bluuebunny/crossref_metadata_2025 huggingface dataset:
Military Simulation Big Data: Background, State of the Art, and Challenges
Authors: Song Xiao , Wu Yulin , Ma Yaofei , Cui Yong , Gong Guanghong
Published: November 2015

Big data technology has undergone rapid development and attained great success in the business field. Military simulation (MS) is another application domain producing massive datasets created by high-resolution models and large-scale simulations. It is used to study complicated problems such as weapon systems acquisition, combat analysis, and military training. This paper firstly reviewed several large-scale military simulations producing big data (MS big data) for a variety of usages and summarized the main characteristics of result data. Then we looked at the technical details involving the generation, collection, processing, and analysis of MS big data. Two frameworks were also surveyed to trace the development of the underlying software platform. Finally, we identified some key challenges and proposed a framework as a basis for future work. This framework considered both the simulation and big data management at the same time based on layered and service oriented architectures. The objective of this review is to help interested researchers learn the key points of MS big data and provide references for tackling the big data problem and performing further research.
Preparation and Characteristic of PC/PLA/TPU Blends by Reactive Extrusion
Authors: Zhou Yueyun , Luo Lifa , Liu Wenyong , Zeng Guangsheng , Chen Yi
Published: November 2015

To overcome the poor toughness of PC/PLA blends due to the intrinsic properties of materials and poor compatibility, thermoplastic urethane (TPU) was added to PC/PLA blends as a toughener; meantime, catalyst di-n-butyltin oxide (DBTO) was also added for catalyzing transesterification of components in order to modify the compatibility of blends. The mechanical, thermal, and rheological properties of blends were investigated systematically. The results showed that the addition of TPU improves the toughness of PC/PLA blends significantly, with the increase of TPU, the elongation at break increases considerably, and the impact strength increases firstly and then falls, while the tensile strength decreases significantly and the blends exhibit a typical plastic fracture behavior. Meantime, TPU is conducive to the crystallinity of PLA in blends which is inhibited seriously by PC and damages the thermal stability of blends slightly. Moreover, the increased TPU makes the apparent viscosity of blends melt decrease due to the well melt fluidity of TPU; the melt is closer to the pseudoplasticity melt. Remarkably, the transesterification between the components improves the compatibility of blends significantly, and more uniform structure results in a higher crystallinity and better mechanical properties.
A Novel Multivariable Algorithm for Detecting and Tracing Metal Mobile Objects Employing a Simple RFID Setup
Authors: Navarro Wendy , Velez Juan C. , Schettini Norelli , Calle Maria
Published: November 2015

Radio Frequency Identification (RFID) is a solution for automated inventory and object detection applications. However, if RFID tags are attached to metal objects, detection errors may occur due to Foucault currents and interferences caused by multiple simultaneous reflections. Errors may increase if metal objects are moving. The paper presents a novel algorithm using RFID low-level reader variables, such as RSSI (Received Signal Strength Indicator), phase angle, and Doppler shift, to detect and trace metal objects. The algorithm was designed to identify if a tag is static or moving and, in the latter case, to compute its speed and direction. The algorithm differs from previous approaches since it uses a simple setup with one commercial portal reader coupled with one single element antenna. Experiments employed one tag located on one metal moving object and 12 static interferer tags, in both outdoor and indoor locations. Results show that the algorithm identifies static tags with no errors. For moving tags, the algorithm shows a maximum 12% error. The algorithm correctly estimates direction and computes object speed. Test conditions emulate fork lift speeds when carrying objects in an industrial warehouse.
Towards Washable Electrotextile UHF RFID Tags: Reliability Study of Epoxy-Coated Copper Fabric Antennas
Authors: Wang Shiqi , Chong Ngai Lok , Virkki Johanna , Björninen Toni , Sydänheimo Lauri , Ukkonen Leena
Published: November 2015

