bluuebunny/crossref_metadata_2025 huggingface dataset:
O22 3D printed polyethylene oxide oral doses with innovative ‘radiator-like’ design: impact of molecular weight on mechanical and rheological properties and drug release
Authors: Peak M , Baj K , Isreb A , Wojsz M , Mohammad I , Albed Alhnan M
Published: May 2019

Background

Despite regulatory advances, lack of age-appropriate formulations (AAFs) remains a challenge in paediatric practice. 3D-printing of oral dosage forms (ODFs) offers potential for AAFs for children. Optimising drug release from 3D-printed ODFs is an important technological step. Despite the abundant use of polyethylene oxides (PEOs) and their extensive use as an excipient, there have been no previous reports of applying this thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. We assessed the impact of polymer molecular weight (MW) on the mechanical properties of the resultant filaments and their rheological properties. In the FDM 3D printing process, we also tested the effect of an innovative radiator-like design of the ODF on the acceleration of drug release patterns.

Methods

Blends of PEO (MW: 100K, 200K, 300K, 600K or 900K) with PEG 6K (plasticiser) and a model drug (theophylline) were prepared by hot-melt extrusion. The resultant filaments were used as a feed for a FDM 3D printer to fabricate innovative designs of ODFs in a radiator-like geometry with inter-connected paralleled plates and inter-plate spacing of either 0.5mm, 1mm, 1.5mm or 2mm.

Results

Varying blends of PEO and PEG allowed formation of mechanically resistant filaments (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with 100K, 200K, 300K, 600K or 900K, respectively). Filaments of PEO at a MW of 200K-600K were compatible with FDM 3D printing. Further increase in PEO MW resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing. A minimum spacing (1 mm) between parallel plates of the radiator-like design was essential to boost drug release from the structure.

Conclusion

These findings are essential in the development of next-generation personalised drug delivery doses using specialised polymer/polymer blends purposely optimised for FDM 3D printing.

Disclosure(s)

Nothing to disclose
O33 Towards personalised weaning of sedatives and analgesics using mechanism-based modelling of iatrogenic withdrawal in critically ill children
Authors: Goulooze S , Krekels E , van Dijk M , Hankemeier T , Tibboel D , Ista E , Knibbe C
Published: May 2019

Background

Prolonged treatment with analgesics and sedatives can result in iatrogenic withdrawal syndrome (IWS) in children being weaned from these drugs.1Personalized weaning strategies might lower the incidence of IWS, but this requires a quantitative understanding of withdrawal over time in individual patients.

Methods

Data from 81 children (aged 1 month to 17 years) collected during an observational clinical study on IWS2 were used, including a total of 1782 withdrawal assessments performed by PICU nurses, on a numerical rating scale (NRSwithdrawal) from 0 (no withdrawal) to 10 (worst withdrawal possible). Population pharmacokinetic models from literature were used to generate concentration-time profiles in each patient of all key analgesics and sedatives: morphine, fentanyl, methadone, midazolam, lorazepam, propofol, esketamine and clonidine. A mechanism-based withdrawal model was developed using NONMEM 7.3 to quantify IWS over time. The final model was used to perform simulations in which different weaning strategies were compared.

Results

A novel mechanism-based withdrawal model structure was developed with a hypothetical compartment, which equilibrates with the central pharmacokinetic compartment, and which characterizes the development and disappearance of drug dependence over time. With this model and available data, withdrawal dynamics could be established with statistical significance for fentanyl (p< 10-6), morphine (p=0.043) and esketamine (p=0.002), and not for any of the other drugs. Compared with fentanyl, development and disappearance of esketamine and morphine dependence is slower.

Conclusions

Given the patient‘s use of fentanyl, morphine and esketamine, the developed model can dynamically predict IWS from these substances under different weaning strategies. The results show that the optimal strategy for weaning of drug dependent children depends on both the type of drug and the drug levels prior to weaning. In this study, there was insufficient information to characterise midazolam withdrawal dynamics, potentially because of slow midazolam weaning with insufficiently high NRSwithdrawal scores.

References

Best KM, Boullata JI, Curley MAQ. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: A Systematic Review and Conceptual Model. Pediatr Crit Care Med ( 2015) 16(2): 175–183.

Ista E, de Hoog M, Tibboel D, Duivenvoorden HJ, van Dijk M. Psychometric evaluation of the sophia observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med ( 2013).14(8): 761–769.

Disclosure(s)

Nothing to disclose
P32 Depiction of haematological and biochemical laboratory normal reference values in a European multicentre paediatric trial
Authors: Farahani S , Feles E , Burckhardt BB , Laeer S ,   on behalf of the LENA consortium
Published: May 2019

Background

The European multicentre paediatric trials for the drug development programme of LENA (FP7 Grant agreement No. 602295); ‘Labeling of Enalapril from Neonates up to Adolescents’ require the determination of laboratory safety parameters. It was anticipated that the laboratory normal reference values and age range classifications vary depending on the clinical site. Thus, the objective was a seamless and clear depiction of the laboratory parameters to allow an adequate subsequent analysis of data.

