bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling Surface Disinfection Needs To Meet Microbial Risk Reduction Targets
Authors: Wilson Amanda M. , Reynolds Kelly A. , Sexton Jonathan D. , Canales Robert A.
Published: July 2018

It is known that the use of EPA-registered surface disinfectant sprays can reduce infection risk if used according to the manufacturer's instructions. However, there are currently no standards for health care environments related to contamination levels on surfaces. The significance of this research is in quantifying needed reductions to meet various risk targets using realistic viral concentrations on surfaces for health care environments. This research informs the design of cleaning protocols by demonstrating that multiple applications may be needed to reduce risk and by highlighting a need for more models exploring the relationship among microbial contamination of surfaces, patient and health care worker behaviors, and infection risks.
Proximity to Other Commercial Turkey Farms Affects Colonization Onset, Genotypes, and Antimicrobial Resistance Profiles of Campylobacter spp. in Turkeys: Suggestive Evidence from a Paired-Farm Model
Authors: Niedermeyer Jeffrey A. , Ring Lynde , Miller William G. , Genger Seiche , Lindsey Christina Parr , Osborne Jason , Kathariou Sophia
Published: July 2018

Colonization of poultry with
Campylobacter
at the farm level is complex, poorly understood, and critically linked to contamination of poultry products, which is known to constitute a leading risk factor for human campylobacteriosis. Here, we investigated the use of a paired-farm design under standard production conditions and in the absence of experimental inoculations to assess potential impacts of farm and host genetics on prevalence, antimicrobial resistance and genotypes of
Campylobacter
in commercial turkeys of two different breeds. Data suggest impacts of farm proximity to other commercial turkey farms on the onset of colonization, genotypes, and antimicrobial resistance profiles of
Campylobacter
colonizing the birds. Furthermore, the significant association of a specific multidrug-resistant
Campylobacter jejuni
strain with turkeys of one breed suggests colonization partnerships at the
Campylobacter
strain-turkey breed level. The study design avoids potential pitfalls associated with experimental inoculations, providing novel insights into the dynamics of turkey colonization with
Campylobacter
in actual farm ecosystems.
Edwardsiella piscicida Type III Secretion System Effector EseK Inhibits Mitogen-Activated Protein Kinase Phosphorylation and Promotes Bacterial Colonization in Zebrafish Larvae
Authors: Cao Huifang , Han Fajun , Tan Jinchao , Hou Mingyu , Zhang Yuanxing , Yang Dahai , Liu Qin
Published: July 2018

Bacteria utilize type III secretion systems (T3SS) to deliver effectors directly into host cells. Hence, it is very important to identify the functions of bacterial (T3SS) effectors to understand host-pathogen interactions.
Localized Induction of Wild-Type and Mutant Alpha-Synuclein Aggregation Reveals Propagation along Neuroanatomical Tracts
Authors: Ayers Jacob I. , Riffe Cara J. , Sorrentino Zachary A. , Diamond Jeffrey , Fagerli Eric , Brooks Mieu , Galaleldeen Ahmad , Hart P. John , Giasson Benoit I.
Published: July 2018

The accumulation of alpha-synuclein (αS) inclusions is a hallmark feature of Parkinson's disease (PD) and PD-related diseases. Recently, a number of studies have demonstrated similarities between the prion protein and αS, including its ability to spread along neuroanatomical tracts throughout the central nervous system (CNS). However, there are caveats in each of these studies in which the injection routes used had the potential to result in a widespread dissemination of the αS-containing inocula, making it difficult to precisely define the mechanisms of spread. In this study, we assessed the spread of pathology following a localized induction of αS inclusions in the lumbar spinal cord following a unilateral injection in the sciatic nerve. Using this paradigm, we demonstrated the ability for αS inclusion spread and/or induction along neuroanatomical tracts within the CNS of two αS-overexpressing mouse models.
Engineered Dengue Virus Domain III Proteins Elicit Cross-Neutralizing Antibody Responses in Mice
Authors: Frei Julia C. , Wirchnianski Ariel S. , Govero Jennifer , Vergnolle Olivia , Dowd Kimberly A. , Pierson Theodore C. , Kielian Margaret , Girvin Mark E. , Diamond Michael S. , Lai Jonathan R.
Published: July 2018

Dengue virus causes approximately 390 million infections per year. Primary infection by one serotype causes a self-limiting febrile illness, but secondary infection by a heterologous serotype can result in severe dengue syndrome, which is characterized by hemorrhagic fever and shock syndrome. This severe disease is thought to arise because of cross-reactive, non- or poorly neutralizing antibodies from the primary infection that are present in serum at the time of secondary infection. These cross-reactive antibodies enhance the infection rather than controlling it. Therefore, induction of a broadly and potently neutralizing antibody response is desirable for dengue vaccine development. Here, we explore a novel strategy for developing immunogens based on domain III of the E glycoprotein, where undesirable epitopes (nonneutralizing or nonconserved) are masked by mutation. This work provides fundamental insight into the immune response to domain III that can be leveraged for future immunogen design.
Use of a three-dimensional scanner for shrinkage curve tests
Authors: Wong Jonathan M. , Elwood David , Fredlund Delwyn G.
Published: July 2018