We investigate the impact of washing on the performance of passive UHF RFID tags based on dipole antennas fabricated from copper fabric and coated with protective epoxy coating. Initially, the tags achieved read ranges of about 8 meters, under the European RFID emission regulation. To assess the impact of washing on the performance of the tags, they were washed repeatedly in a washing machine and measured after every washing cycle. Despite the reliability challenges related to mechanical stress, the used epoxy coating was found to be a promising coating for electrotextile tags in moist conditions.
Pharyngeal Electrical Stimulation for Treatment of Poststroke Dysphagia: Individual Patient Data Meta-Analysis of Randomised Controlled Trials
Authors: Scutt Polly , Lee Han S. , Hamdy Shaheen , Bath Philip M.
Published: November 2015

Background. Dysphagia after stroke is common, associated independently with poor outcome, and has limited treatment options. Pharyngeal electrical stimulation (PES) is a novel treatment being evaluated for treatment of poststroke dysphagia.Methods. We searched electronically for randomised controlled trials of PES in dysphagic patients within 3 months of stroke. Individual patient data were analysed using regression, adjusted for trial, age, severity, and baseline score. The coprimary outcomes were radiological aspiration (penetration aspiration score, PAS) and clinical dysphagia (dysphagia severity rating scale, DSRS) at 2 weeks; secondary outcomes included functional outcome, death, and length of stay in hospital.Results. Three completed trials were identified: 73 patients, age 72 (12) years, severity (NIHSS) 11 (6), DSRS 6.7 (4.3), mean PAS 4.3 (1.8). Compared with no/sham stimulation, PES was associated with lower PAS, 3.4 (1.7) versus 4.1 (1.7), mean difference −0.9 (p=0.020), and lower DSRS, 3.5 (3.8) versus 4.9 (4.4), mean difference −1.7 (p=0.040). Length of stay in hospital tended to be shorter: 50.2 (25.3) versus 71.2 (60.4) days (p=0.11). Functional outcome and death did not differ between treatment groups.Conclusions. PES was associated with less radiological aspiration and clinical dysphagia and possibly reduced length of stay in hospital across three small trials.
3D Culture of MIN-6 Cells on Decellularized Pancreatic Scaffold: In Vitro and In Vivo Study
Authors: Wu Di , Wan Jian , Huang Yan , Guo Yibing , Xu Tianxin , Zhu Mingyan , Fan Xiangjun , Zhu Shajun , Ling Changchun , Li Xiaohong , Lu Jingjing , Zhu Hui , Zhou Pengcheng , Lu Yuhua , Wang Zhiwei
Published: November 2015

Type 1 diabetes is an autoimmune disease which is due to the lack ofβcells. The ideal therapy to cure the disease is pancreas transplantation, but its application is confined to a limited number of people due to the shortage of organ and the need for life-long immunosuppression. Regenerative medicine methods such as a tissue engineered pancreas seem to provide a useful method. In order to construct a microenvironment similar to the native pancreas that is suitable for not only cell growth but also cellular function exertion, a decellularized mouse pancreas was used as a natural 3D scaffold in this experiment. MIN-6βcells were planted in the bioscaffold. The cell engraftment was verified by HE staining and SEM. Immunostaining procedures were performed to confirm the normal function of the engrafted cells. qRT-PCR demonstrated that insulin gene expression of the recellularized pancreas was upregulated compared with conventional plate-cultured cells. In vivo experiment was also accomplished to further evaluate the function of the recellularized bioscaffold and the result was inspiring. And beyond doubt this will bring new hope for type 1 diabetic patients.
Hypersurface Constrained Elasticae in Lorentzian Space Forms
Authors: Garay Óscar J. , Pámpano Álvaro , Woo Changhwa
Published: November 2015

We study geodesics in hypersurfaces of a Lorentzian space formM1n+1(c), which are critical curves of theM1n+1(c)-bending energy functional, for variations constrained to lie on the hypersurface. We characterize critical geodesics showing that they live fully immersed in a totally geodesicM13(c)and that they must be of three different types. Finally, we consider the classification of surfaces in the Minkowski 3-space foliated by critical geodesics.
The Impact of KLT Coder on the Image Distortion in Astronomy
Authors: Pata Petr
Published: November 2015