Methods

Fourteen haematological and biochemical safety parameters plus the biomarker N-terminal pro-brain natriuretic peptide were considered. The laboratory normal reference values received from eight clinical sites were screened on data gaps, uncertainties, misclassifications and overlap of age range classifications. These aspects were revised. If further data were necessary for clarification the responsible person of the respective laboratory was contacted by email or telephone.

Results

Data gaps and uncertainties of the laboratory normal reference values such as missing data for one sex, missing data for an age range classification, missing data for a parameter or overlap of age range classification were identified. All issues were solved by communication with the sites. Each laboratory parameter was categorized in between 1 and 23 age range classifications between an age from birth to 4744 days depending on the classification of the clinical site. Furthermore, up to 4 various units were recorded per laboratory parameter and subsequently harmonised into one unit.

Conclusion

The developed seamless depiction of the laboratory parameters will allow the assessment and classification of the paediatric trial data and are essential for the adequate subsequent analysis.

Disclosure(s)

Samieh Farahani, Elisabeth Feles, Bjoern B. Burckhardt, Stephanie Laeer declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grand agreement n°602295 (LENA)
P34 Reliable results in continuous bioanalysis of paediatric renin samples – comprehensive quality assessment within clinical studies in children
Authors: Feickert M , Burdman I , Makowski N , Ali M , Farahani S , Majid H , Ciplea AM , Bartel A , Burckhardt BB
Published: May 2019

Background

As the initiator of the Renin-Angiotensin-Aldosterone-system, renin plays an essential role in the vicious circle of heart failure. Therefore, renin was determined in the investigators driven ‘Labelling of Enalapril from neonates up to adolescents’ (LENA) study to evaluate its role in paediatric heart failure. Due to the often long-lasting periods of recruitment of paediatric subjects, the assay performance has to be guaranteed over the whole recruiting time. Therefore, to ensure the high quality of the determined renin study samples after successful assay validation,1 a multi-step quality approach was used to get reliable results over a period of 30 months.

Methods

Based on a multi-step quality approach consisting of calibration standards (CSs), quality controls (QCs) and incurred sample reanalysis (ISR), study samples of unknown renin concentrations were determined. Results within predefined limits of CSs (6 levels) and QCs according to European Medicine Agency (EMA) guidelines were required for evaluating the study samples.2 ISR was performed for randomly selected paediatric samples to evaluate the long-term accuracy of the validated assay.

Results

133 analytical runs were conducted for renin from February 2016 to August 2018. In 119 (88.8%) valid runs, a total number of 1414 of CCs and 952 of QCs were determined. Thereof 99.9% of CCs and 98.3% of QCs were in the predefined limits according to EMA. 143 incurred sample pairs were reanalysed resulting in 95.8% of samples within EMA guidelines. Using this multi-step quality approach, the reliable determination of 965 LENA paediatric study samples was guaranteed.

Conclusion

In addition to the assay validation, the multi-step quality approach ensured the reliability of the determined renin concentrations in the continuous bioanalysis of the paediatric study samples and guaranteed the high quality of the collected data in the LENA study.

References

Schaefer J, Burckhardt BB, Tins J, et al. Validated low-volume immunoassay for the reliable determination of direct renin especially valuable for pediatric investigations. J Immunoass Immunochem 2017;38:579–94. doi:10.1080/15321819.2017.1350707

Guideline on bioanalytical method validation. European Medicines Agency, London, UK (2011).

Disclosure(s)

Martin Feickert, Ilja Burdman, Nina Makowski, Moshin Ali, Anke Bartel, and Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)
P42 External validation of model-based dosing guidelines for vancomycin, gentamicin and tobramycin in critically ill children
Authors: Hartman S , Zwaag S , Orriëns L , Poel T , de Hoop - Sommen M , de Wildt S
Published: May 2019

Background

Pharmacokinetic models are frequently used to simulate dosing strategies for special populations, including critically ill children. The Dutch Pediatric Formulary (DPF) partially bases its guidelines on these models. However, prospective validation of updated dosing regimens is rare. We aimed to identify target attainment and safety of vancomycin, gentamicin and tobramycin after a dose update in the DPF for critically ill neonates and children.

Methods

Retropsective cohort study in PICU and NICU patients receiving vancomycin, gentamicin or tobramycin between January 2015 and March 2017 in 2 university hospitals. Demographic clinical laboratory and TDM-data were collected. Target (steady state) trough concentrations for vancomycin, gentamicin and tobramycin used were 10–15, ≤1 and ≤1 mg/l, respectively. Target gentamicin peak concentrations used were 8–12 mg/l.