A procedure is proposed for conducting shrinkage limit tests using a three-dimensional (3D) scanner. Shrinkage limit tests were conducted on 27 different soils of varying plasticity. In this study only eight of the shrinkage curves were determined using 3D scanning techniques, while the remaining 19 were taken from literature. An individual specimen was scanned between 30 and 50 times to produce a high-resolution shrinkage curve. Shrinkage curves for each material were obtained by curve fitting a shrinkage model to the measured dataset. The primary intent of the research was to relate the shrinkage curve equation to the plasticity of a given soil. Using linear regression analysis, an empirical correlation was developed to reasonably relate parameter cshfrom the shrinkage model to the ratio of the plastic and liquid limits. The shrinkage curves produced based on the model have an average difference of ∼1.2% in terms of measured void ratio and predicted void ratio. The method was demonstrated to be robust for materials of low, medium, and high plasticity. The proposed methodology also presents a means of estimating a shrinkage curve in its entirety based solely on the volume of an air-dried sample, the specific gravity, and Atterberg limits of the specimen. This effectively reduces the amount of work needed to derive the shrinkage curve and could potentially reduce the time for a shrinkage limit test by half or more.
Robust control for permanent magnet in-wheel motor in electric vehicles using adaptive fuzzy neural network with inverse system decoupling
Authors: Li Yong , Zhang Bohan , Xu Xing
Published: July 2018

To eliminate the chattering phenomenon and effectively enhance the robustness and dynamic response of the speed control system of a permanent magnet in-wheel motor (PMIWM), a novel decoupling approach is proposed. The speed control system of the PMIWM is analyzed and modeled. By introducing the inverse model into the original PMIWM system, a new decoupling pseudo-linear system is established. A control method based on adaptive fuzzy neural network (AFNN) is investigated to obtain an accurate speed trajectory. The inverse system control approach is introduced into the AFNN-based control system. The PMIWM speed is decoupled completely by the proposed adaptive fuzzy neural network inverse (AFNNI) method. Experiments are carried out on a hardware-in-the-loop (HIL) test bench. Compared with traditional PID control scheme, the proposed AFNNI control strategy can realize a better speed control performance and ensure the robust stability of the PMIWM, even though the motor may suffer from both sudden change in velocity and severe variation under different drive cycles.
Flos Magnoliae Inhibits Chloride Secretion via ANO1 Inhibition in Calu-3 Cells
Authors: Kim Hyun Jong , Nam Yu Ran , Nam Joo Hyun
Published: July 2018

Flos Magnoliae (FM, Chinese name: Xin-yi) is an oriental medicinal herb commonly used for symptomatic relief from allergic rhinitis, sinusitis, and headache, including in traditional Chinese and Korean medicine formulations. FM inhibits histamine release from mast cells and cytokine secretion from T cells. However, the mechanism of action of FM on the anoctamin-1 (ANO1) ion channel, which is responsible for nasal hypersecretion in allergic rhinitis, has not been elucidated. Therefore, in this study, we investigated the effect of a 30% ethanolic extract of FM (FMEtOH) and its chemical constituents on ANO1 activity. We used high-performance liquid chromatography analysis to identify five major chemical constituents of FMEtOH: vanillic acid, tiliroside, eudesmin, magnolin, and fargesin. Using a conventional whole-cell patch clamp method, we found that FMEtOH (30, 100, and 300[Formula: see text][Formula: see text]g/mL) and its chemical constituent tiliroside inhibited ANO1 activity in ANO1-overexpressing HEK293T cells. In addition, we found that the treatment of the airway epithelial cell line Calu-3 with interleukin 4 significantly increased Ca[Formula: see text] activated Cl[Formula: see text] current (ICaCC), but not cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride current (ICFTR). FMEtOH and tiliroside specifically inhibited ICaCC. Thus, in this study, we identified a novel mechanism underlying the alleviation of allergic rhinitis by FMEtOH. Our results indicate that FMEtOH and its chemical constituent tiliroside are promising and potent agents for the prevention and treatment of allergic rhinitis.
A High Value, Linear and Tunable CMOS Pseudo-Resistor for Biomedical Applications
Authors: Nagulapalli R. , Hayatleh K. , Barker S. , Georgiou P. , Lidgey F. J.
Published: July 2018

A subthreshold MOS-based pseudo-resistor featuring a very high value and ultra-low distortion is proposed. A bandpass neural amplifier with a very low high-pass cutoff frequency is designed, to demonstrate the linearity of the proposed resistor. A BJT less CTAT current generator has been introduced to minimize the temperature drift of the resistor and make tuning easier. The standalone resistor has achieved 0.5% better linearity and a 12% improved temperature coefficient over the existing architectures. A neural amplifier has been designed with the proposed resistor as a feedback element. It demonstrated 31[Formula: see text]dB mid-band gain and a low-pass cutoff frequency of 0.85[Formula: see text]Hz. The circuit operates from a 1[Formula: see text]V supply and draws 950[Formula: see text]nA current at room temperature.
The Yamada polynomial of spatial graphs obtained by edge replacements
Authors: Li Miaowang , Lei Fengchun , Li Fengling , Vesnin Andrei
Published: July 2018

We present formulae for computing the Yamada polynomial of spatial graphs obtained by replacing edges of plane graphs, such as cycle-graphs, theta-graphs, and bouquet-graphs, by spatial parts. As a corollary, it is shown that zeros of Yamada polynomials of some series of spatial graphs are dense in a certain region in the complex plane, described by a system of inequalities. Also, the relation between Yamada polynomial of graphs and the chain polynomial of edge-labeled graphs is obtained.
Randomized feasible interpolation and monotone circuits with a local oracle
Authors: Krajíček Jan
Published: July 2018