Presented paper is devoted to the application of Karhunen-Loève transform (KLT) for compression and to study of KLT impact on the image distortion in astronomy. This transform is an optimal fit for images with Gaussian probability density function in order to minimize the root mean square error (RMSE). The main part of the encoder is proposed in relation to statistical image properties. Selected astronomical image processing algorithms are used for the encoder testing. The astrometry and point spread function distortion are selected as the most important criteria. The results are compared with JPEG2000 standard. The KLT encoder provides better results from the RMSE point of view. These results are promising and show the novel approach to the design of lossy image compression algorithms and also suitability for algorithms of image data structuring for retrieving, transfer, and distribution.
Seromuscular Colonic Flap for Intrapelvic Soft-Tissue Coverage: A Reconstructive Option for Plastic Surgeons When Traditionally Used Flaps Are Not Available
Authors: Aho Johnathon , Winocour Sebastian , Hammoudeh Ziyad S. , Nelson Heidi , Rose Peter , Tran Nho V.
Published: November 2015

Background. Reconstruction of intrapelvic defects can be a challenging problem in patients with limited regional muscle flap options and previously resected omentum. In such situations, alternative methods of mobilizing vascularized tissue may be required.Methods. A case of a patient that underwent pelvic extirpation for recurrent rectal cancer who had limited donor sites for flap reconstruction is presented. The mucosa was removed from a blind loop of colon, and a pedicled seromuscular flap based on the colonic mesentery was placed into the pelvis for vascularized soft-tissue coverage and elimination of dead space.Results. The postoperative course was only complicated by a small subcutaneous fluid collection beneath the sacrectomy skin incision, which was drained with radiological assistance. The patient recovered without any major postoperative complications.Conclusion. Seromuscular colonic flap is a useful option for soft-tissue coverage after pelvic extirpation and should be considered by plastic surgeons when other reconstruction options are not available.
A Rank-Constrained Matrix Representation for Hypergraph-Based Subspace Clustering
Authors: Sun Yubao , Li Zhi , Wu Min
Published: November 2015

This paper presents a novel, rank-constrained matrix representation combined with hypergraph spectral analysis to enable the recovery of the original subspace structures of corrupted data. Real-world data are frequently corrupted with both sparse error and noise. Our matrix decomposition model separates the low-rank, sparse error, and noise components from the data in order to enhance robustness to the corruption. In order to obtain the desired rank representation of the data within a dictionary, our model directly utilizes rank constraints by restricting the upper bound of the rank range. An alternative projection algorithm is proposed to estimate the low-rank representation and separate the sparse error from the data matrix. To further capture the complex relationship between data distributed in multiple subspaces, we use hypergraph to represent the data by encapsulating multiple related samples into one hyperedge. The final clustering result is obtained by spectral decomposition of the hypergraph Laplacian matrix. Validation experiments on the Extended Yale Face Database B, AR, and Hopkins 155 datasets show that the proposed method is a promising tool for subspace clustering.
Data Analysis with a Wireless Multisensory Toxic Gas Detection System
Authors: Wu Qiong , Shi Yunbo
Published: November 2015

This paper proposes a wireless multisensory toxic gas detection system. The system allows remote wireless detection of four types of toxic gases, specifically Cl2, CO, NO2, and SO2, using gas detection technologies and wireless communication technologies such as ZigBee and Wi-Fi. Further, we analyze the data collected from sensors to determine a correspondence between the sensors and the gases and establish recognition models for different gases. Through multiple data calibration levels and industrial experiments, we have verified the feasibility of the system, along with its gas detection accuracy and long-term stability.
Complete Resolution of Pseudomalignant Erosion in a Reflux Gastroesophageal Polyp with Proton Pump Inhibitor
Authors: Nakajima Takahiko , Yagi Haruo , Baba Hayato , Minamisaka Takashi , Miwa Shigeharu , Hayashi Shinichi , Nishida Takeshi , Hatta Hideki , Tsuneyama Koichi , Imura Johji
Published: November 2015