Results

486 patients were included in total (165 vancomycin, 97 gentamicin and 224 tobramycin). Trough concentrations of vancomycin, gentamicin and tobramycin were within the target range in 37.5%, 85.3% and 77.2% of patients, respectively. Target attainment of gentamicin peak concentrations in NICU patients was 31%. Non-target trough concentrations were most prevalent in term NICU patients (vancomycin 70%, gentamicin 26% and tobramycin 36.8%). Gentamicin peak concentrations were subtherapeutic in 91% and 45.5% for term and preterm NICU patients, respectively. Creatinine concentrations correlated positively with antibiotic concentrations (correlation coefficient range 0.46–0.54, p≤0.01 in all cohorts).

Conclusion

Despite recent model-based dosing alterations, sub- and supratherapeutic concentrations of vancomycin, gentamicin and tobramycin are still frequent in critically ill children. Linear dose alterations did offer improvements in target attainment, but did not fully address all relevant covariates that contribute to the large interindividual variation in clearance and/or volume of distribution in these patients. Creatinine clearance was consistently correlated with concentrations of all 3 drugs, but future research is needed to identify whether including this parameter in dosing can improve target attainment and safety.

Disclosure(s)

Nothing to disclose
P52 Low and erratic exposure of oral acetaminophen in critically ill children determined with a 14C microtracer study: a case for IV acetaminophen for acute pain management?
Authors: Kleiber N , Calvier E , Mooij MG , Krekels EHJ , Vaes WH , Windhorst AD , Hendrikse H , Tibboel D , Knibbe CAJ , de Wildt SN
Published: May 2019

Background

Despite being the most commonly used analgesic and antipyretic, oral APAP bioavailability has not been determined in children.

The aim of this study is to compare exposure after oral vs iv APAP using the PK data of the first pediatric oral bioavailability 14C microtracer study.

Methods

Design

bioavailability microtracer population PK study

Participants

patients < 6 yrs old in the pediatric ICU who received 15 mg/kg iv APAP q6h

Intervention

a single microdose of 14CAPAP (3µg/kg) given orally at the same time as a therapeutic iv dose

Data collection

Blood was sampled 8 times up to 24 h post-dose

Data analysis

population PK analysis using NONMEM. Based on the model, exposure after oral vs iv was compared by simulating the concentration-time profiles and Css (targeted: 10 mg/L ± 20% deviation).

3 doses were simulated: 15 mg/kg q6h oral and iv and 22.5 mg/kg oral q6h. 1000 simulations were performed and the percentage of patients reaching the targeted mean Css of 10 mg/L±20% were compared.

Results

Oral bioavailibity was 72% (range:11–91%). After 15 mg/kg APAP, the median simulated oral Css was subtherapeutic (6.5 mg/L), but therapeutic (10 mg/L) for IV dosing (15 mg/kg). Patients were 2.5 times less likely to reach therapeutic plasma concentrations with 15 mg/kg oral vs iv APAP.

With the maximal recommended oral doses of 22.5 mg/kg 6 h aimed to overcome the 72% bioavailability, median mean Css were therapeutic but overexposure and underexposure were more common than with iv (37 vs 32% Css< 8 mg/L and 30 vs 21% Css>12 mg/L).

Conclusion

Compared to IV, the usual (15 mg/kg) oral APAP doses result in low systemic exposure with subsequent risk of therapeutic failure. When oral doses are increased to overcome the low bioavailability, underdosing still occurs and overdosing was observed in patients with high bioavailability. IV APAP should therefore be preferred for acute pain management.

Disclosure(s)

Nothing to disclose
First-dose idarubicin cardiomyopathy: a case of new heart failure after induction chemotherapy for acute myeloid leukaemia
Authors: Ahmed Zarir , Davaro Elizabeth , Batanian Jacqueline , Verma Nilesh
Published: May 2019

Anthracyclines are an effective chemotherapy agent. However, very few cases of idarubicin-induced cardiomyopathy exist. Herein, we describe a case of first-dose idarubicin-related acute heart failure in a woman with a history of myelodysplastic syndrome converted to acute myeloid leukaemia.
Effect of an integrated neonatal care kit on neonatal health outcomes: a cluster randomised controlled trial in rural Pakistan
Authors: Pell Lisa G , Turab Ali , Bassani Diego G , Shi Joy , Soofi Sajid , Hussain Masawar , Ariff Shabina , Bhutta Zulfiqar A , Morris Shaun K
Published: May 2019

Introduction

In 2016, 2.6 million children died during their first month of life. We assessed the effectiveness of an integrated neonatal care kit (iNCK) on neonatal survival and other health outcomes in rural Pakistan.

