bluuebunny/crossref_metadata_2025 huggingface dataset:
A pyramid MOT with integrated optical cavities as a cold atom platform for an optical lattice clock
Authors: Bowden William , Hobson Richard , Hill Ian R. , Vianello Alvise , Schioppo Marco , Silva Alissa , Margolis Helen S. , Baird Patrick E. G. , Gill Patrick
Published: August 2019

We realize a two-stage, hexagonal pyramid magneto-optical trap (MOT) with strontium, and demonstrate loading of cold atoms into cavity-enhanced 1D and 2D optical lattice traps, all within a single compact assembly of in-vacuum optics. We show that the device is suitable for high-performance quantum technologies, focusing especially on its intended application as a strontium optical lattice clock. We prepare 2 × 104 spin-polarized atoms of 87Sr in the optical lattice within 500 ms; we observe a vacuum-limited lifetime of atoms in the lattice of 27 s; and we measure a background DC electric field of 12 V m−1 from stray charges, corresponding to a fractional frequency shift of (−1.2 ± 0.8) × 10−18 to the strontium clock transition. When used in combination with careful management of the blackbody radiation environment, the device shows potential as a platform for realizing a compact, robust, transportable optical lattice clock with systematic uncertainty at the 10−18 level.
PD-1 of Sigmodon hispidus: Gene identification, characterization and preliminary evaluation of expression in inactivated RSV vaccine-induced enhanced respiratory disease
Authors: Muralidharan Abenaya , Larocque Louise , Russell Marsha , Creskey Marybeth , Li Changgui , Chen Wangxue , Van Domselaar Gary , Cao Jingxin , Cyr Terry , Rosu-Myles Michael , Wang Lisheng , Li Xuguang
Published: August 2019

Sigmodon hispidus or cotton rat is an excellent animal model for studying human infections of respiratory viruses including respiratory syncytial virus (RSV), which is the leading cause of hospitalization in infants and causes high rates of infection in the elderly and immunocompromised patient populations. Despite several decades of research, no vaccine has been licensed whereas inactivated vaccines have been shown to induce severe adverse reaction in a clinical trial, with other forms of RSV vaccine also found to induce enhanced disease in preclinical animal studies. While arguably the cotton rat is the best small animal model for evaluation of RSV vaccines and antivirals, many important genes of the immune system remain to be isolated. Programmed cell death-1 (PD-1) plays an integral role in regulating many aspects of immunity by inducing suppressive signals. In this study, we report the isolation of mRNA encoding the cotton rat PD-1 (crPD-1) and characterization of the PD-1 protein. crPD-1 bound to its cognate ligand on dendritic cells and effectively suppressed cytokine secretion. Moreover, using the newly acquired gene sequence, we observed a decreased level of crPD-1 levels in cotton rats with enhanced respiratory disease induced by inactivated RSV vaccine, unraveling a new facet of vaccine-induced disease.
Imaging of sacroiliac joints in patients with acromegaly
Authors: Ugur Kader , Karatas Ahmet , Oz Burak , Artas Hakan , Aydin Suleyman , Koca Suleyman Serdar
Published: August 2019

Acromegaly can lead to structural alterations of joints and bones. Patients with acromegaly may, therefore, have musculoskeletal complaints. In this study, sacroiliac joints are investigated in patients with acromegaly. 33 patients with acromegaly were enrolled. Sacroiliac joints were examined by X-ray and magnetic resonance imaging (MRI). In acromegaly, sacroiliac joints were abnormal in 36% of the patients by X-ray and 12.1% by MRI. When current axial spondylarthritis (SpA) classification criteria were taken into account, 6.1% of acromegaly patients could be classified as non-radiographic axial SpA and 2% as radiographic axial SpA. Sacroiliac joints are frequently affected in acromegaly and thus this disorder mimics the features of AS and SpA. Acromegaly should be kept in mind in the differential diagnosis of AS and SpA.
Dual-responsive (pH/temperature) Pluronic F-127 hydrogel drug delivery system for textile-based transdermal therapy
Authors: Chatterjee Sudipta , Hui Patrick Chi-leung , Kan Chi-wai , Wang Wenyi
Published: August 2019

A dual-responsive hydrogel (pH/temperature) was developed from a thermos-responsive polymer, pluronic F-127 (PF127), and pH-responsive polymers, N,N,N-trimethyl chitosan (TMC) and polyethylene glycolated hyaluronic acid (PEG-HA). Gallic acid, the principal component of the traditional Chinese drug Cortex Moutan was loaded into the hydrogel (PF127/TMC/PEG-HA) for possible application in textile-based transdermal therapy as Cortex Moutan has been proven to be an effective drug for the treatment of atopic dermatitis (AD). TMC and PEG-HA were synthesized, characterized (1H-NMR and FTIR), and added to the formulations to enhance drug release from the hydrogels, and increase the drug targeting of the carriers. The thermo-responsive properties of the hydrogel were assessed by dynamic viscosity analysis and the tube inversion method, and the pH-responsiveness of the formulation was determined by changing the pH of the external media. Rheology study of the hydrogels showed that complex viscosity and storage/loss moduli for PF127/TMC/PEG-HA hydrogel formulation are higher than PF127 hydrogel. The microstructure analysis by reflection SAXS indicated similar type of frozen inhomogeneity of hydrogel formulations. Various characterizations such as FTIR, SEM, TEM, zeta potential, and degradation of the hydrogel formulation indicated that the PF127/TMC/PEG-HA hydrogel showed better physico-chemical properties and morphology than did the PF127 hydrogel, and drug release was also higher for the PF127/TMC/PEG-HA hydrogel than for PF127. The drug release from hydrogels followed more closely first-order rate model than other rate models.
Semiaquatic mammals might be intermediate hosts to spread avian influenza viruses from avian to human
Authors: Zhao Ping , Sun Lingsha , Xiong Jiasheng , Wang Chuan , Chen Liang , Yang Pengfei , Yu Hao , Yan Qingli , Cheng Yan , Jiang Lufang , Chen Yue , Zhao Genming , Jiang Qingwu , Xiong Chenglong
Published: August 2019