The feasible interpolation theorem for semantic derivations from [J. Krajíček, Interpolation theorems, lower bounds for proof systems, and independence results for bounded arithmetic, J. Symbolic Logic 62(2) (1997) 457–486] allows to derive from some short semantic derivations (e.g. in resolution) of the disjointness of two [Formula: see text] sets [Formula: see text] and [Formula: see text] a small communication protocol (a general dag-like protocol in the sense of Krajíček (1997) computing the Karchmer–Wigderson multi-function [Formula: see text] associated with the sets, and such a protocol further yields a small circuit separating [Formula: see text] from [Formula: see text]. When [Formula: see text] is closed upwards, the protocol computes the monotone Karchmer–Wigderson multi-function [Formula: see text] and the resulting circuit is monotone. Krajíček [Interpolation by a game, Math. Logic Quart. 44(4) (1998) 450–458] extended the feasible interpolation theorem to a larger class of semantic derivations using the notion of a real communication complexity (e.g. to the cutting planes proof system CP). In this paper, we generalize the method to a still larger class of semantic derivations by allowing randomized protocols. We also introduce an extension of the monotone circuit model, monotone circuits with a local oracle (CLOs), that does correspond to communication protocols for [Formula: see text] making errors. The new randomized feasible interpolation thus shows that a short semantic derivation (from a certain class of derivations larger than in the original method) of the disjointness of [Formula: see text], [Formula: see text] closed upwards, yields a small randomized protocol for [Formula: see text] and hence a small monotone CLO separating the two sets. This research is motivated by the open problem to establish a lower bound for proof system [Formula: see text] operating with clauses formed by linear Boolean functions over [Formula: see text]. The new randomized feasible interpolation applies to this proof system and also to (the semantic versions of) cutting planes CP, to small width resolution over CP of Krajíček [Discretely ordered modules as a first-order extension of the cutting planes proof system, J. Symbolic Logic 63(4) (1998) 1582–1596] (system R(CP)) and to random resolution RR of Buss, Kolodziejczyk and Thapen [Fragments of approximate counting, J. Symbolic Logic 79(2) (2014) 496–525]. The method does not yield yet lengths-of-proofs lower bounds; for this it is necessary to establish lower bounds for randomized protocols or for monotone CLOs.
A Genetic Algorithm-Based Classification Approach for Multicriteria ABC Analysis
Authors: Kaabi Hadhami , Jabeur Khaled , Ladhari Talel
Published: July 2018

ABC analysis is a widespread classification technique designed to manage inventory items in an effective way by relaxing controls on low valued items and applying more rigorous controls on high valued items. In the literature, many classification models issued from different methodologies such as Mathematical Programming (MP), Metaheuristics, Artificial Intelligence (AI) and Multicriteria Decision Making (MCDM) are proposed to perform the ABC inventory classification. To the best of our knowledge, the cross-fertilization of classification models issued from different methodologies is rarely tackled in the literature. This paper proposes some hybrid classification models based on both Genetic Algorithm (Metaheuristics) and two MCDM methods (Weighted Sum (WS) and Technique for Order Preference by Similarity to Ideal Solution (TOPSIS)) to carry out the ABC inventory classification. To test the performance of the proposed classification models with respect to some existing models, a benchmark dataset from a Hospital Respiratory Therapy Unit (HRTU) is used. The computational results show that our proposed models outperformed the existing classification models according to some inventory performance measures. An additional performance analysis has also shown the effectiveness of our proposed models in inventory management.
The SOFIA Telescope in Full Operation
Authors: Reinacher Andreas , Graf Friederike , Greiner Benjamin , Jakob Holger , Lammen Yannick , Peter Sarah , Wiedemann Manuel , Zeile Oliver , Kaercher Hans J.
Published: July 2018

The SOFIA telescope is a 2.5[Formula: see text]m class Cassegrain telescope with Nasmyth focus. It is the largest telescope ever integrated into an aircraft. The telescope is exposed to the stratospheric environment during the observations and the fact that the telescope’s foundation, which is a Boeing 747 SP, is vibrating and moving in all degrees of freedom (DoF) requires a highly specialized and sophisticated design. Based on the telescope of its predecessor, the Kuiper Airborne Observatory (KAO), the SOFIA telescope design had to evolve to accommodate a telescope 2.5 times the size of KAO. In several hundred successful observation flights, the telescope proved that it performs not only as specified, but is also extremely reliable. Nevertheless, the telescope’s software and hardware are continuously upgraded to optimize its performance without interfering with the observation schedules to reach even more ambitious image size and pointing jitter goals to enable additional science cases. In addition, manufacturing of the line-replaceable units is in process to ensure that the SOFIA telescope can perform without any major interruptions for the envisioned 20 year lifetime. Some of the main features of the SOFIA telescope are its suspension assembly (SUA), which decouples the telescope from SOFIA’s fuselage with air springs and a spherical oil bearing, the extremely stiff Nasmyth tube (NT), which connects cavity and cabin mounted components of the dumbbell design, and the Secondary Mirror Assembly (SMA), which is used for chopping and fast pointing corrections. This paper aims to give an overview of these and all other major telescope subsystems in operation today. In addition, some of the upgrades, either implemented recently or slated for implementation shortly, are introduced.
Systematically Understanding the Cyber Attack Business
Authors: Huang Keman , Siegel Michael , Madnick Stuart
Published: July 2018

