bluuebunny/crossref_metadata_2025 huggingface dataset:
Feature Selection and Overlapping Clustering-Based Multilabel Classification Model
Authors: Peng Liwen , Liu Yongguo
Published: January 2018

Multilabel classification (MLC) learning, which is widely applied in real-world applications, is a very important problem in machine learning. Some studies show that a clustering-based MLC framework performs effectively compared to a nonclustering framework. In this paper, we explore the clustering-based MLC problem. Multilabel feature selection also plays an important role in classification learning because many redundant and irrelevant features can degrade performance and a good feature selection algorithm can reduce computational complexity and improve classification accuracy. In this study, we consider feature dependence and feature interaction simultaneously, and we propose a multilabel feature selection algorithm as a preprocessing stage before MLC. Typically, existing cluster-based MLC frameworks employ a hard cluster method. In practice, the instances of multilabel datasets are distinguished in a single cluster by such frameworks; however, the overlapping nature of multilabel instances is such that, in real-life applications, instances may not belong to only a single class. Therefore, we propose a MLC model that combines feature selection with an overlapping clustering algorithm. Experimental results demonstrate that various clustering algorithms show different performance for MLC, and the proposed overlapping clustering-based MLC model may be more suitable.
Yuk-Mi-Jihwang-Tang, a Traditional Korean Multiple Herbal Formulae, Improves Hippocampal Memory on Scopolamine Injection‐Induced Amnesia Model of C57BL/6 Mice
Authors: Lee Hye-Lim , Lim Sung-Ah , Lee Hye-Won , Yoo Ho-Ryong , Kim Hyeong-Geug
Published: January 2018

We evaluated neuropharmacological properties of Yuk‐Mi‐Jihwang‐Tang (YJT) against scopolamine injection‐induced memory impairment mice model. Mice were orally administered with YJT (50, 100, or 200 mg/kg) or tacrine (TAC, 12.5 mg/kg) for 10 days. At the first day of Morris water maze task, scopolamine (2 mg/kg) was intraperitoneally injected before 30 min of it. The hippocampal memory function was determined by the Morris water maze task for 5 days consecutively. Scopolamine drastically increased escape latency and decreased time spent in target quadrant. Pretreatment YJT properly improved them. Regarding the redox status, YJT significantly reduced the oxidative stress and it also exerted much effort to improve both superoxide dismutase and catalase activities in hippocampal gene expression and protein levels. These effects were well coincided with immunohistochemical analysis of 4‐hydroxyneal‐positive signals in hippocampal areas. Additionally, acetylcholine esterase activities and brain‐derived neurotrophic factor abnormalities in the hippocampal protein levels were significantly normalized by YJT, and their related molecules were also improved. The neuronal proliferation in hippocampal regions was markedly inhibited by scopolamine, whereas YJT notably recovered them. Collectively, YJT exerts much effort to enhance memorial functions through improving redox status homeostasis and partially regulates acetylcholine esterase activities as well as neuronal cell proliferation.
A Numerical Research on Crack Process of Gypsum Containing Single Flaw with Different Angle and Length in Uniaxial Loading
Authors: Bing Dai , Guicheng He , Zhijun Zhang
Published: January 2018

To investigate the crack behaviour of rock or rock‐like material in uniaxial loading, a series of numerical simulations were conducted on gypsum specimens containing a single flaw with different inclination angle (0°–90°) and length (10 mm–30 mm). Based on the numerical simulations results, the effect of flaw length on peak strength, the CI stress, and the CD stress were investigated with different inclination angles. The results show that the peak strength decreased initially and then increased with increasing of the flaw angle. Meanwhile, the peak strength decreased gradually when the length of the preexisting flaw increased. When the inclination angle was 30°, 45°, and 60°, the reduction degree of peak strength increased with increasing of the flaw length. The CI stress and CD stress not only depend on the inclination angle but also depend on flaw length. Four types of crack were observed in numerical simulations. The present research facilitates increased understanding of crack behaviour of rock under different conditions.
Quantitative Assessment of the Physiological Parameters Influencing QT Interval Response to Medication: Application of Computational Intelligence Tools
Authors: Polak Sebastian , Wiśniowska Barbara , Mendyk Aleksander , Pacławski Adam , Szlęk Jakub
Published: January 2018

Human heart electrophysiology is complex biological phenomenon, which is indirectly assessed by the measured ECG signal. ECG trace is further analyzed to derive interpretable surrogates including QT interval, QRS complex, PR interval, and T wave morphology. QT interval and its modification are the most commonly used surrogates of the drug triggered arrhythmia, but it is known that the QT interval itself is determined by other nondrug related parameters, physiological and pathological. In the current study, we used the computational intelligence algorithms to analyze correlations between various simulated physiological parameters and QT interval. Terfenadine given concomitantly with 8 enzymatic inhibitors was used as an example. The equation developed with the use of genetic programming technique leads to general reasoning about the changes in the prolonged QT. For small changes of the QT interval, the drug-related IKr and ICa currents inhibition potentials have major impact. The physiological parameters such as body surface area, potassium, sodium, and calcium ions concentrations are negligible. The influence of the physiological variables increases gradually with the more pronounced changes in QT. As the significant QT prolongation is associated with the drugs triggered arrhythmia risk, analysis of the role of physiological parameters influencing ECG seems to be advisable.
Spectral Unmixing Imaging for Differentiating Brown Adipose Tissue Mass and Its Activation
Authors: Yang Jing , Yang Jian , Ran Chongzhao
Published: January 2018