Avian influenza A viruses (AIVs) can occasionally transmit to mammals and lead to the development of human pandemic. A species of mammal is considered as a mixing vessel in the process of host adaptation. So far, pigs are considered as a plausible intermediate host for the generation of human pandemic strains, and are labelled ‘mixing vessels’. In this study, through the analysis of two professional databases, the Influenza Virus Resource of NCBI and the Global Initiative on Sharing Avian Influenza Data (GISAID), we found that the species of mink (Neovison vison) can be infected by more subtypes of influenza A viruses with considerably higher α-diversity related indices. It suggested that the semiaquatic mammals (riverside mammals), rather than pigs, might be the intermediate host to spread AIVs and serve as a potential mixing vessel for the interspecies transmission among birds, mammals and human. In epidemic areas, minks, possibly some other semiaquatic mammals as well, could be an important sentinel species for influenza surveillance and early warning.
The Clinical and Epidemiological Study of Children with Hand, Foot, and Mouth Disease in Hunan, China from 2013 to 2017
Authors: Qiu Jun , Yan Haipeng , Cheng Nianci , Lu Xiulan , Hu Xia , Liang Lijuan , Xiao Zhenghui , Tan Lihong
Published: August 2019

Hand, foot, and mouth disease (HFMD) is endemic in the Pacific region, especially in mainland China. The case-fatality ratio of HFMD is increasing steadily. Knowledge of the changing epidemiology of HFMD in different regions is necessary for implementing appropriate intervention strategies. In this study, we describe the clinical and epidemiological characteristics of HFMD in Hunan Children’s Hospital between 2013 and 2017. A total of 7203 patients with HFMD were admitted, with complication and mortality rates of 35.62% and 0.78%, respectively. The total number of children with HFMD, proportion of severely ill children, and HFMD mortality rate were the highest in 2014. The number of cases caused by EV-A71 and CV-A16 decreased continuously, while the number of cases caused by ‘other enteroviruses’ increased yearly since 2014, suggesting that other enteric viruses will gradually replace EV-A71 and CV-A16 as the main pathogenic HFMD agents. Furthermore, EV-A71 and mixed infections accounted for the high case fatality rates in children with severe HFMD, among whom EV-A71 infection resulted in the highest complication and mortality rates; the mild form of the disease was dominated by ‘other enteroviruses’. In conclusion, the changing etiological pattern highlights the need to improve pathogen surveillance and vaccine strategies for HFMD control.
Epoxy pre-polymers as new and effective materials for corrosion inhibition of carbon steel in acidic medium: Computational and experimental studies
Authors: Dagdag Omar , Safi Zaki , Hsissou Rachid , Erramli Hamid , El Bouchti Mehdi , Wazzan Nuha , Guo Lei , Verma Chandrabhan , Ebenso E. E. , El Harfi Ahmed
Published: August 2019

Present study is designed for the synthesis, characterization and corrosion inhibition behavior of two diamine aromatic epoxy pre-polymers (DAEPs) namely, N1,N1,N2,N2-tetrakis (oxiran-2-ylmethyl) benzene-1,2-diamine (DAEP1) and 4-methyl-N1,N1,N2,N2-tetrakis (oxiran-2-ylmethyl) benzene-1,2-diamine (DAEP2) for carbon steel corrosion in acidic medium. Synthesized DAEPs were characterized using spectral (Nuclear magnetic resonance (1H NMR) and Fourier transform infrared-attenuated total reflection (FTIR-ATR)) techniques. Viscosity studies carried out at four different temperatures (20–80 °C) increase in temperature causes significant reduction in their viscosities. The anticorrosive properties of DAEPs differing in the nature of substituents, for carbon steel corrosion in 1 M HCl solution was evaluated using several experimental and computational techniques. Both experimental and computational studies showed that inhibitor (DAEP2) that contains electron releasing methyl (-CH3) showed higher protectiveness as compared to the inhibitor (DAEP1) without substituent (-H). Electrochemical results demonstrate that DAEPs act as reasonably good inhibitors for carbon steel in 1 M HCl medium and their effectiveness followed the sequence: DAEP2 (92.9%) > DAEP1 (91.7%). The PDP results show that the diamine aromatic epoxy pre-polymers molecules (DAEPs) act as mixed type inhibitors. Electrochemical study was also supported using scanning electron microscopy (SEM) method were significant improvement in the surface morphology of inhibited (by DAEPs) metallic specimens was obtained. Results derived from computational density functional theory (DFT) and molecular dynamics (MD) simulationsand studies were consistent with the experimental results derived from SEM, EIS and PDP electrochemical studies. Adsorption of the DAEPs obeyed the Langmuir adsorption isotherm model.
Reaction mechanisms at the homogeneous–heterogeneous frontier: insights from first-principles studies on ligand-decorated metal nanoparticles
Authors: Ortuño Manuel A. , López Núria
Published: August 2019