Pseudomalignant erosion is a diagnostic pitfall for pathologists in the differential diagnosis of malignant neoplasms. Here, we present a challenging case of a biopsy specimen from the eroded head of a polyp at the esophagogastric junction. A malignant neoplasm could not be ruled out due to the presence of bizarre stromal cells. A second biopsy performed after the administration of a proton pump inhibitor (PPI) for 4 weeks revealed endoscopic resolution of the polyp along with the complete histological resolution of the bizarre stromal cells and led to the diagnosis of pseudomalignant erosion in a reflux gastroesophageal polyp. In conclusion, histological and endoscopic response to PPI therapy is an important clue for the correct diagnosis of reflux gastroesophageal polyps with pseudomalignant erosion.
De NovoAssembly of the Pea (Pisum sativumL.) Nodule Transcriptome
Authors: Zhukov Vladimir A. , Zhernakov Alexander I. , Kulaeva Olga A. , Ershov Nikita I. , Borisov Alexey Y. , Tikhonovich Igor A.
Published: November 2015

The large size and complexity of the garden pea (Pisum sativumL.) genome hamper its sequencing and the discovery of pea gene resources. Although transcriptome sequencing provides extensive information about expressed genes, some tissue-specific transcripts can only be identified from particular organs under appropriate conditions. In this study, we performed RNA sequencing of polyadenylated transcripts from young pea nodules and root tips on an Illumina GAIIx system, followed byde novotranscriptome assembly using the Trinity program. We obtained more than 58,000 and 37,000 contigs from “Nodules” and “Root Tips” assemblies, respectively. The quality of the assemblies was assessed by comparison with pea expressed sequence tags and transcriptome sequencing project data available from NCBI website. The “Nodules” assembly was compared with the “Root Tips” assembly and with pea transcriptome sequencing data from projects indicating tissue specificity. As a result, approximately 13,000 nodule-specific contigs were found and annotated by alignment to known plant protein-coding sequences and by Gene Ontology searching. Of these, 581 sequences were found to possess full CDSs and could thus be considered as novel nodule-specific transcripts of pea. The information about pea nodule-specific gene sequences can be applied for gene-based markers creation, polymorphism studies, and real-time PCR.
Study and Experiment on a Wheat Precision Seeding Robot
Authors: Haibo Lin , Shuliang Dong , Zunmin Liu , Chuijie Yi
Published: November 2015

The wheat precision seeding technology provided an advanced agricultural support for the high yield of wheat. But the lack of effective agricultural machine made this technique difficult to apply widely. In this paper a wheel mobile robot to achieve the wheat precision seeding technology was designed. The kinematic model of the robot was built and simulated. And experimental study was taken under different operating conditions. Because of multiple effort factors, a quadratic orthogonal rotation combination design method was applied in the experiments, identifying the main factors by analysis. Then the field test was carried out according to the main factors. The experiment results showed that the qualified rates of seeding exceed 93% in different sowing speed. That reached the agronomic requirements of wheat precision seeding.
Investigation on Structural and Optical Properties of Willemite Doped Mn2+Based Glass-Ceramics Prepared by Conventional Solid-State Method
Authors: Samsudin Nur Farhana , Matori Khamirul Amin , Liew Josephine Ying Chi , Wing Fen Yap , Mohd Zaid Mohd Hafiz , Nadakkavil Alassan Zarifah
Published: November 2015

Mn-doped willemite (Zn2SiO4:Mn2+) glass-ceramics derived from ZnO-SLS glass system were prepared by a conventional melt-quenching technique followed by a controlled crystallization step employing the heat treatment process. Soda lime silica (SLS) glass waste, ZnO, and MnO were used as sources of silicon, zinc, and manganese, respectively. The obtained glass-ceramic samples were characterized using the X-ray diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR), UV-Visible (UV-Vis), and photoluminescence (PL) spectroscopy. The results of XRD revealed that ZnO crystal and willemite (β-Zn2SiO4) were presented as major embedded crystalline phases. This observation was consistent with the result of FESEM which showed the presence of irregularity in shape and size of willemite crystallites. FTIR spectroscopy exhibits the structural evolution of willemite based glass-ceramics. The optical band gap shows a decreasing trend as the Mn-doping content increased. Photoluminescent technique was applied to characterize the role of Mn2+ions when entering the willemite glass-ceramic structure. By measuring the excitation and emission spectra, the main emission peak of the glass-ceramic samples located at a wavelength of 585 nm after subjecting to 260 nm excitations. The following results indicate that the obtained glass-ceramics can be applied as phosphor materials.
Cofunctional Subpathways Were Regulated by Transcription Factor with Common Motif, Common Family, or Common Tissue
Authors: Su Fei , Shang Desi , Xu Yanjun , Feng Li , Yang Haixiu , Liu Baoquan , Su Shengyang , Chen Lina , Li Xia
Published: November 2015