Methods

We conducted a community-based, cluster randomised, pragmatic, open-label, controlled intervention trial in Rahim Yar Khan, Punjab, Pakistan. Clusters, 150 villages and their lady health workers (LHWs), were randomly assigned to deliver the iNCK (intervention) or standard of care (control). In intervention clusters, LHWs delivered the iNCK and education on its use to pregnant women. The iNCK contained a clean birth kit, chlorhexidine, sunflower oil, a continuous temperature monitor (ThermoSpot), a heat reflective blanket and reusable heat pack. LHWs were also given a hand-held scale. The iNCK was implemented primarily by caregivers. The primary outcome was all-cause neonatal mortality. Outcomes are reported at the individual level, adjusted for cluster allocation. Enrolment took place between April 2014 and July 2015 and participant follow-up concluded in August 2015.

Results

5451 pregnant women (2663 and 2788 in intervention and control arms, respectively) and their 5286 liveborn newborns (2585 and 2701 in intervention and control arms, respectively) were enrolled. 147 newborn deaths were reported, 65 in the intervention arm (25.4 per 1000 live births) compared with 82 in the control arm (30.6 per 1000 live births). Neonatal mortality was not significantly different between treatment groups (risk ratio 0.83, 95% CI 0.58 – 1.18; p = 0.30).

Conclusion

Providing co-packaged interventions directly to women did not significantly reduce neonatal mortality. Further research is needed to improve compliance with intended iNCK use.
Management of an outbreak of multiple equine herpesvirus type 1 abortions among vaccinated mares on a large UK Thoroughbred stud farm
Authors: Moore Sarah E , Strang Camilla L , Marr Celia M , Newton Richard , Cameron Ian J
Published: May 2019

An outbreak of equine herpesvirus type 1 (EHV‐1) abortions on a UK Thoroughbred stud farm between February 23 and April 2, 2016, is described. The outbreak resulted in the loss of 10 Thoroughbred foals, confirmed pathologically and virologically as EHV‐1 infection at postmortem. All aborting mares were vaccinated against EHV‐1 according to manufacturer’s recommendations, but had contact with the index aborting mare, either as field companions or housed in the American barn at the time she and subsequent mares aborted. Control measures were implemented in accordance with the Thoroughbred Industry’s Code of Practice on recognising the index case and were maintained until the outbreak had resolved. The report illustrates that prompt investigation and management of this disease outbreak can optimise the safe return of the stud farm to normal breeding operations and highlights EHV‐1’s continued potential for multiple late gestation pregnancy losses in mares, despite vaccination.
Dynamic response of pile groups subjected to horizontal loads
Authors: Luan Lubao , Ding Xuanming , Zheng Changjie , Kouretzis George , Wu Qi
Published: May 2019

This paper presents an analytical method for calculating the dynamic impedance of pile groups comprising an arbitrary number of cylindrical piles connected with a rigid cap. The solution allows consideration of ground waves due to pile vibration that propagate along both the horizontal and vertical planes, as well as the effect of the actual pile section geometry on the reaction from the surrounding soil. For that, we introduce a dynamic pile–soil–pile interaction factor that is defined on the basis of soil reaction developing on receiver piles, instead of the classical displacement-based interaction factor used in past studies. Despite the fact that the solution is applicable to problems where low-to-moderate soil strains are expected to develop, it poses as an attractive, efficient alternative to numerical methods for the analysis of very large pile groups.
Density, snow, and seasonality lead to variation in muskox (Ovibos moschatus) habitat selection during summer
Authors: Tomassini Orlando , van Beest Floris M. , Schmidt Niels M.
Published: May 2019

Understanding how environmental conditions influence habitat selection and suitability of free-ranging animals is critical, as the outcome may have implications for individual fitness and population dynamics. Density and snow are among the most influential environmental conditions driving habitat-selection patterns of northern ungulates. We used two decades of census data from high Arctic Greenland to quantify inter- and intra-annual variations in muskox (Ovibos moschatus (Zimmermann, 1780)) habitat selection and suitability during the Arctic summer (July through October). Across years, habitat selection varied considerably, and the strength of habitat selection appeared negatively related to both muskox density and spring snow cover. In early summer, habitat suitability was high and spatially rather uniform. Towards the autumn, suitable habitats contracted to just the lower elevations, when muskoxen exhibited increasingly stronger habitat selection towards low elevations and dense vegetation. This selection strategy clearly reflects the need to build up fat reserves for the upcoming winter, highlighting the energetic importance of the Arctic summer. Extreme climatic events such as freezing rain in autumn are increasing in frequency in Greenland and limit muskox access to high-quality forage in fens. Such events may therefore negatively affect the energy acquisition process of muskox with potential cascading consequences on population dynamics.
An effective similarity measure based on kernel spectral method for complex networks
Authors: Li Longjie , Wang Lu , Bai Shenshen , Fang Shiyu , Cheng Jianjun , Chen Xiaoyun
Published: May 2019