Cyber attacks are increasingly menacing businesses. Based on the literature review and publicly available reports, this article conducts an extensive and consistent survey of the services used by the cybercrime business, organized using the value chain perspective, to understand cyber attack in a systematic way. Understanding the specialization, commercialization, and cooperation for cyber attacks helps us to identify 24 key value-added activities and their relations. These can be offered “as a service” for use in a cyber attack. This framework helps to understand the cybercriminal service ecosystem and hacking innovations. Finally, a few examples are provided showing how this framework can help to build a more cyber immune system, like targeting cybercrime control-points and assigning defense responsibilities to encourage collaboration.
Religion and Climate Change
Authors: Jenkins Willis , Berry Evan , Kreider Luke Beck
Published: July 2018

Understanding the cultural dimensions of climate change requires understanding its religious aspects. Insofar as climate change is entangled with humans, it is also entangled with all the ways in which religion attends human ways of being. Scholarship on the connections between religion and climate change includes social science research into how religious identity figures in attitudes toward climate change, confessional and constructive engagements of religious thought with climate change from various communities and traditions, historical and anthropological analyses of how climate affects religion and religion interprets climate, and theories by which climate change may itself be interpreted as a religious event. Responses to climate change by indigenous peoples challenge the categories of religion and of climate change in ways that illuminate reflexive stresses between the two cultural concepts.
The Rise of International Regime Complexity
Authors: Alter Karen J. , Raustiala Kal
Published: July 2018

The signature feature of twenty-first-century international cooperation is arguably not the regime but the regime complex. A regime complex is an array of partially overlapping and nonhierarchical institutions that includes more than one international agreement or authority. The institutions and agreements may be functional or territorial in nature. International regime complexity refers to international political systems of global governance that emerge because of the coexistence of rule density and regime complexes. This article highlights insights and questions that emerge from the last 15 years of scholarship on the politics of international regime complexity, explaining why regime complexes arise, what factors sustain them, and the range of political effects regime complexity creates. Our conclusion explains why, in a post-American world order, the trend of greater international regime complexity will likely accelerate.
Age-dependent cardiac function during experimental sepsis: effect of pharmacological activation of AMP-activated protein kinase by AICAR
Authors: Inata Yu , Piraino Giovanna , Hake Paul W. , O’Connor Michael , Lahni Patrick , Wolfe Vivian , Schulte Christine , Moore Victoria , James Jeanne M. , Zingarelli Basilia
Published: July 2018

Age represents a major risk factor for multiple organ failure, including cardiac dysfunction, in patients with sepsis. AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis that controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-γ coactivator-1α and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation contributes to age-dependent cardiac injury in young (2–3 mo) and mature adult (11–13 mo) male mice subjected to sepsis by cecal ligation and puncture and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside affords cardioprotective effects. Plasma proinflammatory cytokines and myokine follistatin were similarly elevated in vehicle-treated young and mature adult mice at 18 h after sepsis. However, despite equivalent troponin I and T levels compared with similarly treated young mice, vehicle-treated mature adult mice exhibited more severe cardiac damage by light and electron microscopy analyses with more marked intercellular edema, inflammatory cell infiltration, and mitochondrial derangement. Echocardiography revealed that vehicle-treated young mice exhibited left ventricular dysfunction after sepsis, whereas mature adult mice exhibited a reduction in stroke volume without apparent changes in load-dependent indexes of cardiac function. At molecular analysis, phosphorylation of the catalytic subunits AMPK-α1/α2 was associated with nuclear translocation of peroxisome proliferator-activated receptor-γ coactivator-1α in vehicle-treated young but not mature adult mice. Treatment with 5-amino-4-imidazole carboxamide riboside ameliorated cardiac architecture derangement in mice of both ages. These cardioprotective effects were associated with attenuation of the systemic inflammatory response and amelioration of cardiac dysfunction in young mice only, not in mature adult animals.

NEW & NOTEWORTHY Our data suggest that sepsis-induced cardiac dysfunction manifests with age-dependent characteristics, which are associated with a distinct regulation of AMP-activated protein kinase-dependent metabolic pathways. Consistent with this age-related deterioration, pharmacological activation of AMP-activated protein kinase may afford cardioprotective effects allowing a partial recovery of cardiac function in young but not mature age.
Erbin Suppresses KSR1-Mediated RAS/RAF Signaling and Tumorigenesis in Colorectal Cancer
Authors: Stevens Payton D. , Wen Yang-An , Xiong Xiaopeng , Zaytseva Yekaterina Y. , Li Austin T. , Wang Chi , Stevens Ashley T. , Farmer Trevor N. , Gan Tong , Weiss Heidi L. , Inagaki Masaki , Marchetto Sylvie , Borg Jean-Paul , Gao Tianyan
Published: July 2018

Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that plays important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colorectal cancer. Analysis of Erbin expression in colorectal cancer patient specimens revealed that Erbin was downregulated at both mRNA and protein levels in tumor tissues. Knockdown of Erbin disrupted epithelial cell polarity and increased cell proliferation in 3D culture. In addition, silencing Erbin resulted in increased amplitude and duration of signaling through Akt and RAS/RAF pathways. Erbin loss induced epithelial–mesenchymal transition, which coincided with a significant increase in cell migration and invasion. Erbin interacted with kinase suppressor of Ras 1 (KSR1) and displaced it from the RAF/MEK/ERK complex to prevent signal propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promoted tumorigenesis and significantly reduced survival. Tumor organoids derived from Erbin/Apc double knockout mice displayed increased tumor initiation potential and activation of Wnt signaling. Results from gene set enrichment analysis revealed that Erbin expression associated positively with the E-cadherin adherens junction pathway and negatively with Wnt signaling in human colorectal cancer. Taken together, our study identifies Erbin as a negative regulator of tumor initiation and progression by suppressing Akt and RAS/RAF signaling in vivo.