The frontiers between homogeneous and heterogeneous catalysis are progressively disappearing.
Salidroside enhances the anti-cancerous effect of imatinib on human acute monocytic leukemia via the induction of autophagy-related apoptosis through AMPK activation
Authors: Ge Chiyu , Zhang Junli , Feng Feng
Published: August 2019

As the typical tyrosine kinase inhibitor, imatinib has been the first-line antineoplastic agent for both chronic myeloid leukemia and acute lymphoblastic leukemia.
Effects of dietary tuna dark muscle enzymatic hydrolysis and cooking drip supplementations on growth performance, antioxidant activity and gut microbiota modulation of Bama mini-piglets
Authors: Zhou Jun , Yang Mingyuan , Han Jiaojiao , Lu Chenyang , Li Ye , Su Xiurong
Published: August 2019

Experiments were conducted to evaluate the enzymatic hydrolysis of tuna dark muscle (EH-TDM) and cooking drip (EH-TCD) as nutrition supplements in Bama mini-piglets.
A comprehensive study of eriocitrin metabolism in vivo and in vitro based on an efficient UHPLC-Q-TOF-MS/MS strategy
Authors: Li Luya , Feng Xue , Chen Yuting , Li Shenghao , Sun Yupeng , Zhang Lantong
Published: August 2019

41 metabolites of eriocitrin in vivo and in vitro was identified based on the efficient UHPLC-Q-TOF-MS/MS strategy.
Compound reinforcement of glaze wear resistance by prestress and second grain phase
Authors: Yu Yougen , Su Huazhi , Guan Kang , Peng Cheng , Wu Jianqing
Published: August 2019

To study the effect of prestress and grain on glaze wear resistance, fused quartz was added to ceramic body to introduce various prestress on glaze, and feldspar opaque glazes with and without zircon grains were coated on the ceramic bodies.
In situ addition of graphitic carbon into a NiCo2O4/CoO composite: enhanced catalysis toward the oxygen evolution reaction
Authors: N. Srinivasa , L. Shreenivasa , Adarakatti Prashanth S. , Hughes Jack P. , Rowley-Neale Samuel J. , Banks Craig E. , S. Ashoka
Published: August 2019

A facile synthesis technique for the production of NiCo2O4/CoO and graphite composites that demonstrate efficient electrocatalysis towards the oxygen evolution reaction.
Using the local ensemble Transform Kalman Filter for upper atmospheric modelling
Authors: Elvidge Sean , Angling Matthew J.
Published: August 2019

The Advanced Ensemble electron density (Ne) Assimilation System (AENeAS) is a new data assimilation model of the ionosphere/thermosphere. The background model is provided by the Thermosphere Ionosphere Electrodynamics General Circulation Model (TIE-GCM) and the assimilation uses the local ensemble transform Kalman filter (LETKF). An outline derivation of the LETKF is provided and the equations are presented in a form analogous to the classic Kalman filter. An enhancement to the efficient LETKF implementation to reduce computational cost is also described. In a 3 day test in June 2017, AENeAS exhibits a total electron content (TEC) RMS error of 2.1 TECU compared with 5.5 TECU for NeQuick and 6.8 for TIE-GCM (with an NeQuick topside).
Rotating Hinge Implants in Knee Arthroplasty
Authors: Petershofer Alexander , Trieb Klemens
Published: August 2019

Due to demographic transition an increasing number of primary knee arthroplasty is expected. A consequence is a rise in frequency in revision knee arthroplasty. Rotating hinge prostheses are a development of former hinge prostheses, due to changes in implant design the outcome of modern rotating hinge implants clearly improved in comparison to former models. Interpretation of outcome in present literature is difficult due to the small number of cases and the heterogeneous indications. Nevertheless the use of rotating hinge knee prostheses in primary and revision arthroplasty is associated with good clinical outcomes, when indicated appropriately.
The Academization of Midwifery in the Context of the Amendment of the German Midwifery Law: Current Developments and Challenges
Authors: Plappert Claudia , Graf Joachim , Simoes Elisabeth , Schönhardt Stefani , Abele Harald
Published: August 2019

Germany faces the challenge of enforcing the academization of midwifery training in the upcoming months in order to comply with Directive 2013/55/EU. This paper outlines the related developments and challenges. At the moment, midwifery training in Germany is still predominantly carried out in technical colleges. In 2019, less than 20% of midwifery training places were college-based. The current standard training is a dual training system which combines vocational training with academic-based courses, but this approach will no longer be feasible once the EU directive has been fully implemented. Although the existing draft legislation completely transfers midwifery training to institutions of higher education, various aspects of this concept have remained vague and do not take account of the laws on higher education in the individual federal states. Moreover, if midwifery training is to be provided by both universities and colleges, this will lead to quite different levels of academization within a relatively small professional group. The concept that universities offer primary qualifications comes closest to the required quality standards for professional, science-based, practical and evidence-based midwifery training.
Development and Evaluation of Record Linkage Rules in a Safety-Net Health System Serving Disadvantaged Communities
Authors: Trick William E. , Doshi Kruti , Ray Michael J. , Angulo Francisco
Published: August 2019

Background There is a need for flexible, accurate record-linkage systems with transparent rules that work across diverse populations.