Recent large-scale clinical analysis indicates that brown adipose tissue (BAT) mass levels inversely correlate with body-mass index (BMI), suggesting that BAT is associated with metabolic disorders such as obesity and diabetes. PET imaging with 18F-FDG is the most commonly used method for visualizing BAT. However, this method is not able to differentiate between BAT mass and BAT activation. This task, in fact, presents a tremendous challenge with no currently existing methods to separate BAT mass and BAT activation. Our previous results indicated that BAT could be successfully imaged in mice with near infrared fluorescent (NIRF) curcumin analogues. However, the results from conventional NIRF imaging could not reflect what portion of the NIRF signal from BAT activation contributed to the signal observed. To solve this problem, we used spectral unmixing to separate/unmix NIRF signal from oil droplets in BAT, which represents its mass and NIRF signal from blood, which represents BAT activation. In this report, results from our proof-of-concept investigation demonstrated that spectral unmixing could be used to separate NIRF signal from BAT mass and BAT activation.
Manipulation of Plant Growth Regulators on Phytochemical Constituents and DNA Protection Potential of the Medicinal Plant Arnebia benthamii
Authors: Parray Javid A. , Kamili Azra N. , Jan Sumira , Mir Mohammad Yaseen , Shameem Nowsheen , Ganai Bashir A. , Abd_Allah Elsayed Fathi , Hashem Abeer , Alqarawi Abdulaziz A.
Published: January 2018

Arnebia benthamii of the family Boraginaceae is a critically endangered nonendemic plant of the Kashmir Himalayas and is used to treat a number of human diseases. The current study was based on developing an in vitro micropropagation protocol vis-à-vis induction of various secondary metabolites under in vitro conditions for the possible biological activity. A tissue culture protocol was developed for A. benthamii for the first time in the Himalayan region using varied combinations and proper media formulations, including various adjuvants: Murashige and Skoog (MS) media, growth hormones, sugars, agar, and so forth. The influence of different media combinations was estimated, and the MS + thidiazuron (TDZ) + indole 3-acetic acid (IAA) combination favors a higher regeneration potential. The higher amounts of chemical constituents were also recorded on the same treatment. The in vitro plant samples also showed a noteworthy effect of scavenging of hydroxyl radicals vis-à-vis protection from oxidative DNA damage. The in vitro raised plants are good candidates for the development of antioxidant molecules.
Inverse Problem Solution and Regularization Parameter Selection for Current Distribution Reconstruction in Switching Arcs by Inverting Magnetic Fields
Authors: Dong Jinlong , Zhang Guogang , Zhang Zhiqiang , Geng Yingsan , Wang Jianhua
Published: January 2018

Current density distribution in electric arcs inside low voltage circuit breakers is a crucial parameter for us to understand the complex physical behavior during the arcing process. In this paper, we investigate the inverse problem of reconstructing the current density distribution in arcs by inverting the magnetic fields. A simplified 2D arc chamber is considered. The aim of this paper is the computational side of the regularization method, regularization parameter selection strategies, and the estimation of systematic error. To address the ill-posedness of the inverse problem, Tikhonov regularization is analyzed, with the regularization parameter chosen by Morozov’s discrepancy principle, the L-curve, the generalized cross-validation, and the quasi-optimality criteria. The provided range of regularization parameter selection strategies is much wider than in the previous works. Effects of several features on the performance of these criteria have been investigated, including the signal-to-noise ratio, dimension of measurement space, and the measurement distance. The numerical simulations show that the generalized cross-validation and quasi-optimality criteria provide a more satisfactory performance on the robustness and accuracy. Moreover, an optimal measurement distance can be expected when using a planner sensor array to perform magnetic measurements.
Meta-Analysis of miRNAs and Their Involvement as Biomarkers in Oral Cancers
Authors: Zahra Andleeb , Rubab Itrat , Malik Sumaira , Khan Amina , Khan Muhammad Jawad , Fatmi M. Qaiser
Published: January 2018