Significance: These findings establish the scaffold protein Erbin as a negative regulator of EMT and tumorigenesis in colorectal cancer through direct suppression of Akt and RAS/RAF signaling. Cancer Res; 78(17); 4839–52. ©2018 AACR.
Functions and Mechanisms of Tumor Necrosis Factor-α and Noncoding RNAs in Bone-Invasive Pituitary Adenomas
Authors: Zhu Haibo , Guo Jing , Shen Yutao , Dong Wei , Gao Hua , Miao Yazhou , Li Chuzhong , Zhang Yazhuo
Published: July 2018

Purpose: To explore the molecular mechanism and prognosis of bone-invasive pituitary adenomas (BIPA).

Experimental design: A total of 274 patients with pituitary adenomas were followed up. Transcriptomic microarrays analysis was performed on 10 pituitary adenomas, including five BIPAs and five non-bone-invasive pituitary adenomas (NBIPA). The targeted molecular markers were validated by qRT-PCR, IHC, ELISA, and osteoclast differentiation.

Results: Clinical variable analyses revealed a significant correlation between bone invasion and female sex, large tumor volume, non-gross total resection (NGTR), and tumor regrowth. BIPAs had worse progression-free survival (PFS) than did NBIPAs in the NGTR and nonfunctional pituitary adenoma (NFPA) groups. Gene ontology functional and KEGG pathway analyses showed that the biological processes and pathways were primarily immune and inflammatory pathways. Pathway act work showed that osteoclast differentiation pathway was significantly implicated in the pathway network. BIPAs had higher expression of TNFα than that of NBIPAs on IHC. In vitro, TNFα could induce RAW264.7 cells to differentiate into mature osteoclasts, leading to bone destruction. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression.

Conclusions: BIPAs had worse PFS than did NBIPAs in the NGTR and NFPA groups. Inflammatory and immune factors play an important role in BIPAs. TNFα can directly induce osteoclast differentiation in BIPAs. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression. TNFα and its related lncRNAs and miRNAs represent potential therapeutic targets for bone-invasive pituitary adenomas in the future. Clin Cancer Res; 24(22); 5757–66. ©2018 AACR.
Molecular Imaging of Radiolabeled Bispecific T-Cell Engager 89Zr-AMG211 Targeting CEA-Positive Tumors
Authors: Waaijer Stijn J.H. , Warnders Frank J. , Stienen Sabine , Friedrich Matthias , Sternjak Alexander , Cheung H. Kam , van Scheltinga Anton G.T. Terwisscha , Schröder Carolien P. , de Vries Elisabeth G.E. , Lub-de Hooge Marjolijn N.
Published: July 2018

Purpose: AMG 211, a bispecific T-cell engager (BiTE) antibody construct, targets carcinoembryonic antigen (CEA) and the CD3 epsilon subunit of the human T-cell receptor. AMG 211 was labeled with zirconium-89 (89Zr) or fluorescent dye to evaluate the tumor-targeting properties.

Experimental Design: 89Zr-AMG211 was administered to mice bearing CEA-positive xenograft tumors of LS174T colorectal adenocarcinoma or BT474 breast cancer cells, as well as CEA-negative HL-60 promyelocytic leukemia xenografts. Biodistribution studies with 2- to 10-μg 89Zr-AMG211 supplemented with unlabeled AMG 211 up to 500-μg protein dose were performed. A BiTE that does not bind CEA, 89Zr-Mec14, served as a negative control. 89Zr-AMG211 integrity was determined in tumor lysates ex vivo. Intratumoral distribution was studied with IRDye800CW-AMG211. Moreover, 89Zr-AMG211 was manufactured according to Good Manufacturing Practice (GMP) guidelines for clinical trial NCT02760199.

Results: 89Zr-AMG211 demonstrated dose-dependent tumor uptake at 6 hours. The highest tumor uptake was observed with a 2-μg dose, and the lowest tumor uptake was observed with a 500-μg dose. After 24 hours, higher uptake of 10-μg 89Zr-AMG211 occurred in CEA-positive xenografts, compared with CEA-negative xenografts. Although the blood half-life of 89Zr-AMG211 was approximately 1 hour, tumor retention persisted for at least 24 hours. 89Zr-Mec14 showed no tumor accumulation beyond background level. Ex vivo autoradiography revealed time-dependent disintegration of 89Zr-AMG211. 800CW-AMG211 was specifically localized in CEA-expressing viable tumor tissue. GMP-manufactured 89Zr-AMG211 fulfilled release specifications.