Node similarity measure is a special important task in complex network analysis and plays a critical role in a multitude of applications, such as link prediction, community detection, and recommender systems. In this study, we are interested in link-based similarity measures, which only concern the structural information of networks when estimating node similarity. A new algorithm is proposed by adopting the idea of kernel spectral method to quantify the similarity of nodes. When computing the kernel matrix, the proposed algorithm makes use of local structural information, but it takes advantage of global information when constructing the feature matrix. Thence, the proposed algorithm could better capture potential relationships between nodes. To show the superiority of our algorithm over others, we conduct experiments on 10 real-world networks. Experimental results demonstrate that our algorithm yields more reasonable results and better performance of accuracy than baselines.
Coevolution of synchronization and cooperation in real networks
Authors: Zhou Mingyang , Li Xiaoyu , Xiong Wenman , Liao Hao
Published: May 2019

As game theory thrives in networked interactions, we usually neglect the cost of information exchange between involved individuals. Individuals may decide (or refuse) to follow the state of their neighbors, which depends on the cost of the interactions. The payoff of a node’s behavior is associated with the state difference between the node and its neighbors. Here, based on Kuramoto model, we investigate the collective behavior of different individuals in the game theory and the synchronization byproduct that is induced by the cooperation of connected nodes. Specially, we investigate the influence of network structure on the coevolutionary progress of cooperation and synchronization. We find that the networks with the higher average degree are more likely to reach synchronization in real networks. Strong synchronization is a sufficient, but not necessary condition to guarantee the cooperation. Besides, we show that synchronization is largely influenced by the average degree in both Erdös–Rényi (ER) and Barabási–Albert (BA) networks, which is also illustrated by theoretical analysis.
Analyzing the driving and dragging force in China’s inter-provincial migration flows
Authors: Li Xiaomeng , Huang Siyu , Chen Qinghua
Published: May 2019

In China, the evolution of inter-provincial migration patterns is from policy orientation to individual selection and hotspot attraction during 1950–2010. These years, China’s abundant regional labor flow brings prosperity to several famous high-growth regions, but also causes the problem of unbalanced development. It needs systematic analysis to do effective guidance and management of population mobility. This paper tries to analyze the driving and dragging force in China’s inter-provincial migration flows with improved multilateral migration model stemming from individual behavior of potential migrants. It revealed the problem of imbalanced regional labor flow has been exacerbated in China since the 1990s, and the driving force for typical hotspots is different, as high income force for Beijing, Shanghai, and low barrier for Guangzhou, Zhejiang. The results of analyzing indicates the the distinct regional mobility barriers help to alleviate the problem of labor loss in some provinces since 1980s, but the regional imbalance in population migration continues to grow in recent years. Finally, with regression, we reveal the essential element affecting regional mobility barriers, and it could explain 70.8% of the influence factors. It also suggests that, for the provinces with labor loss, improving economic, welfare environment will mitigate the problem effectively.
Fisetin Inhibits Cell Proliferation through the Induction of G0/G1 Phase Arrest and Caspase-3-Mediated Apoptosis in Mouse Leukemia Cells
Authors: Tsai Yu-Hsiang , Lin Jen-Jyh , Ma Yi-Shih , Peng Shu-Fen , Huang An-Cheng , Huang Yi-Ping , Fan Ming-Jen , Lien Jin-Cherng , Chung Jing-Gung
Published: May 2019

Fisetin, a naturally occurring flavonoid, is found in common fruits and vegetables and has been shown to induce cytotoxic effects in many human cancer cell lines. No information has shown that fisetin induced cell cycle arrest and apoptosis in mouse leukemia WEHI-3 cells. We found that fisetin decreased total viable cells through G0/G1 phase arrest and induced sub-G1 phase (apoptosis). We have confirmed fisetin induced cell apoptosis by the formation of DNA fragmentation and induction of apoptotic cell death. Results indicated that fisetin induced intracellular Ca[Formula: see text] increase but decreased the ROS production and the levels of [Formula: see text]m in WEHI-3 cells. Fisetin increased the activities of caspase-3, -8 and -9. Cells were pre-treated with inhibitors of caspase-3, -8 and -9 and then treated with fisetin and results showed increased viable cell number when compared to fisetin treated only. Fisetin reduced expressions of cdc25a but increased p-p53, Chk1, p21 and p27 that may lead to G0/G1 phase arrest. Fisetin inhibited anti-apoptotic protein Bcl-2 and Bcl-xL and increased pro-apoptotic protein Bax and Bak. Furthermore, fisetin increased the protein expression of cytochrome c and AIF. Fisetin decreased cell number through G0/G1 phase arrest via the inhibition of cdc25c and induction of apoptosis through caspase-dependent and mitochondria-dependent pathways. Therefore, fisetin may be useful as a potential therapeutic agent for leukemia.
Amentoflavone Effectively Blocked the Tumor Progression of Glioblastoma via Suppression of ERK/NF-κB Signaling Pathway
Authors: Hsu Fei-Ting , Chiang I-Tsang , Kuo Yu-Cheng , Hsia Te-Chun , Lin Chin-Chung , Liu Yu-Chang , Chung Jing-Gung
Published: May 2019