Objectives We developed rules responsive to challenges in linking records for an urban safety-net health system; we calculated performance characteristics for our algorithm.

Methods We evaluated encounters during January 1, 2012 through September 30, 2018. We compared our algorithm, using name (first-last), date-of-birth (DOB), and last four of social security number to our electronic health record (EHR) system's reconciliation process. We applied our algorithm to unreconciled real-time Admission-Discharge-Transfer registration data, and compared match results to reconciled identities from our enterprise data warehouse. We manually validated matches for randomly sampled discordant pairs; we calculated sensitivity/specificity. We evaluated predictors of discordance, including census tract information.

Results Of 771,477 unique medical record numbers, most (95%) were concordant between systems; a substantial minority (5%) was discordant. Of 38,993 discordant pairs, most (n = 36,539; 94%) were detected by our local algorithm. The sensitivity of our algorithm was higher than the EHR process (99% vs. 81%), but with lower specificity (98.6% vs. 99.9%). Our highest-yield rules, beyond full first and last name plus complete DOB match, were first three initials of first name, transposed first-last names, and DOB offsets (+1 and +365 days). Factors associated with discordance were homelessness (adjusted odds ratio [aOR] = 2.4; 95% confidence interval [CI], 2.2–2.6) and living in a census tract with high levels of poverty (aOR = 1.4; 95% CI, 1.3–1.4).

Conclusion Our algorithm had superior sensitivity compared to our EHR process. Homelessness and poverty were associated with unmatched records. Improved sensitivity was attributable to several critical input-variable processing steps useful for similar difficult-to-link populations.
Zeitarbeit in der Pflege: Boom mit „Riesen-Sprengstoff“
Authors: Kohrs Jens
Published: August 2019

Zeitarbeit ist vom Problemlöser zu einem echten Problem geworden: Dass immer mehr Pflegekräfte lieber bei Personaldienstleistern als in Festanstellung in einem Team arbeiten, bringt die Kliniken nicht nur finanziell in Schwierigkeiten: Auf den Stationen rumort es. Nun soll es (auch) die Politik richten.
„Digitale Versorgung“-Gesetz (DVG): Das Gesetz wird Tempo in den Markt bringen
Authors: Hissel Yvonne
Published: August 2019

Mit dem Gesetz für eine bessere Versorgung durch Digitalisierung und Innovation will Bundesgesundheitsminister Jens Spahn digitale Angebote im Gesundheitswesen vorantreiben. Wir haben mit Frank Sarangi, Anwalt für Medizinrecht, über das geplante Gesetz gesprochen.
Bundessozialgericht urteilt zu Honorararzt: Rechtssicherheit ohne Perspektive
Authors: Porten Stephan
Published: August 2019

Ein kleiner Honorararztverband war mit viel Selbstvertrauen nach Kassel gefahren, um beim Bundessozialgericht Rechtssicherheit für Honorarärzte zu erkämpfen. Nach der Entscheidung des Gerichts gibt es nun zwar Rechtssicherheit – aber leider keine Honorarärzte mehr. Auch den Honorarpflegekräften ist es nicht besser ergangen – sie sind ebenfalls in Kassel gescheitert.
Electromechanical Brillouin scattering in integrated planar photonics
Authors: Li Huan , Liu Qiyu , Li Mo
Published: August 2019

The exploitation of Brillouin scattering, the scattering of light by sound, has led to demonstrations of a broad spectrum of novel physical phenomena and device functionalities for practical applications. Compared with optomechanical excitation by optical forces, electromechanical excitation of acoustic waves with transducers on a piezoelectric material features intense acoustic waves sufficient to achieve near-unity scattering efficiency within a compact device footprint, which is essential for practical applications. Recently, it has been demonstrated that gigahertz acoustic waves can be electromechanically excited to scatter guided optical waves in integrated photonic waveguides and cavities, leading to intriguing phenomena such as induced transparency and nonreciprocal mode conversion, and advanced optical functionalities. The new integrated electromechanical Brillouin devices, utilizing state-of-the-art nanofabrication capabilities and piezoelectric thin film materials, succeed guided wave acousto-optics with unprecedented device integration, ultrahigh frequency, and strong light-sound interaction. Here, we experimentally demonstrate large-angle (60°) acousto-optic beam deflection of guided telecom-band light in a planar photonics device with electromechanically excited gigahertz (∼11 GHz) acoustic Lamb waves. The device consists of integrated transducers, waveguides, and lenses, all fabricated on a 330 nm thick suspended aluminum nitride membrane. In contrast, conventional guided-wave acousto-optic devices can only achieve a deflection angle of a few degrees at most. Our work shows the promises of such a new acousto-optic device platform, which may lead to potential applications in on-chip beam steering and routing, optical spectrum analysis, high-frequency acousto-optic modulators, RF or microwave filters and delay lines, as well as nonreciprocal optical devices such as optical isolators.
Physical properties of calcium fluoride nanopowder after irradiation by relativistic electrons
Authors: Sokovnin S Yu , Il’ves V G , Uimin M A
Published: August 2019