Conclusions: 89Zr-AMG211 showed dose-dependent CEA-specific tumor targeting and localization in viable tumor tissue. Our data enabled its use to clinically evaluate AMG 211 in vivo behavior. Clin Cancer Res; 24(20); 4988–96. ©2018 AACR.
Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives
Authors: Alastruey-Izquierdo Ana , Cadranel Jacques , Flick Holger , Godet Cendrine , Hennequin Christophe , Hoenigl Martin , Kosmidis Chris , Lange Christoph , Munteanu Oxana , Page Iain , Salzer Helmut J.F. ,   on behalf of CPAnet
Published: July 2018

Chronic pulmonary aspergillosis (CPA) complicates conditions including tuberculosis, chronic obstructive pulmonary disease and sarcoidosis, and is associated with high morbidity and mortality. Surgical cure should be considered where feasible; however, many patients are unsuitable for surgery due to extensive disease or poor respiratory function. Azoles are the only oral drug with anti-Aspergillus activity and itraconazole and voriconazole are considered as first-line drugs. A randomized controlled trial demonstrated improvement or stability in three-quarters of patients given 6 months of itraconazole, but a quarter relapsed on stopping therapy. Long-term treatment may therefore be required in some cases. Itraconazole, voriconazole and posaconazole require therapeutic drug monitoring. No published data are yet available for isavuconazole. Adverse drug effects of azoles are common, including peripheral neuropathy, heart failure, elevated liver enzymes, QTc prolongation and sun sensitivity. Many serious drug-drug interactions occur, including major interactions with rifamycins, simvastatin, warfarin, clopidogrel, immunosuppressant drugs like sirolimus. Furthermore, drug resistance occurs, including cross-resistance to all azoles, but the true prevalence is not yet determined. Intravenous therapy is possible with echinocandins or amphotericin B, but long-term use is challenging. Hemoptysis complicates CPA and can be fatal. Tranexamic acid should be given acutely to reduce bleeding. Bronchial artery embolization can stop acute bleeds. In some circumstances, emergency surgery may be necessary to resect the source of the bleed. Current CPA treatments can be beneficial but have many drawbacks. New oral anti-Aspergillus agents are needed, along with optimization of currently available treatments.
Mastocytic Enterocolits and the Role of Mast Cells in Functional and Inflammatory Intestinal Disorders: A Systematic Review
Authors: Capannolo Annalisa , Ciccone Fabiana , Latella Giovanni
Published: July 2018

Background: Chronic diarrhoea affects 5–10% of the adult population. Histologic lesions of possible diagnostic significance are found under normal colonoscopy in approximately 30% of patients affected by chronic diarrhoea. Mastocytic enterocolitis is characterized by an increase in the number of mucosal mast cells (MC) in the gut of patients with chronic intractable diarrhoea, detected by immunohistochemical staining, responding to mast-cell targeted drugs. The question arises whether to search for MC infiltration in specific subsets of patients as a matter of routine clinical practice. Summary: A systematic electronic search of the English literature up to December 2017 was performed, using Medline, EMBASE, Web of Science, Scopus, and the Cochrane Library. This revealed 9 studies reporting an increased number of MC in the gut mucosa of patients with chronic diarrhoea. No consensus was found, however, on the actual cutoff point, the overlap in range between patients and controls being too great to be of clinical significance. The available evidence does not therefore justify the routine evaluation of MC count. Key Messages: More studies are needed to better define MC count and the significance of MC degranulation in normal and pathological settings. Until these become available, the search for MC infiltration in specific subsets of patients should be restricted to research settings.
The Expression of MAS1, an Angiotensin (1–7) Receptor, in the Eutopic Proliferative Endometria of Endometriosis Patients
Authors: Nakajima Takahiro , Chishima Fumihisa , Nakao Takehiro , Hayashi Chuyu , Kasuga Akiko , Shinya Kaori , Nakayama Takuo , Azuma Hiromitsu , Ichikawa Go , Komatsu Atsushi , Yamamoto Tatsuo , Kawana Kei
Published: July 2018

Background/Aim: We demonstrated that AT1 and AT2 are expressed and both pathways balance the renin-angiotensin system in endometriosis. MAS1, a specific receptor of angiotensin (1–7), opposes AT1 pathway-associated tissue remodelling. It is not known whether MAS1 has an effect on the pathogenesis of endometriosis or not. Materials and Methods: Ovarian endometriotic tissues (endo-Ov) and eutopic endometrial tissues (endo-Em) were obtained from 29 patients with endometrial cysts. Normal endometrial tissues (cont-Em) were obtained from patients without endometriosis. Immunohistochemical staining was performed for MAS1, AT1 and AT2 in the endometriosis-associated tissues. The mRNA levels of these receptors were examined by quantitative reverse transcription PCR. Results: MAS1 was immune-positive at the apical side of the glandular epithelium in the endometriotic lesions. The MAS1 mRNA levels in endo-Ov were increased significantly, irrespective of the menstrual cycle phase. The MAS1 mRNA levels were significantly higher in the proliferative-tissues of the endometriosis patients than in those of the controls. The ratio of the MAS1 to the AT1 mRNA in the proliferative tissues was increased predominantly in the endometriosis patients compared with that in the controls. Conclusion: High MAS1 expression in the endometrium might promote the initiation of endometriosis via migration of proliferative tissue.
Comparison of Serum A Disintegrin and Metalloproteinase with Thrombospondin Motifs-19 Levels in Different Fertility Situations: Could It Be a Serum Marker of Ovarian Function and Oocyte Pool?
Authors: Ersoy Ebru , Özler Sibel , Öztaş Efser , Ersoy Ali Özgür , Ergin Merve , Tokmak Aytekin , Yilmaz Nafiye
Published: July 2018