Oral Squamous Cell Carcinoma (OSCC) is one of the most common cancers worldwide. Recent studies have highlighted the role of miRNA in disease pathology, indicating its potential use as an early diagnostic marker. Dysregulated expression of miRNAs is known to affect cell growth, and these may function as tumor suppressors or oncogenes in various cancers. The main objective of this study was to characterize the extracellular miRNAs involved in oral cancer (OC) that can potentially be used as biomarkers of OC. A total of 318 miRNAs involved in oral carcinoma were shortlisted. Differentially expressed genes (DEGs) of oral carcinoma from reported experiments were identified. Common genes between lists of DEGs of OC of each miRNA were identified. These common genes are the targets of specific miRNA, which may be used as biomarkers of OC. A list of significant biomarkers for cancer was generated like CDH2 and CDK7, and functional enrichment analysis identified the role of miRNAs in major pathways like cell adhesion molecules pathway affected by cancer. We observed that at least 25 genes like ABCF3, ALDH2, CD163L1, and so forth are regulated by a maximum number of miRNAs; thereby, they can be used as biomarkers of OC.
Circulating Serum Level of Visfatin in Patients with Endometrial Cancer
Authors: Cymbaluk-Płoska Aneta , Chudecka-Głaz Anita , Pius-Sadowska Ewa , Sompolska-Rzechuła Agnieszka , Machaliński Bogusław , Menkiszak Janusz
Published: January 2018

Obesity is a well-known factor that leads to many diseases including endometrial cancer. The adipose tissue is a heterogeneous organ of internal secretion. Visfatin is a newly discovered protein produced by fat tissues. The purpose of this work was to evaluate serum level concentrations of visfatin in patients with endometrial cancer based on clinical progression and histopathological tumor differentiation. The diagnostic capabilities of visfatin protein in high differentiation (FIGO III and IV) from a lower (FIGO I and II) clinical stage and prognostic degree of cell differentiation (G1 versus G2, G2 versus G3) on the basis of the analysis of the area under the ROC curve are as follows: 0.87, 0.81, and 0.86. Significantly higher concentrations of visfatin have been observed in patients with invasion of the blood vessels (p=0.02) and lymph node metastases (p=0.01) in reference to the depth of infiltration of the endometrium (p=0.004), as well as the size of the tumor (p=0.003). Visfatin serum concentrations did not differ due to the invasion of the lymphatic vessels only. Visfatin seems to be a good marker of endometrial cancer progress. High visfatin serum level predicts poor prognosis in endometrial cancer patients.
Incorporation of Inefficiency Associated with Link Flows in Efficiency Measurement in Network DEA
Authors: Shamsijamkhaneh Abolghasem , Hadjimolana Seyed Mohammad , Rahmani Parchicolaie Bijan , Hosseinzadehlotfi Farhad
Published: January 2018

Data Envelopment Analysis (DEA) is a mathematical programming approach to measure the relative efficiency of peer decision making units (DMUs) which use multiple inputs to produce multiple outputs. One of the drawbacks of traditional DEA models is the neglect of internal structures of the DMUs. Network DEA models are able to overcome the shortcoming of the traditional DEA models. In network DEA a DMU is made up of some divisions linked together by intermediate products. An intermediate product has the dual role of output from one division and input to another one. Improving the efficiency of one process may reduce the efficiency of another process. To address the conflict caused by the dual role of intermediate measures, this paper presents a new approach which categorizes the intermediate measures into either input or output type endogenously, while keeping the continuity of link flows between divisions. This categorization allows us to measure the inefficiencies associated with intermediate measures and account their indirect effects on the objective function. In this paper we propose a new Slacks-based measure which includes any nonzero slacks identified by the model and inherits the properties of monotonicity in slacks and units invariance from the conventional SBM approach.
Therapy-Educated Mesenchymal Stem Cells Enrich for Tumor-Initiating Cells
Authors: Timaner Michael , Letko-Khait Nitzan , Kotsofruk Ruslana , Benguigui Madeleine , Beyar-Katz Ofrat , Rachman-Tzemah Chen , Raviv Ziv , Bronshtein Tomer , Machluf Marcelle , Shaked Yuval
Published: January 2018

Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo. These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10–CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.

Significance: These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge. Cancer Res; 78(5); 1253–65. ©2018 AACR.
Deletion of the von Hippel-Lindau Gene in Hemangioblasts Causes Hemangioblastoma-like Lesions in Murine Retina
Authors: Wang Herui , Shepard Matthew J. , Zhang Chao , Dong Lijin , Walker Dyvon , Guedez Liliana , Park Stanley , Wang Yujuan , Chen Shida , Pang Ying , Zhang Qi , Gao Chun , Wong Wai T. , Wiley Henry , Pacak Karel , Chew Emily Y. , Zhuang Zhengping , Chan Chi-Chao
Published: January 2018

von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. LOH of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl-Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl-Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl-mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histologic analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by “tumorlet” cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in “tumorlet” cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL.