Mesoporous CaF2 nanopowders with specific surface area up to 91.5 m2/g have been obtained through evaporation by electron beam in vacuum. The effect of relativistic e-beam irradiation in air on magnetic and texture properties of CaF2 nanoparticles has been studied. The influence of annealing and irradiation on the specific surface area and magnetization of CaF2 nanopowder has been discovered for the first time.
Coating of optical fiber by thin films for creating sensors based on interaction with cladding modes
Authors: Yusupova L I , Ivanov O V
Published: August 2019

Transmission spectra of a fiber-optic structure based on a section of SM450 fiber with a small core are investigated when a thin-film coating is deposited to the fiber cladding. Asetup for deposition of films on fiber by dip coating process is created. A wavelength shift in the spectra was found in fibers coated by thin polyvinyl alcohol films. The dependence of wavelength shift on drawing speed determining the film thickness is measured.
New horizons in deprescribing for older people
Authors: Woodford Henry J , Fisher James
Published: August 2019

Deprescribing has gained interest recently, driven by an ageing population seeing an increasing number living with multiple long-term conditions. This, coupled with disease-specific guidelines derived from clinical trials in younger people, has led to an increase in exposure to polypharmacy and the associated therapeutic burden. Older people, especially those living with frailty, tend to experience lower efficacy of these medications along with a higher risk of drug adverse effects. Explanations for these differences include the physiological effects of frailty, drug–drug interactions, drug–disease interactions and reduced medication adherence. Adverse drug reactions often go unnoticed and can trigger further prescribing. Certain medications have been recognised as potentially inappropriate for people with frailty, yet their use remains common. Evidence suggests that many older people are open to the concept of reducing medications. Deprescribing should be based around a shared decision-making approach. Trials to date have suggested that it can often be achieved without harm. To date, there are few data to support improvements in hospitalisation or mortality rates. However, there is some evidence that it may reduce polypharmacy, improve medication adherence, reduce financial costs and improve quality of life. In the future, it will be necessary to grow the evidence base and improve public and clinician awareness of the potential benefits of deprescribing. It will require excellent team working and communication between all of those involved in the prescribing and administration of medications, also supported by improved healthcare informatics. Non-pharmacological approaches will need to be promoted. Fewer drugs is not less care.
Using the CODIT model to explain secondary metabolites of xylem in defence systems of temperate trees against decay fungi
Authors: Morris Hugh , Hietala Ari M , Jansen Steven , Ribera Javier , Rosner Sabine , Salmeia Khalifah A , Schwarze Francis W M R
Published: August 2019

Background

In trees, secondary metabolites (SMs) are essential for determining the effectiveness of defence systems against fungi and why defences are sometimes breached. Using the CODIT model (Compartmentalization of Damage/Dysfunction in Trees), we explain defence processes at the cellular level. CODIT is a highly compartmented defence system that relies on the signalling, synthesis and transport of defence compounds through a three-dimensional lattice of parenchyma against the spread of decay fungi in xylem.

Scope

The model conceptualizes ‘walls’ that are pre-formed, formed during and formed after wounding events. For sapwood, SMs range in molecular size, which directly affects performance and the response times in which they can be produced. When triggered, high-molecular weight SMs such as suberin and lignin are synthesized slowly (phytoalexins), but can also be in place at the time of wounding (phytoanticipins). In contrast, low-molecular weight phenolic compounds such as flavonoids can be manufactured de novo (phytoalexins) rapidly in response to fungal colonization. De novo production of SMs can be regulated in response to fungal pathogenicity levels. The protective nature of heartwood is partly based on the level of accumulated antimicrobial SMs (phytoanticipins) during the transitionary stage into a normally dead substance. Effectiveness against fungal colonization in heartwood is largely determined by the genetics of the host.

Conclusion

Here we review recent advances in our understanding of the role of SMs in trees in the context of CODIT, with emphasis on the relationship between defence, carbohydrate availability and the hydraulic system.We also raise the limitations of the CODIT model and suggest its modification, encompassing other defence theory concepts. We envisage the development of a new defence system that is modular based and incorporates all components (and organs) of the tree from micro- to macro-scales.
ROBOKOP: an abstraction layer and user interface for knowledge graphs to support question answering
Authors: Morton Kenneth , Wang Patrick , Bizon Chris , Cox Steven , Balhoff James , Kebede Yaphet , Fecho Karamarie , Tropsha Alexander
Published: August 2019

Knowledge graphs (KGs) are quickly becoming a common-place tool for storing relationships between entities from which higher-level reasoning can be conducted. KGs are typically stored in a graph-database format, and graph-database queries can be used to answer questions of interest that have been posed by users such as biomedical researchers. For simple queries, the inclusion of direct connections in the KG and the storage and analysis of query results are straightforward; however, for complex queries, these capabilities become exponentially more challenging with each increase in complexity of the query. For instance, one relatively complex query can yield a KG with hundreds of thousands of query results. Thus, the ability to efficiently query, store, rank and explore sub-graphs of a complex KG represents a major challenge to any effort designed to exploit the use of KGs for applications in biomedical research and other domains. We present Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways as an abstraction layer and user interface to more easily query KGs and store, rank and explore query results.