Background/Aims: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) enzymes take part in extracellular matrix (ECM) remodeling which has been shown to contribute to the ovulation and follicular functions. We aimed to compare serum levels of ADAMTS-19 in patients with different fertility situations. Methods: A total of 86 women were enrolled to this cross sectional and case-control study. Four groups were constituted with respect to women’s clinical and hormonal status: group 1, women with premature ovarian failure (POF; n = 21); group 2, women with natural menopause (n = 21); group 3, women with polycystic ovary syndrome (PCOS; n = 22); and group 4, healthy fertile controls. Serum ADAMTS-19 levels and individual characteristics were compared among groups. Results: ­ADAMTS-19 levels were found as 36.7 ± 10.2, 40.1 ± 12.6, 46.7 ± 16.1, and 51.0 ± 18.8 ng/mL in POF, fertile, natural menopause, and PCOS groups, respectively (p = 0.012). Especially, ADAMTS-19 levels in the PCOS group were significantly higher than the POF group, as found in dual comparisons (p = 0.010). Conclusions: ADAMTS-19 was found to be higher in PCOS patients than in POF patients. This work provides a novel vantage point for function of ECM within the ovary. ADAMTS-19 may have a potential for being an important marker of ovarian function and oocyte pool.
Implementation of Intravenous Drip Infusion Therapy with Peripheral Venous Catheters and the Incidence of Related Complications in Home-Based Medical Care Settings in Japan
Authors: Nakayama Naomi , Higashiguchi Takashi , Hanada Kozue , Maniwa Akiko , Kanemoto Yukiko , Sugiura Hiroaki , Hara Yoshie , Nakayama Kentaro
Published: July 2018

Background/Aims: Home-based medical care is rapidly expanding in Japanese health care settings. We aimed to clarify the implementation status of drip injection with peripheral venous catheters (PVCs) and the incidence of related complications. Methods: We investigated the number of patients who required intravenous drip infusion therapy at home. We also examined the incidence rate of PVC-related complications and their statistical correlation with patients’ characteristics. Results: Of 139 patients, 30 (21.6%) received intravenous drip infusion therapy through PVCs at home. Patients’ activities of daily living (bed-ridden) and the presence of underlying disease (terminal cancer) were significantly correlated with the requirement for drip infusion therapy (p < 0.0001 and p < 0.0001, respectively). A high incidence of PVC-related complications (75%: 15 out of 20 patients) was observed. More than 50% of patients experienced multiple needling due to difficulty in securing venous access. Conclusions: This is the first report to reveal the relatively high incidence of PVC-related complications in home-based medical care settings. Safer vascular devises should be incorporated for more stable intervention.
The Impact of Pregnancy on Hemorrhagic Stroke in Young Women
Authors: Miller Eliza C. , Sundheim Kathryn M. , Willey Joshua Z. , Boehme Amelia K. , Agalliu Dritan , Marshall Randolph S.
Published: July 2018

Background: Pregnancy is a sex-specific risk factor for causing hemorrhagic stroke (HS) in young adults. Unique physiological characteristics during pregnancy may alter the relative risk for HS in pregnant/postpartum (PP) women compared to HS in other young women. We compared patient characteristics and HS subtypes between young non-pregnant and PP women. Methods: We reviewed the medical records of all women 18–45 years old admitted to our center with HS from October 15, 2008 through March 31, 2015, and compared patient characteristics and stroke mechanisms using logistic regression. Results: Of the 130 young women with HS during the study period, 111 were non-PP women, and 19 PP women. PP women had lower proportions of vascular risk factors such as hypertension, prior stroke, and smoking, and a higher proportion of migraine (36.8 vs. 14.4%, p = 0.01). After adjusting for hypertension, smoking, migraine, prior stroke and prior myocardial infarction, PP women had lower odds of having an underlying vascular lesion (OR 0.14, 95% CI 0.04–0.44, p = 0.0009) and a higher proportion of the reversible cerebral vasoconstriction syndrome (RCVS) as cause of their HS. Conclusions: Women with pregnancy-associated HS had fewer cerebrovascular risk factors, lower odds of having ­underlying vascular lesions, and higher proportion of ­migraine and RCVS compared with similar-aged non-­pregnant women. Pregnancy-associated HS appears to represent a unique pathophysiological process, requiring targeted study.
Iron Homeostasis Pathways as Therapeutic Targets in Acute Kidney Injury
Authors: Swaminathan Sundararaman
Published: July 2018

Background: Iron is critical for fundamental biologic functions such as cell division and mitochondrial electron transport. However, by the virtue of its ability to donate electrons, iron is probably the most effective oxidant in biologic systems. Summary: To avoid damage from iron-mediated oxidative injury or ferroptosis, multiple defense mechanisms exist including iron binding proteins and robust glutathione-dependent intracellular pathways. Hepcidin, through its ability to sequester iron within macrophages and induce H-ferritin, serves as an endogenous protective molecule against ferroptosis. Key Messages: Recent studies have demonstrated the protective role of hepcidin in both ischemic reperfusion injury and heme-mediated models of acute kidney injury (AKI). Ferroptosis-inhibiting drugs and hepcidin offer exciting novel prospects to treat AKI.
Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy
Authors: Kagemoto Tatsuya , Oyama Kotaro , Yamane Mitsunori , Tsukamoto Seiichi , Kobirumaki-Shimozawa Fuyu , Li Amy , Dos Remedios Cristobal , Fukuda Norio , Ishiwata Shin’ichi
Published: July 2018

Background:

Left ventricular wall motion is depressed in patients with dilated cardiomyopathy (DCM). However, whether or not the depressed left ventricular wall motion is caused by impairment of sarcomere dynamics remains to be fully clarified.