Glioblastoma is the most common primary malignant tumor of the central nervous system, with an annual incidence of 5.26 per 100000 people. The clinical outcome of standard therapy and the survival rate remain poor; therefore, there is an unmet need for a new strategy to treat this lethal disease. Although amentoflavone was known to have anticancer potential in various types of cancers, its antiglioblastoma ability and mechanism remain unrecognized. We demonstrated that amentoflavone may suppress glioblastoma invasion and migration by transwell assay. Moreover, we established NF-[Formula: see text]B reporter gene system and used that for verifying NF-[Formula: see text]B inhibition efficacy of amentoflavone on in vitro and in vivo studies. Here, we indicated that amentoflavone not only diminished NF-[Formula: see text]B activation, but also reduced NF-[Formula: see text]B-mediated downstream oncogenes expression, such as MMP-2, MMP-9, XIAP, cyclinD1 and VEGF, which was elucidated by Western blot and immunohistochemistry (IHC). Tumor growth inhibition and NF-[Formula: see text]B reduction was found in the amentoflavone treatment group, which was revealed by the glioblastoma-bearing animal model. In this study, we also used ERK inhibitor and NF-[Formula: see text]B inhibitor (QNZ) to confirm whether the beneficial result of amentoflavone on glioblastoma was mainly regulated by blockage of ERK/NF-[Formula: see text]B signaling. In summary, ERK/NF-[Formula: see text]B signaling pathway has a role in the inhibition of tumor growth by amentoflavone in glioblastoma.
Binding energies and photoionization cross-sections of donor and acceptor impurities in inverted core/shell ellipsoidal quantum dots: Effects of magnetic field, ellipsoid anisotropy and impurity position
Authors: Shi Lei , Yan Zu-Wei
Published: May 2019

Within the framework of the effective-mass approximation and by using a variational and perturbation approach, the binding energies and photoionization cross-sections of donor and acceptor impurities in an inverted core/shell ellipsoidal spherical quantum dot under an applied magnetic field have been studied. We have calculated the binding energies of both donor and acceptor impurities as a function of the core and shell sizes and shapes with different impurity positions under the applied magnetic field. In addition, the corresponding photoionization cross-section is calculated. Our results show that the binding energy of the acceptor impurity is larger than that of the donor impurity, and both of them with different impurity positions and quantum ellipsoid anisotropies will exhibit a nonmonotonic change. The peak value of the photoionization cross-section will reach a maximum with the increasing ratio R1/R2. It is found that the applied magnetic field can be an effective means of enhancing the photoionization cross-section of an impurity state in such core/shell quantum dot system.
Classification of Fashion Article Images Based on Improved Random Forest and VGG-IE Algorithm
Authors: Liu Jian , Zheng Yuchen , Dong Ke , Yu Haitong , Zhou Jianjun , Jiang Ye , Jiang Zhaoneng , Guo Sujie , Ding Rui
Published: May 2019

In classification of fashion article images based on e-commerce image recommendation system, the classification accuracy and computation time cannot meet the actual requirements. Herein, for the first time to our knowledge, we present two diverse image recognition approaches for classification of fashion article images called random-forest method based on genetic algorithm (GA-RF) and Visual Geometry Group-Image Enhancement algorithm (VGG-IE) to solve classification accuracy and computation time problem. In GA-RF, the number of segmentation times and the decision trees are the key factors affecting the classification results. Improved genetic algorithm is introduced into the parameter optimization of forests to determine the optimal combination of the two parameters with minimal manual intervention. Finally, we propose six different Deep Neural Network architectures, including VGG-IE, to improve classification accuracy. The VGG-IE algorithm uses batch normalization and seven kinds training-data augmentation for ease and promotion of learning process. We investigate the effectiveness of the proposed method using Fashion-MNIST dataset and 70[Formula: see text]000 pictures, Experimental results demonstrate that, in comparison with the state-of-the-art algorithms for 10 categories of image recognition, our VGG algorithm has the shortest computational time when it satisfies certain classification accuracy. VGG-IE approach has the highest classification accuracy.
Characterizing the Minimal Essential Graphs of Maximal Ancestral Graphs
Authors: Li Yanying
Published: May 2019

Learning ancestor graph is a typical NP-hard problem. We consider the problem to represent a Markov equivalence class of ancestral graphs with a compact representation. Firstly, the minimal essential graph is defined to represent the equivalent class of maximal ancestral graphs with the minimum number of invariant arrowheads. Then, an algorithm is proposed to learn the minimal essential graph of ancestral graphs based on the detection of minimal collider paths. It is the first algorithm to use necessary and sufficient conditions for Markov equivalence as a base to seek essential graphs. Finally, a set of orientation rules is presented to orient edge marks of a minimal essential graph. Theory analysis shows our algorithm is sound, and complete in the sense of recognizing all minimal collider paths in a given ancestral graph. And the experiment results show we can discover all invariant marks by these orientation rules.
A distance for circular Heegaard splittings
Authors: Lamb Kevin , Weed Patrick
Published: May 2019