Significance: This study describes a model that phenotypically recapitulates a form of retinal pathogenesis that is driven by genetic loss of the VHL tumor suppressor, providing a useful tool for its study and therapeutic intervention. Cancer Res; 78(5); 1266–74. ©2018 AACR.
Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer
Authors: Dávila-González Daniel , Choi Dong Soon , Rosato Roberto R. , Granados-Principal Sergio M. , Kuhn John G. , Li Wen-Feng , Qian Wei , Chen Wen , Kozielski Anthony J. , Wong Helen , Dave Bhuvanesh , Chang Jenny C.
Published: January 2018

Purpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC.

Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition + docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay.

Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9.

Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy. Clin Cancer Res; 24(5); 1152–62. ©2018 AACR.
Identification of a Novel, EBV-Based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan
Authors: Coghill Anna E. , Pfeiffer Ruth M. , Proietti Carla , Hsu Wan-Lun , Chien Yin-Chu , Lekieffre Lea , Krause Lutz , Teng Andy , Pablo Jocelyn , Yu Kelly J. , Lou Pei-Jen , Wang Cheng-Ping , Liu Zhiwei , Chen Chien-Jen , Middeldorp Jaap , Mulvenna Jason , Bethony Jeff , Hildesheim Allan , Doolan Denise L.
Published: January 2018

Background. Epstein–Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, approximately 90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective.

Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy [area under the curve (AUC)] of this risk score, and its performance relative to currently used biomarkers, was evaluated in two independent Taiwanese cohorts.

Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between stage I/IIa NPC cases and controls (P < 0.0002). Risk prediction analyses identified antibody targets that best discriminated NPC status—BXLF1, LF2,BZLF1, BRLF1, EAd, BGLF2, BPLF1, BFRF1, and BORF1. When combined with currently used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95% CI, 87%–98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%; 95% CI, 75%–90%, P ≤ 0.01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%; 95% CI, 82%–96%) compared with current biomarkers (78%; 95% CI, 66%–90%, P ≤ 0.03).

Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC. Clin Cancer Res; 24(6); 1305–14. ©2017 AACR.
Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma
Authors: Abou-Elkacem Lotfi , Wang Huaijun , Chowdhury Sayan M. , Kimura Richard H. , Bachawal Sunitha V. , Gambhir Sanjiv S. , Tian Lu , Willmann Jürgen K.
Published: January 2018

Purpose: To engineer a dual human and murine Thy1-binding single-chain-antibody ligand (Thy1-scFv) for contrast microbubble–enhanced ultrasound molecular imaging of pancreatic ductal adenocarcinoma (PDAC).

Experimental Design: Thy1-scFv were engineered using yeast-surface-display techniques. Binding to soluble human and murine Thy1 and to Thy1-expressing cells was assessed by flow cytometry. Thy1-scFv was then attached to gas-filled microbubbles to create MBThy1-scFv. Thy1 binding of MBThy1-scFv to Thy1-expressing cells was evaluated under flow shear stress conditions in flow-chamber experiments. MBscFv-scrambled and MBNon-targeted were used as negative controls. All microbubble types were tested in both orthotopic human PDAC xenografts and transgenic PDAC mice in vivo.

Results: Thy1-scFv had a KD of 3.4 ± 0.36 nmol/L for human and 9.2 ± 1.7 nmol/L for murine Thy1 and showed binding to both soluble and cellularly expressed Thy1. MBThy1-scFv was attached to Thy1 with high affinity compared with negative control microbubbles (P < 0.01) as assessed by flow cytometry. Similarly, flow-chamber studies showed significantly (P < 0.01) higher binding of MBThy1-scFv (3.0 ± 0.81 MB/cell) to Thy1-expressing cells than MBscFv-scrambled (0.57 ± 0.53) and MBNon-targeted (0.43 ± 0.53). In vivo ultrasound molecular imaging using MBThy1-scFv demonstrated significantly higher signal (P < 0.01) in both orthotopic (5.32 ± 1.59 a.u.) and transgenic PDAC (5.68 ± 2.5 a.u.) mice compared with chronic pancreatitis (0.84 ± 0.6 a.u.) and normal pancreas (0.67 ± 0.71 a.u.). Ex vivo immunofluorescence confirmed significantly (P < 0.01) increased Thy1 expression in PDAC compared with chronic pancreatitis and normal pancreas tissue.

Conclusions: A dual human and murine Thy1-binding scFv was designed to generate contrast microbubbles to allow PDAC detection with ultrasound. Clin Cancer Res; 24(7); 1574–85. ©2018 AACR.
Establishing a Preclinical Multidisciplinary Board for Brain Tumors
Authors: Nimmervoll Birgit V. , Boulos Nidal , Bianski Brandon , Dapper Jason , DeCuypere Michael , Shelat Anang , Terranova Sabrina , Terhune Hope E. , Gajjar Amar , Patel Yogesh T. , Freeman Burgess B. , Onar-Thomas Arzu , Stewart Clinton F. , Roussel Martine F. , Guy R. Kipling , Merchant Thomas E. , Calabrese Christopher , Wright Karen D. , Gilbertson Richard J.
Published: January 2018

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.

Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with “standard-of-care” surgery and radiotherapy.

Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.

Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.
Novel Iron-Whey Protein Microspheres Protect Gut Epithelial Cells from Iron-Related Oxidative Stress and Damage and Improve Iron Absorption in Fasting Adults
Authors: Wang Jun , Radics Gabor , Whelehan Michael , OʼDriscoll Aoibhe , Healy Anne Marie , Gilmer John F. , Ledwidge Mark
Published: January 2018

Background: Iron food fortification and oral iron formulations are frequently limited by poor absorption, resulting in the widespread use of high-dose oral iron, which is poorly tolerated. Methods: We evaluated novel iron-denatured whey protein (Iron-WP) microspheres on reactive oxygen species (ROS) and viability in gut epithelial (HT29) cells. We compared iron absorption from Iron-WP versus equimolar-dose (25 mg elemental iron) ferrous sulphate (FeSO4) in a prospective, randomised, cross-over study in fasting volunteers (n = 21 per group) dependent on relative iron depletion (a ferritin level ≤/>30 ng/mL). Results: Iron-WP caused less ROS generation and better HT29 cell viability than equimolar FeSO4. Iron-WP also showed better absorption with a maximal 149 ± 39% increase in serum iron compared to 65 ± 14% for FeSO4 (p = 0.01). The response to both treatments was dependent on relative iron depletion, and multi-variable analysis showed that better absorption with Iron-WP was independent of baseline serum iron, ferritin, transferrin saturation, and haemoglobin in the overall group and in the sub-cohort with relative iron depletion at baseline (p < 0.01). Conclusions: Novel Iron-WP microspheres may protect gut epithelial cells and improve the absorption of iron versus FeSO4. Further evaluation of this approach to food fortification and supplementation with iron is warranted.
Handlungsempfehlungen für die dolmetschergestützte Psychotherapie mit Flüchtlingen und Asylbewerbern: Ergebnisse qualitativer Interviews mit Psychotherapeuten und Dolmetschern zu Chancen und Herausforderungen in der Triade
Authors: Hanft-Robert Saskia , Römer Maximilian , Morgenroth Olaf , Redlich Alexander , Metzner Franka
Published: January 2018

Hintergrund: Aufgrund der vielen geflüchteten Menschen in Deutschland, bei denen sich hohe Prävalenzen für psychische Erkrankungen zeigen, steht die psychotherapeutische Versorgung von Flüchtlingen zunehmend im Fokus. Für die Psychotherapie mit geflüchteten Menschen müssen Psychotherapeuten in der Regel Dolmetscher einsetzen. Material und Methoden: Mithilfe leitfadengestützter Interviews wurden Chancen, Herausforderungen und Empfehlungen für die dolmetschergestützte Therapie aus Sicht von Psychotherapeuten (n = 5) und Dolmetschern (n = 3) untersucht und mittels qualitativer Inhaltsanalyse nach Mayring ausgewertet. Ergebnisse: Als äußere Rahmenbedingungen für eine erfolgreiche Psychotherapie zu dritt nannten die Interviewpartner die Notwendigkeit einer gesetzlich geregelten Finanzierung der Dolmetscherkosten, den Aufbau fester Dolmetscherpools sowie den Ausbau spezialisierter Therapiezentren. Die Interviewpartner betonten die Wichtigkeit einer klaren Rollenverteilung, des regelmäßigen Führens von Vor- und Nachgesprächen, der Passung von Patient und Dolmetscher im Hinblick auf den kulturellen Hintergrund sowie der vollständigen und genauen Übersetzung in der Ich-Form. Innerhalb der Triade wurde insbesondere die Bedeutung einer stimmigen Therapeuten-Dolmetscher-Beziehung zusätzlich zur Therapeuten-Patienten-Beziehung deutlich. Schlussfolgerungen: Bei der dolmetschergestützten Psychotherapie müssen der strukturelle Rahmen und die Fähigkeiten und Belastungen von Psychotherapeuten und Dolmetschern berücksichtigt werden, damit die Behandlung gelingen kann. Weitere empirische Untersuchungen unter Einbezug der Patientenperspektive sind notwendig.
Young Blood Rejuvenates Old Bodies: A Call for Reflection when Moving from Mice to Men
Authors: Hofmann Bjørn
Published: January 2018