Methods and Results:

We analyzed the mechanical properties of single sarcomere dynamics during sarcomeric auto-oscillations (calcium spontaneous oscillatory contractions [Ca-SPOC]) that occurred at partial activation under the isometric condition in myofibrils from donor hearts and from patients with severe DCM (New York Heart Association classification III-IV). Ca-SPOC reproducibly occurred in the presence of 1 μmol/L free Ca
2+
in both nonfailing and DCM myofibrils, and sarcomeres exhibited a saw-tooth waveform along single myofibrils composed of quick lengthening and slow shortening. The period of Ca-SPOC was longer in DCM myofibrils than in nonfailing myofibrils, in association with prolonged shortening time. Lengthening time was similar in both groups. Then, we performed Tn (troponin) exchange in myofibrils with a DCM-causing homozygous mutation (K36Q) in cTnI (cardiac TnI). On exchange with the Tn complex from healthy porcine ventricles, period, shortening time, and shortening velocity in cTnI-K36Q myofibrils became similar to those in Tn-reconstituted nonfailing myofibrils. Protein kinase A abbreviated period in both Tn-reconstituted nonfailing and cTnI-K36Q myofibrils, demonstrating acceleration of cross-bridge kinetics.

Conclusions:

Sarcomere dynamics was found to be depressed under loaded conditions in DCM myofibrils because of impairment of thick-thin filament sliding. Thus, microscopic analysis of Ca-SPOC in human cardiac myofibrils is beneficial to systematically unveil the kinetic properties of single sarcomeres in various types of heart disease.
ɸ-Features at the Syntax-Semantics Interface: Evidence from Nominal Inflection
Authors: Kučerová Ivona
Published: July 2018

I argue for a novel model of feature valuation in the CI interface and explore under what circumstances a syntactic feature is semantically interpretable. As the groundwork for the investigation, I propose an explicit Distributed Morphology model of Italian nouns of profession. The data provide evidence that the morphology accesses the narrow-syntax representation at two different temporal points within a phase: the earlier point (Spell-Out) returns a morphological realization faithful to feature values present in narrow syntax, while the later point (Transfer) allows for a narrow-syntax representation to be enriched by the CI component. Thus, there is no syntactic distinction between interpretable and uninterpretable features: a syntactic feature appears to be interpretable only if it has been licensed by the CI interface.
On the Difference between the Lexicon and Computation (Regarding Slavic Yers)
Authors: Scheer Tobias
Published: July 2018

This article discusses three concerns regarding Becker and Gouskova’s (2016) analysis of Russian yers that relies on cluster-based yer vocalization and two sublexicons (morphemes with and without yers), to which lexically specific constraints refer. First, it misses the basic generalization about Slavic yers expressed by the established analysis (Lower): yer vocalization is triggered by five different mechanisms, instead of one mechanism under Lower. It is further shown that the major objection against Lower disappears when the existence of final empty nuclei is recognized. Second, Becker and Gouskova confound generalizations about the lexical distribution of yers in morphemes and the computational mechanism that decides which yers appear on the surface. They argue that Lower was established before relevant cluster-based generalizations were discovered, hence misses out on relevant empirical material that invalidates its central idea, that clusters are irrelevant for yer vocalization. However, the phenomena their argument is based on do not concern yer vocalization (computation): they are lexical in kind and therefore confirm the irrelevance of clusters for yer vocalization, supporting Lower. Third, although generalizations about yer-deletion-created clusters are central for Becker and Gouskova’s analysis, they are irrelevant for learners (children or adults). The authors’ experimental evidence precisely shows that speakers are happy to lexicalize and compute sequences (such as yerCC) that are absent from the lexicon. The gaps at hand are thus accidental, rather than systematic.
“Trump’s First Year in Asia: Accelerating a Long-term Trend”
Authors: Kang David C.
Published: July 2018

What has been the impact of Donald J. Trump’s presidency on the place of the United States in East Asia? Trump already has shown a proclivity for upending the mainstream American consensus about grand strategy to East Asia, with the real possibility of a trade war with China or a shooting war with North Korea on the horizon. However, this article will place President Trump’s first year in office into a larger context of long-term decline of U.S. leadership and influence in East Asia, arguing that this trend has been underway for quite some time, and that Trump has not altered fundamentally this trajectory. Some of Trump’s actions may accelerate a decline in U.S. leadership, but by no means was Trump the first nor will he be the last U.S. president to deal with a swiftly changing East Asia. The region has been changing rapidly for decades, and there are no indications that this will stop anytime soon. However, continuing and gradual U.S. withdrawal from leadership does not mean less American-East Asia interaction. East Asia will remain the most important trading and investment region for the U.S. for the foreseeable future.