For a knot [Formula: see text], its exterior [Formula: see text] has a singular foliation by Seifert surfaces of [Formula: see text] derived from a circle-valued Morse function [Formula: see text]. When [Formula: see text] is self-indexing and has no critical points of index 0 or 3, the regular levels that separate the index-1 and index-2 critical points decompose [Formula: see text] into a pair of compression bodies. We call such a decomposition a circular Heegaard splitting of [Formula: see text]. We define the notion of circular distance (similar to Hempel distance) for this class of Heegaard splitting and show that it can be bounded under certain circumstances. Specifically, if the circular distance of a circular Heegaard splitting is too large: (1) [Formula: see text] cannot contain low-genus incompressible surfaces, and (2) a minimal-genus Seifert surface for [Formula: see text] is unique up to isotopy.
Menopause and FOXP3+ Treg cell depletion eliminate female protection against T cell-mediated angiotensin II hypertension
Authors: Pollow Dennis P. , Uhlorn Joshua A. , Sylvester Megan A. , Romero-Aleshire Melissa J. , Uhrlaub Jennifer L. , Lindsey Merry L. , Nikolich-Zugich Janko , Brooks Heddwen L.
Published: May 2019

Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that 1) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and 2) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1−/− mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3+ T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1−/− menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females.

NEW & NOTEWORTHY Whether progression into menopause eliminated female protection against T cell-mediated hypertension was examined. Menopausal mice without T cells remained protected against angiotensin II (ANG II) hypertension; however, in the presence of T cells, blood pressure responses to ANG II increased significantly in menopause. Underlying mechanisms examined were anti-inflammatory protection provided by T regulatory cells in premenopausal females and renal inflammatory processes involving macrophage infiltration and cytokine activation.
Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants
Authors: Wu Lang , Wang Jifeng , Cai Qiuyin , Cavazos Taylor B. , Emami Nima C. , Long Jirong , Shu Xiao-Ou , Lu Yingchang , Guo Xingyi , Bauer Joshua A. , Pasaniuc Bogdan , Penney Kathryn L. , Freedman Matthew L. , Kote-Jarai Zsofia , Witte John S. , Haiman Christopher A. , Eeles Rosalind A. , Zheng Wei
Published: May 2019

Genome-wide association study–identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10−6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10−6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology.

Significance:

This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.
Inhibition of ATM Increases Interferon Signaling and Sensitizes Pancreatic Cancer to Immune Checkpoint Blockade Therapy
Authors: Zhang Qiang , Green Michael D. , Lang Xueting , Lazarus Jenny , Parsels Joshua D. , Wei Shuang , Parsels Leslie A. , Shi Jiaqi , Ramnath Nithya , Wahl Daniel R. , Pasca di Magliano Marina , Frankel Timothy L. , Kryczek Ilona , Lei Yu L. , Lawrence Theodore S. , Zou Weiping , Morgan Meredith A.
Published: May 2019

Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Because ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1- and SRC-dependent, manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1–blocking antibody in association with increased tumoral CD8+ T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer.

Significance:

This study demonstrates that ATM inhibition induces a T1IFN-mediated innate immune response in pancreatic cancer that is further enhanced by radiation and leads to increased sensitivity to anti–PD-L1 therapy.

See related commentary by Gutiontov and Weichselbaum, p. 3815
κ-Opioid Receptor Modulation of GABAergic Inputs onto Ventrolateral Periaqueductal Gray Dopamine Neurons
Authors: Li Chia , Kash Thomas L.
Published: May 2019

The κ-opioid receptor (KOR) system has been implicated in the regulation of many behaviors including pain. While there are numerous studies suggesting KOR regulation of pain being mediated spinally, there have been reports of pain-like behaviors regulated by central KOR signaling. In particular, oxytocin-induced analgesia appears to be mediated by KOR receptors within the ventrolateral periaqueductal gray (vlPAG). We recently found that activation of dopamine (DA) neurons within the vlPAG is antinociceptive. In this study, we sought to determine the impact of KOR signaling on ­GABAergic inputs onto vlPAG DA neurons, and the mechanism through which KOR impacts these inputs. We found that activation of KOR reduced GABAergic transmission onto vlPAG DA neurons. In addition, our data suggest this effect is mediated presynaptically via the G protein βγ-subunit. They raise the possibility that KOR activation disinhibits ­vlPAG DA neurons, which could lead to altered regulation of pain-related behaviors.
To Win the Battle, First Know Your Enemy: Error Rates in Immunohematology External Quality Assessment Results
Authors: Buchta Christoph , Coucke Wim , Mayr Wolfgang R. , Müller Mathias M. , Körmöczi Günther F.
Published: May 2019

