interleukin-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumour microenvironment of cancer patients, where concentrations correlate with the grade of malignancy. In prostate cancer, interleukin-4 has been associated with activation of the androgen receptor, increased proliferation and activation of survival pathways such as Akt and NF-κB. However, its role in therapy resistance has not yet been determined. Here we investigate the influence of interleukin-4 on primary epithelial cells from prostate cancer patients. Our data demonstrate an increase in the clonogenic potential of these cells when cultured in the presence of interleukin-4. In addition, a Phospho-Kinase Array revealed that in contrast to previously published work, signal transducer and activator of transcription6 (STAT6) is the only signalling molecule activated after interleukin-4 treatment. Using the STAT6-specific inhibitor AS1517499 we could confirm the role of STAT6 in increasing colony-forming frequency. However, clonogenic recovery assays revealed that interleukin-4 does not rescue the effects of either irradiation or docetaxel treatment. We therefore propose that although the interleukin-4/STAT6 axis does not appear to be involved in therapy resistance, it does play a crucial role in the colony-forming abilities of the basal cell population in prostate cancer. IL-4 may therefore contribute to disease relapse by providing a niche that is favourable for the clonogenic growth of prostate cancer stem cells.
Clinical responses to ERK inhibition in BRAF
V600E-mutant colorectal cancer predicted using a computational model
Authors: Kirouac Daniel C. , Schaefer Gabriele , Chan Jocelyn , Merchant Mark , Orr Christine , Huang Shih-Min A. , Moffat John , Liu Lichuan , Gadkar Kapil , Ramanujan Saroja
Published: May 2017

Approximately 10% of colorectal cancers harbor BRAFV600E mutations, which constitutively activate the MAPK signaling pathway. We sought to determine whether ERK inhibitor (GDC-0994)-containing regimens may be of clinical benefit to these patients based on data from in vitro (cell line) and in vivo (cell- and patient-derived xenograft) studies of cetuximab (EGFR), vemurafenib (BRAF), cobimetinib (MEK), and GDC-0994 (ERK) combinations. Preclinical data was used to develop a mechanism-based computational model linking cell surface receptor (EGFR) activation, the MAPK signaling pathway, and tumor growth. Clinical predictions of anti-tumor activity were enabled by the use of tumor response data from three Phase 1 clinical trials testing combinations of EGFR, BRAF, and MEK inhibitors. Simulated responses to GDC-0994 monotherapy (overall response rate = 17%) accurately predicted results from a Phase 1 clinical trial regarding the number of responding patients (2/18) and the distribution of tumor size changes (“waterfall plot”). Prospective simulations were then used to evaluate potential drug combinations and predictive biomarkers for increasing responsiveness to MEK/ERK inhibitors in these patients.
Structural and physicochemical characterization of sulfonylhydrazone derivatives designed as hypoglycemic agents
Authors: Ibiapino Amanda L. , de Figueiredo Laysa P. , Lima Lídia M. , Barreiro Eliezer J. , Punzo Francesco , Ferreira Fabio F.
Published: May 2017

By solving and refining the structures of two APIs a complete experimental andin silicophysico-chemical characterization was carried out.