Connecting the circulatory system of old and young mice (parabiosis) is documented to have rejuvenating effects on cells, tissues, organs, and functions. A wide range of benefits are envisioned. Blood-based rejuvenation can come to totally change population health and aging. The first blood rejuvenation studies on humans with Alzheimer's disease have started. It puts blood at the center of therapy and revitalizes the historical line of humoral pathology from Hippocrates and Harvey, creating a new type of ‘bloodletting.' However, moving from mice to men requires careful consideration. Parabiosis actualizes well-known ethical challenges, such as just distribution of health care, avoiding disparities, and providing equal access to health care resources, as well as issues of human enhancement. However, it also poses new problems. Using internal substances in some persons as means to rejuvenate others calls for ethical reflection. New type of ‘blood bonds' may result from the continuous demand for specific types of blood. Even if rejuvenating substances from blood may be artificially and cheaply produced and justly distributed, problems arise: survival may have to be balanced against reproduction, as reproductive age increases. Eternal youth and endless bliss have always been vital human dreams. Although parabiosis may bring us closer to the fountain of youth than ever, it is still too early to provide full-fledged assessments of its implications or to foresee how it will change health, aging, medicine, and society. However, in order to bring our reflective abilities on par with our technical skills, we need to start reflection now.
A Brief Measure of the International Classification of Diseases-11 Adjustment Disorder: Investigation of Psychometric Properties in an Adult Help-Seeking Sample
Authors: Kazlauskas Evaldas , Gegieckaite Goda , Eimontas Jonas , Zelviene Paulina , Maercker Andreas
Published: January 2018

Adjustment disorder is one of the most prevalent mental disorders. However, there are almost no measures available for its assessment. We aimed to analyze the psychometric properties of a brief version of the International Classification of Diseases (ICD)-11 adjustment disorder scale (Adjustment Disorder New Module-8; ADNM-8) in a help-seeking sample. Data from 1,174 participants with an average age of 35 years who registered for the internet-based self-help adjustment disorder intervention were analyzed. Psychometric properties of the brief 8-item self-report (ADNM-8) scale measuring the 2 core adjustment disorder symptoms of preoccupation and failure to adapt were tested. Confirmatory factor analysis (CFA) was applied for the analysis of construct validity. CFA supported the 2-factor structure of ADNM-8. Further research is needed for validation of ADNM-8 in cross-cultural studies.
Long-Term Prognosis after Myectomy in Hypertrophic Obstructive Cardiomyopathy with Severe Left Ventricular Hypertrophy
Authors: An Shuoyan , Fan Chaomei , Yang Yinjian , Hang Fei , Wang Zhimin , Zhang Yuhui , Zhang Jian
Published: January 2018

Objectives: Patients with hypertrophic obstructive cardiomyopathy (HOCM) and severe left ventricular hypertrophy (maximal left ventricular wall thickness ≥30 mm) are at high risk of sudden cardiac death (SCD). In this study, we aimed to determine whether HOCM patients with severe hypertrophy had a lower incidence of SCD after myectomy. Methods: HOCM patients with severe hypertrophy were consecutively enrolled from Fuwai Hospital in China between 2000 and 2013. Long-term outcomes were retrospectively compared between the 2 groups, namely the myectomy group and medical group. Results: A total of 244 patients (118 in the myectomy group and 126 in the medical group) were involved. The mean follow-up durations for the myectomy and medical groups were 5.07 ± 3.73 and 6.23 ± 4.15 years, respectively. During the follow-up period, the annual cardiovascular mortality rate was 0.84% in the myectomy group and 2.04% in the medical group (p = 0.041). The annual SCD rate was 0.33% in the myectomy group and 1.40% in the medical group (p = 0.040). Multivariate Cox regression analysis showed that myectomy was independently associated with lower rates of cardiovascular death and SCD. Conclusions: In HOCM patients with severe hypertrophy, those that underwent myectomy had a lower risk of cardiovascular death and SCD than those treated with medicines only.
Impact of Preoperative Left Ventricular Remodelling Patterns on Long-Term Outcome after Aortic Valve Replacement for Severe Aortic Stenosis
Authors: Bohbot Yohann , Rusinaru Dan , Delpierre Quentin , Marechaux Sylvestre , Tribouilloy Christophe
Published: January 2018

Objectives: Four patterns of left ventricular (LV) geometry have been described in aortic stenosis (AS): normal geometry, concentric remodelling (LVCR), concentric hypertrophy (CH), and eccentric hypertrophy (EH). LVCR and CH are independently associated with an increased risk of mortality in patients with medically managed AS. No data are available on the impact of aortic valve replacement (AVR) on the negative prognostic implications of LV remodelling patterns. Methods: This study evaluated the long-term postoperative prognostic value of preoperative LV patterns in a cohort of 779 patients (mean age 73 years) with severe AS and ejection fraction >50% undergoing AVR. Results: Long-term postoperative all-cause and cardiovascular mortality in patients with LVCR (adjusted HR = 0.50 [0.17-1.45], p = 0.202, and 0.45 [0.10-2.15], p = 0.373, respectively), CH (adjusted HR = 0.98 [0.68-1.40], p = 0.915, and 1.25 [0.60-2.40], p = 0.556, respectively), or EH (adjusted HR = 1.02 [0.79-1.32], p = 0.870, and 1.18 [0.70-1.99], p = 0.537, respectively) were comparable to those of patients with normal LV geometry. Conclusions: Despite the negative prognostic impact of LVCR and CH observed in patients with medically managed AS, these LV remodelling patterns are not associated with excess mortality after AVR. Surgery should therefore be discussed in patients with LVCR or CH and severe AS to avoid the risk of increased mortality observed under conservative management.
Cause and Clinical Presentation of Anaphylaxis in Singapore: From Infancy to Old Age
Authors: Goh Si Hui , Soh Jian Yi , Loh Wenyin , Lee Khai Pin , Tan Sze Chin , Heng Wei Jian Kenneth , Ibrahim Irwani , Lee Bee Wah , Chiang Wen Chin
Published: January 2018