Availability and implementation

An instance of the ROBOKOP UI for exploration of the ROBOKOP Knowledge Graph can be found at http://robokop.renci.org. The ROBOKOP Knowledge Graph can be accessed at http://robokopkg.renci.org. Code and instructions for building and deploying ROBOKOP are available under the MIT open software license from https://github.com/NCATS-Gamma/robokop.

Supplementary information

Supplementary data are available at Bioinformatics online.
Reforming Judicial Supervision of Chinese Arbitration
Authors: Chen Meng
Published: August 2019

Balancing arbitration autonomy and sovereignty supervision is the essential rhythm of international arbitration development. Influenced by the international trend of relaxing national judicial supervision, the Chinese judicial system, led by the Chinese Supreme People’s Court (SPC), has promoted a series of judicial reforms to coordinate domestic arbitration and international practice. This article elaborates the SPC’s recent reforms of the Chinese mechanisms of arbitration judicial supervision. The article first explores the international trend of the restraint of the national judicial supervision of arbitration. Then, the article introduces how such a trend impacts China’s recent reforms of its arbitration judicial supervision. By focusing on the rules established by the SPC regarding the judicial review of both international and domestic arbitral awards, this article exposes the essential factors and corresponding solutions that hinder the efficiency of the judicial supervision of Chinese arbitration.
BSCI-01. ACTIVATION OF c-Met/β1-INTEGRIN COMPLEX RESULTS IN INCREASE OF MESENCHYMAL GENE EXPRESSION AND STEM CELL POPULATION IN METASTATIC BREAST CANCER TO THE BRAIN AND SPINE
Authors: Lau Darryl , Wadhwa Harsh , Nguyen Alan , Chandra Ankush , Aghi Manish
Published: August 2019

INTRODUCTION: C-met and β-integrins play a central role in nearly all stages of cancer metastasis. They bind at the cell surface, driving ligand independent co-activation of downstream pathways. Greater complex is seen in metastatic tumors vs. its primary tumor counterparts in patients. The molecular, cellular, and clinical effects of complex formation in metastatic breast cancer are investigated. METHODS: Utilizing variations of the MDA-231 breast cancer cell lines (standard MDA-231, inducible complex formation MDA-231, brain seeking MDA 231, lung seeking MDA 231, and bone seeking MDA-231), in vitro and in vivo studies were performed. Clinical correlates from patient samples were studied. RESULTS: Induction of c-Met/β1 complex promotes breast cancer invasion (p< 0.001), migration (p< 0.05), circulation intravasation (p< 0.01), and adhesion (p< 0.01). These effects may be driven by the increased mesenchymal character (p< 0.05) and larger stem cell population (p< 0.001) caused by inducing c-Met/β1 complex formation. OS2966 (a therapeutic β1 integrin blocking antibody) decreases invasion (p< 0.05), intravasation (p< 0.05), and mesenchymal form factor (p< 0.001) and gene expression (p< 0.001) in MDA-MB-231 cells. Brain- and bone-seeking breast cancer cells have higher c-Met/β1 complex than parental controls and preferentially adhere to tissue-specific matrix (p< 0.01). In intracardiac metastasis models, complex formation resulted in significantly higher metastatic burden and shorter survival times (p< 0.001). qPCR data suggests that complex formation may drive exiting and colonization of cancer cells (micrometastasis) rather than tumor growth. Patient brain and bone metastases demonstrated high β1/c-Met levels. CONCLUSIONS: The c-Met/β1 complex drives intravasation and extravasation of breast cancer cells from the circulation. Preferential affinity for tissue-specific matrix enables the c-Met/β1 complex to drive formation of breast cancer metastases to the brain and bone. Pharmacological and genetic targeting of the complex with agents may provide therapeutic approaches to prevent metastases, particularly to the brain and bone.
BSCI-03. T CELL EXHAUSTION SIGNATURES VARY BY TUMOR TYPE AND ARE INDEPENDENT OF INTRACRANIAL LOCATION
Authors: Woroniecka Karolina , Chongsathidkiet Pakawat , Cui Xiuyu , Dechant Cosette , Wilkinson Daniel , Fecci Peter
Published: August 2019

T-cell exhaustion is a hindrance to the efficacy of immune checkpoint blockade. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating murine models of brain metastasis, including breast, lung, and melanoma cancers. Furthermore, this study demonstrates the utility of a 4-1BB agonist antibody in certain tumors resistant to PD-1 blockade alone. METHODS: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers. Levels of exhaustion-associated inhibitory receptors and post-stimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. Anti-PD-1 and anti-4-1BB monoclonal antibodies were utilized as a therapeutic exhaustion-countering strategy and median survival was assessed. RESULTS: Our data reveal that tumors, regardless of their intracranial or subcutaneous location, elicit unique T-cell exhaustion signatures among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations. Anti-PD-1 monoclonal antibody alone did not improve median survival in any tumor type tested. In tumors with high levels of 4-1BB expression, anti-4-1BB and anti-PD-1 therapy resulted in improvement in median survival. CONCLUSIONS: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. Each tumor type demonstrated a unique T cell exhaustion signature regardless of location. 4-1BB may serve as a therapeutic adjunct to anti-PD-1 monoclonal therapy in tumors which may be resistant to PD-1 blockade alone.
BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
Authors: Ferraro Gino , Arvanitis Costas , Askoxylakis Vasileios , Guo Yutong , Datta Meenal , Bernabeu Miguel , Fukumura Dai , McDannold Nathan , Jain Rakesh
Published: August 2019

Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in HER2-positive breast cancer brain metastases at cellular resolution: the non-targeted chemotherapeutic doxorubicin and the antibody-drug conjugate ado- trastuzumab emtansine (T-DM1). Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate multifold increases in the extravasation of both agents (7-fold and 2-fold for doxorubicin and T-DM1, respectively) and we provide evidence of increased drug penetration (>100μm vs. < 20μm and 42±7μm vs. 12±4μm for doxorubicin and T-DM1, respectively) after application of FUS as compared to control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via increase in hydraulic conductivity. Combination of experimental data and PBPK modeling suggests that FUS in combination with microbubbles increases the endothelial cell transmembrane transport and uptake. PBPK modelling indicates selective increase in transvascular transport of the non- targeted small chemotherapeutic doxorubicin through small vessel-wall pores size with a narrow range (Diameter: 10-50nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of novel therapeutic strategies against brain metastases.
BSCI-10. NEUROLOGICAL DYSFUNCTION CAUSED BY BRAIN TUMOR-GENERATED SOLID STRESS IS REVERSED BY LITHIUM
Authors: Seano Giorgio , Nia Hadi , Emblem Kyrre , Datta Meenal , Ren Jun , Kloepper Jonas , Krishnan Shanmugarajan , Ghosh Mitrajit , Pinho Marco , Askoxylakis Vasileios , Ferraro Gino , Riedemann Lars , Gerstner Elizabeth , Batchelor Tracy , Wen Patrick , Lin Nancy , Grodzinsky Alan , Fukumura Dai , Huang Peigen , Baish James , Padera Timothy , Munn Lance , Jain Rakesh
Published: August 2019

The compression of brain tissue by a tumor mass is believed to be a major cause of the clinical symptoms seen in patients. However, the biological consequences of these physical stresses on the brain tissue are unknown. Using clinical imaging and preclinical studies, we discovered that a subgroup of primary and metastatic brain tumors, classified as nodular based on the growth pattern, exert compressive solid stress on the surrounding brain tissue, leading to a decrease in local vascular perfusion, as well as neuronal death and impaired function. We demonstrated a causal link between solid stress and neurological dysfunction, by applying and removing cerebral compression, mimicking the mechanics of tumor growth and surgical resection respectively. Finally, we showed that treatment with lithium reduced solid stress-induced neuronal death and improved motor coordination in mice. Our results indicate that brain tumor-generated solid stress impairs neurological function in patients and show lithium as a potential therapeutic intervention to counter these effects.
BSCI-16. HEMODYNAMIC SHEAR STRESS SELECTS A SUBPOPULATION OF LUNG ADENOCARCINOMA CELLS WITH HIGHER METASTATIC CAPACITY
Authors: Alvarado-Estrada Keila N , Marenco-Hillembrand Lina , Mampre David , Quinones-Hinojosa Alfredo , Sarabia-Estrada Rachel , Zhang Yu Shrike , Maharjan Sushila , Chaichana Kaisorn
Published: August 2019

Patients with primary cancers often develop delayed brain metastases. One of the most common cancer types and sources of brain metastasis is lung cancer. For metastasis from lung cancer the 3-year survival is < 5%. Cancer cells in circulation are responsible for metastatic spread. The mechanical microenvironment plays an important role in cancer cells behavior. When cancer cells reach the bloodstream they are exposed to hemodynamic shear stress. It has been shown that most of the circulating tumor cells die once they reach the bloodstream, but the biology of the survival cells is poorly understood. We designed a microfluidics system that simulated the mechanical stress in the human circulating system such as turbulence, change in pressure (0.4-15dyn/cm2) and flow rate (1.06–106.1mm/s). Lung adenocarcinoma cells (A549) were put into circulation and collected after 72 hours. It was found that, 1.4±0.3% of the cells survived, and viability was evaluated by LDH and calcein. CD133, SOX2, and NANOG were downregulated and EMT genes were upregulated in the circulating cancer cells (CCCs) compared with cells in static-suspension or 2D. After re-seeding in 2D, CCCs overexpressed CD133. Female athymic nude rats (6-8weeks,n=16) received intracardiac injections of CCCs or 2D cells (GFP-LUC lentivirus traduced). Bioluminescence imaging was performed every week; the survival in of the CCCs group was lower than the 2D group. One-way ANOVA test was used to analyze survival and gene expression. Survival data was plotted on a Kaplan-Meier curve and compared using the Mantel-Cox logrank test, p=< 0.05. We have isolated a cellular subpopulation of lung adenocarcinoma with high resistance to hemodynamic shear stress that shows a higher metastatic capacity and genetic plasticity compared with cells growing in suspension or 2D. Targeting these cells would potentially allow us to develop personalized treatments to help to stop metastatic spread and improve actual therapeutical strategies.
BSCI-17. YOUNG AGE PROMOTES BREAST CANCER METASTASIS TO THE BRAIN
Authors: Wu Alex , Gossa Selam , Chung Monika , Dolan Emma , Yang Howard , Isanogle Kristine , Robinson Christina , Difilippantonio Simone , Gril Brunilde , Lee Maxwell , McGavern Dorian , Wakefield Lalage , Steeg Patricia
Published: August 2019