Background: As some errors in pretransfusion testing remain unrecognized, error rates and the resulting need for corrective measures are probably underestimated. External quality assessment (EQA) schemes could provide valuable input for identifying error-prone laboratory tests because they are designed to monitor test performance and errors. So far, however, there are only limited published data on error rates in such schemes. Methods: The types and incidence of incorrect results in an EQA scheme for red cell immunohematology with 187 participating laboratories were examined. The results of 58 distributions between 1999 and 2017 were evaluated, considering also the employed determination methods. Results: Out of a total of 58,726 results, 563 (0.96%) were incorrect. Error rates were 5.45% for antibody identification, 1.39% for Rh phenotyping, 0.83% for serologic cross-match, 0.60% for direct antiglobulin test, 0.20% for Kell phenotyping, 0.16% for antibody screening, and 0.14% for ABO phenotyping. During the observation period, 53 participants reported error-free results, while 37 reported one incorrect result and 97 repeatedly reported incorrect results for one or more analytes. Error rates obtained by manual methods significantly surpassed those obtained by automated methods (1.04 vs. 0.42%). The introduction of double testing with two different systems reduced error rates in Rh phenotyping from 1.55 to 0.50%. Conclusion: Risk assessment should consider that error rates in pretransfusion test results vary. These data delineate the error risk potential of individual laboratory tests and thus should aid in tailoring appropriate improvement measures.
Risk Factors for Preterm Birth following Open Fetal Myelomeningocele Repair: Results from a Prospective Cohort
Authors: Kahr Maike Katja , Winder Franziska , Vonzun Ladina , Meuli Martin , Mazzone Luca , Moehrlen Ueli , Krähenmann Franziska , Hüsler Margaret , Zimmermann Roland , Ochsenbein-Kölble Nicole
Published: May 2019

Background: Fetal myelomeningocele (fMMC) repair is a therapeutic option in selected cases. This study aimed to identify risk factors for preterm birth (PTB) following open fMMC repair. Methods: Sixty-seven women underwent fMMC repair and delivered a baby between 2010 and 2018 at our center. Demographic, surgical, and pregnancy complications, including potential risk factors for PTB such as preterm premature rupture of membranes (PPROM), chorioamniotic membrane separation (CMS), and placental abruption were evaluated. Results: Maternal body mass index, maternal age, parity, previous uterine surgery, gestational age at fetal surgery, total surgery duration, surgical subcutaneous hematoma, oligohydramnios, and amniotic fluid leakage were not identified as risk factors for PTB. CMS (p = 0.028, 92 vs. 52%) and PPROM (p = 0.001, 95 vs. 52%) were highly associated with PTB. Placental abruption was found more often in women after fMMC repair than in a general obstetrical population (12 vs. 1%) and ended in premature birth in all cases (p = 0.024, 100 vs. 60%). However, the majority of women delivered at a gestational age >35 weeks. Conclusions: In our study cohort, risk factors for PTB were PPROM, CMS, and placental abruption, whereas surgery duration did not influence outcome. We conclude that the surgery technique should aim to minimize CMS and amniotic fluid leakage.
Recommendations Regarding Practical DEL Typing Strategies for Serologically D-Negative Asian Donors
Authors: Kim Tae Yeul , Hong Yun Ji , Kim Mi Jung , Kim Hyungsuk , Kim Taek Soo , Park Jeong Su , Park Kyoung Un , Han Kyou-Sup
Published: May 2019

Background: DEL, the weakest D variant, is mistyped as D-negative by routine serological assays. Transfusion of red blood cells expressing the DEL phenotype has the potential to elicit anti-D alloimmunization in D-negative recipients. The goal of this study was to recommend DEL typing strategies for serologically D-negative Asian donors. Methods: RhCE phenotyping and the adsorption-elution test were performed on 674 serologically D-negative samples. RHD genotyping using real-time polymerase chain reaction and melting curve analysis were also undertaken to identify DEL alleles. Costs and turnaround time of RhCE phenotyping, the adsorption-elution test, and RHD genotyping were estimated. Results: Sensitivity and specificity of the adsorption-elution test for serologically D-negative samples were 94.9% (93/98) and 91.5% (527/576), respectively. C+ phenotypes were detected in all 98 samples with DEL alleles. Despite comparable costs, RHD genotyping was more accurate and rapid than the adsorption-elution test. Conclusions: Two practical DEL typing strategies using RhCE phenotyping as an initial screening method were recommended for serologically D-negative Asian donors. Compared with DEL typing using RHD genotyping, serological DEL typing using adsorption-elution test is predicted to increase the incidence of anti-D alloimmunization and decrease the D-negative donor pool without having any cost-competitiveness but can be used in laboratories where molecular methods are not applicable.