Background: The study objective was to compare age-related differences in the cause and clinical presentation of anaphylaxis. Methods: We conducted a prospective study of patients visiting the emergency department for anaphylaxis. Data were collected from 3 emergency departments from 1 April 2014 to 31 December 2015. Patient electronic records with the diagnoses of allergy, angioedema, urticaria, and anaphylaxis (ICD-9 codes 9953, 9951, 7080, 9950, 7089) were screened and cases fulfilling World Allergy Organisation criteria for anaphylaxis were included. Results: A total of 426 cases of anaphylaxis were identified with a median age of 23 years (range 3 months to 88 years and 9 months). The causes of anaphylaxis were food (n = 236, 55%), drugs (n = 85, 20%), idiopathic (n = 64, 15%), and insect bites or stings (n = 28, 7%). The most common food was shellfish (n = 58, 14%) and the most common drugs were non-steroidal anti-inflammatory drugs (n = 26, 6%). There were more cases of food anaphylaxis in children than in adults (72 vs. 42%, p < 0.001) and more cases of drug anaphylaxis in adults than in children (28 vs. 10%, p < 0.001). Compared to patients of other ages, infants and young children had more gastrointestinal symptoms (adjusted odds ratio [aOR] 2.1, 95% CI 1.1-3.9), while schoolchildren and adolescents had more respiratory symptoms (aOR 2.7, 95% CI 1.4-5.2). Adults had more cardiovascular symptoms (aOR 2.9, 95% CI 1.8-4.6) and hypotension (aOR 3.7, 95% CI 2.1-6.8) compared to children. However, 42% of the infants lacked blood pressure measurements. Conclusions: Knowledge of age-related variation in the cause and clinical presentation of anaphylaxis aids in diagnosis and acute management.
Vesicoenteric Fistula Arising from an Adenocarcinoma of Ectopic Pancreatic Tissue in a Meckel Diverticulum
Authors: Fujita Naoyuki , Tambo Mitsuhiro , Terado Yuichi , Fujita Michio , Okegawa Takatsugu , Nutahara Kikuo
Published: January 2018

We report a case of a vesicoenteric fistula arising from an adenocarcinoma of ectopic pancreatic tissue in a Meckel diverticulum in a 58-year-old man. The patient suffered from refractory micturition pain and increased urinary frequency. Computerized tomography with a contrast agent showed a ring-shaped enhanced mass near the dome of the urinary bladder. Magnetic resonance imaging showed a cystic mass close to the urinary bladder with partly irregular wall and fistula formation to the urinary bladder. Surgical findings showed a Meckel diverticulum in the ileum, which formed a fistula with the urinary bladder, and Meckel diverticulectomy and partial cystectomy were performed. Histological findings revealed a vesicoenteric fistula arising from a papillary adenocarcinoma of ectopic pancreatic tissue in a Meckel diverticulum. The patient has survived without recurrence for more than 4 years since surgery.
Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod
Authors: Fujimura Taku , Kambayashi Yumi , Sato Yota , Tanita Kayo , Furudate Sadanori , Tsukada Akira , Tono Hisayuki , Hashimoto Akira , Aiba Setsuya
Published: January 2018

Simultaneous or sequential, planned administration of ipilimumab could significantly enhance the antitumor effects of nivolumab in advanced melanoma patients. On the other hand, the efficacy of ipilimumab for nivolumab-resistant advanced melanoma is extremely poor. Therefore, additional supportive therapy for anti-PD-1 antibody therapy-resistant advanced melanoma has been widely investigated. In this report, we describe a case of multiple in-transit melanomas developing in a nivolumab-resistant patient successfully treated with ipilimumab in combination with imiquimod. Our present case suggested a possible therapy for nivolumab-resistant multiple in-transit melanomas using ipilimumab in combination with topical imiquimod.
The Effect of Cisplatin on Blood Ammonia Elevation by Alanyl-Glutamine Supplementation
Authors: Obayashi Yoko , Kajiwara Kenta , Nakamura Eiji
Published: January 2018