Younger women (< 40 years old) diagnosed with breast cancer often have a poorer outcome and a higher risk of developing brain metastases compared to women diagnosed at an older age. Multi-variate analyses have shown that even after accounting for differences in primary tumor characteristics, young age is still an independent predictor of poorer outcome. We therefore hypothesize that rather than intrinsic tumor properties, age-related changes to microenvironmental factors can affect breast cancer metastasis. To test this hypothesis, human and mouse breast cancer cells were injected into young (< 6 month) and old (> 13 month) mice and metastatic tumor burden was quantified. Young mice injected with brain-seeking breast cancer cells (MDA-MB-231BR, 4T1-BR, and 99LN-BrM) developed significantly more brain metastases compared to their older counterparts. In contrast, age had no effect on lung metastatic tumor burden in five breast cancer models. The effect of age is organ-specific, and the young brain is more permissive for breast cancer metastasis. To gain mechanistic insight, the transcriptome of young and old mouse brains were analyzed by RNAseq, the metastatic microenvironment was analyzed by laser capture microdissection and mass spectrometry, immune populations have been identified by flow cytometry, and functional immune contributions analyzed by immunodepleting antibodies. Multiple brain immune subsets were altered with age. In vivo depletion experiments showed no significant contribution of CD4+ T-cells and GR1+ myeloid cells to baseline brain metastatic colonization. A subpopulation of microglia in aged metastatic brains had a high side-scatter profile, which is consistent with published reports that aged microglia are in a “pro-inflammatory” state. Depletion of microglia reduced baseline brain metastatic colonization by 50% and experiments are underway to determine their contribution to an age effect.
BSCI-25. THE ROLE OF THE IFNγ PATHWAY IN BREAST CANCER BRAIN METASTASIS FORMATION
Authors: Pedrosa Route , Schrijver Benjamin , Marques Rute B , Leenen Pieter J M , Dik Wim A , Kros Johan M , Mustafa Dana A M
Published: August 2019

In previous work, we showed the prominence of the T cell response in the formation of brain metastases of primary ER-negative breast cancers. We also showed that prior co-cultured breast cancer cells with stimulated T lymphocytes bear an overexpression of Guanylate-binding protein 1 (GBP1) and possess an increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to the brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. In the present work, we show that activated CD8+ cytotoxic T lymphocytes, rather than CD4+ lymphocytes, are the main cause of increasing the ability of breast cancer cells to cross the BBB. While synthetic IFNγ does not change the ability of breast cancer cells to cross the BBB, this study shows that the T lymphocyte-secreted IFNγ activates the STAT1-dependent IFNγ pathway in breast cancer cells, enabling them to cross the in vitro BBB. Direct inhibition of soluble IFNγ or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. The results illustrate that IFNγ signaling pathway is one of the crucial pathways in the formation of brain metastasis of ER- breast cancer. The interference with the IFNγ pathway will develop preventive strategies against the formation of brain metastases of breast cancer.
LPTO-02. INTRATHECAL (IT) TRASTUZUMAB (T) FOR THE TREATMENT OF LEPTOMENINGEAL DISEASE (LM) IN PATIENTS (PTS) WITH HUMAN EPIDERMAL RECEPTOR-2 POSITIVE (HER2+) CANCER: A MULTICENTER PHASE 1/2 STUDY
Authors: Kumthekar Priya , Lassman Andrew B , Lin Nancy , Grimm Sean , Gradishar William , Pentsova Elena , Jeyapalan Suriya , Groves Morris , Melisko Melissa , Raizer Jeffrey
Published: August 2019

Patients with HER2+ breast cancer have frequent LM. A multi center phase 1/2 study assessing safety and efficacy of IT T in LM patients was conducted. The primary endpoint in Phase 2 was response rate (RR). Complete response (CR) required cytologic CR (CCR) + radiographic CR (RCR) + stable clinical function. Partial response (PR) required either CCR with stable/improved imaging or RCR with stable cytology + stable/improved clinical symptoms. Pts received IT T via intraventricular Ommaya reservoir. Phase 1 dosing started at 10 mg, then increasing by 20 mg up to 80 mg. Each cycle (C) was 4 weeks with 2x treatment/week in C1, weekly in C2, and every two weeks after C2. Pts were allowed to continue on hormonal agents if systemic disease was controlled at the time of LM development. Concurrent radiation therapy was not allowed unless exceptionally needed locally for pain control. 34 pts were enrolled with 26 its in the phase 2. The median age was 51 (25–69). IT T was well tolerated with no DLTs seen throughout; determined MTD was 80 mg for phase 2. All patients treated in the Phase 2 had HER2+ breast cancer, 2 patients in the Phase 1 had non-breast histologies. Median cycles completed was 2 (1–22). Median follow up was 9.1 months (0.4- 28.9). In Phase 2, 5 pts (19.2%) had PR, 13 (50%) had SD, and 8 (30.8%) had PD. For Phase 2 pts, median PFS was 2.4 months (CI 1.0–5.5) and median OS was 12.1 months (CI 4.3–19.6) IT T was well tolerated up to a dose of 80 mg. Primary endpoint of 25% RR was not met, however 69% had clinical benefit (stable disease or better). Median OS exceeded historical controls. Future studies are warranted to evaluate IT T in HER2+ LM.