Background: Although there are many clinical studies in which the beneficial effect of glutamine formulation on mucositis induced by chemo/radiotherapy was evaluated, the results are sometimes conflicting with the report of clinical deterioration. Then, we hypothesized that chemotherapy may increase the incidence of hyperammonemia without comparable change of major parameters of hepatic/renal disorder. Methods: To verify our hypothesis, we examined the increase in blood ammonia level with 1-h intravenous infusion of alanyl-glutamine on day 1–4 after cisplatin (CDDP) administration in rats and assessed the correlation with hepatic/renal parameters. Results: Hepatic parameters (glutamate-oxaloacetic transaminase [GOT] and glutamic-pyruvic transaminase [GPT]) with CDDP did not change until day 3 and only GOT increased on day 4. Renal parameters (plasma creatinine, blood urea nitrogen) with CDDP continuously increased up to day 4. Alanyl-glutamine infusion significantly elevated blood ammonia level of CDDP rats with the peak on day 3, although the same dose did not change that of control rats. Conclusion: These results indicates that CDDP enhances the increase in blood ammonia level by glutamine supplementation without correlating with primary parameters for hepatic/renal dysfunction.
Assessment of the Airway Smooth Muscle Relaxant Effect of Drotaverine
Authors: Patai Zoltán , Guttman András , Mikus Endre G.
Published: January 2018

Background: Drotaverine, a type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, blocks the degradation of 3’,5’-cyclic adenosine monophosphate. However, published receptor binding data showed that drotaverin also binds to the L-type voltage-operated calcium channel (L-VOCC). Based on these molecular mechanisms of action, a direct and indirect (by blocking the constrictor response) relaxant effect on airway smooth muscle can be predicted, which has not yet been assessed. Summary: Accordingly, drotaverine and reference agents were tested both on the histamine-, methacholine-, or KCl-induced contraction response and on precontracted guinea pig tracheal preparations. It was found that drotaverine not only relaxed the precontracted tracheal preparations but also decreased mediator-induced contraction. These effects of drotaverine were concentration dependent, with a significantly higher potency on the KCl-induced response, than on either the histamine or methacholine induced one. A similar result was noted for nifedipine. The PDE inhibitor, theophylline, also relaxed the precontracted preparations but was ineffective on the mediator-induced contraction in a physiologically relevant concentration range. Moreover, theophylline did not show selectivity and was the least potent relaxant among the 3 tested molecules. Key Message: These results show that drotaverine is a more potent airway smooth muscle relaxant molecule than theophylline. This enhanced potency on relaxation and inhibition of the constrictor response, at least partly, may be explained by the combined L-VOCC blocking and PDE inhibitory potential of drotaverine.
Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification
Authors: Viegas Carla S.B. , Santos Lúcia , Macedo Anjos L. , Matos António A. , Silva Ana P. , Neves Pedro L. , Staes An , Gevaert Kris , Morais Rute , Vermeer Cees , Schurgers Leon , Simes Dina C.
Published: January 2018

Objective—

Inhibition of mineral crystal formation is a crucial step in ectopic calcification. Serum calciprotein particles (CPPs) have been linked to chronic kidney disease (CKD) calcification propensity, but additional knowledge is required to understand their function, assemblage, and composition. The role of other circulating nanostructures, such as extracellular vesicles (EVs) in vascular calcification is currently unknown. Here, we investigated the association of GRP (Gla-rich protein) with circulating CPP and EVs and the role of CKD CPPs and EVs in vascular calcification.

Approach and Results—

Biological CPPs and EVs were isolated from healthy and CKD patients and comparatively characterized using ultrastructural, analytic, molecular, and immuno-based techniques. Our results show that GRP is a constitutive component of circulating CPPs and EVs. CKD stage 5 serum CPPs and EVs are characterized by lower levels of fetuin-A and GRP, and CPPs CKD stage 5 have increased mineral maturation, resembling secondary CPP particles. Vascular smooth muscle cell calcification assays reveal that CPPs CKD stage 5 and EVs CKD stage 5 are taken up by vascular smooth muscle cells and induce vascular calcification by promoting cell osteochondrogenic differentiation and inflammation. These effects were rescued by incubation of CPPs CKD stage 5 with γ-carboxylated GRP. In vitro, formation and maturation of basic calcium phosphate crystals was highly reduced in the presence of γ-carboxylated GRP, fetuin-A, and MGP (matrix gla protein), and a similar antimineralization system was identified in vivo.

Conclusions—

Uremic CPPs and EVs are important players in the mechanisms of widespread calcification in CKD. We propose a major role for cGRP as inhibitory factor to prevent calcification at systemic and tissue levels.
Resident and Monocyte-Derived Macrophages in Cardiovascular Disease
Authors: Honold Lisa , Nahrendorf Matthias
Published: January 2018

Macrophages are ubiquitous cells that reside in all major tissues. Counter to long-held beliefs, we now know that resident macrophages in many organs are seeded during embryonic development and self-renew independently from blood monocytes. Under inflammatory conditions, those tissue macrophages are joined and sometimes replaced by recruited monocyte-derived macrophages. Macrophage function in steady state and disease depends on not only their developmental origin but also the tissue environment. Here, we discuss the ontogeny, function, and interplay of tissue-resident and monocyte-derived macrophages in various organs contributing to the development and progression of cardiovascular disease.