Dissecting the characteristics of the transcription factor (TF) regulatory subpathway is helpful for understanding the TF underlying regulatory function in complex biological systems. To gain insight into the influence of TFs on their regulatory subpathways, we constructed a global TF-subpathways network (TSN) to analyze systematically the regulatory effect of common-motif, common-family, or common-tissue TFs on subpathways. We performed cluster analysis to show that the common-motif, common-family, or common-tissue TFs that regulated the same pathway classes tended to cluster together and contribute to the same biological function that led to disease initiation and progression. We analyzed the Jaccard coefficient to show that the functional consistency of subpathways regulated by the TF pairs with common motif, common family, or common tissue was significantly greater than the random TF pairs at the subpathway level, pathway level, and pathway class level. For example, HNF4A (hepatocyte nuclear factor 4, alpha) and NR1I3 (nuclear receptor subfamily 1, group I, member 3) were a pair of TFs with common motif, common family, and common tissue. They were involved in drug metabolism pathways and were liver-specific factors required for physiological transcription. In short, we inferred that the cofunctional subpathways were regulated by common-motif, common-family, or common-tissue TFs.
Swarm Intelligence Integrated Graph‐Cut for Liver Segmentation from 3D‐CT Volumes
Authors: Eapen Maya , Korah Reeba , Geetha G.
Published: November 2015

The segmentation of organs in CT volumes is a prerequisite for diagnosis and treatment planning. In this paper, we focus on liver segmentation from contrast‐enhanced abdominal CT volumes, a challenging task due to intensity overlapping, blurred edges, large variability in liver shape, and complex background with cluttered features. The algorithm integrates multidiscriminative cues (i.e., prior domain information, intensity model, and regional characteristics of liver in a graph‐cut image segmentation framework). The paper proposes a swarm intelligence inspired edge‐adaptive weight function for regulating the energy minimization of the traditional graph‐cut model. The model is validated both qualitatively (by clinicians and radiologists) and quantitatively on publically available computed tomography (CT) datasets (MICCAI 2007 liver segmentation challenge, 3D‐IRCAD). Quantitative evaluation of segmentation results is performed using liver volume calculations and a mean score of 80.8% and 82.5% on MICCAI and IRCAD dataset, respectively, is obtained. The experimental result illustrates the efficiency and effectiveness of the proposed method.
A Rare Colocalization of Lichen Planus and Vitiligo
Authors: Veitch David , Kravvas Georgios , Hughes Sian , Bunker Christopher
Published: November 2015

We report an unusual manifestation of vitiligo colocalizing with lichen planus (LP). A 76-year-old Greek male presented with a history of a red, scaly, itchy, asymmetrical patch located at the umbilicus within a well-demarcated depigmented macule of vitiligo. Histology showed features of a lichenoid interface dermatitis, favouring a diagnosis of LP. Colocalization of LP and vitiligo has rarely been reported in the literature. After reviewing the literature, we believe that at present there is insufficient evidence to resolve the uncertainties in the aetiology of this colocalization. It seems to us that the association between LP and vitiligo is more than coincidental, but none of the theories discussed in this paper can sufficiently account for it. Rather, the association is likely to be multifactorial in its pathogenesis.
Analysis of an Impulsive One-Predator and Two-Prey System with Stage-Structure and Generalized Functional Response
Authors: Ma Xiangmin , Shao Yuanfu , Wang Zhen , Fang Xianjia , Luo Zhenguo
Published: November 2015

An impulsive one-predator and two-prey system with stage-structure and generalized functional response is proposed and analyzed. By reasonable assumption and theoretical analysis, we obtain conditions for the existence and global attractivity of the predator-extinction periodic solution. Sufficient conditions for the permanence of this system are established via impulsive differential comparison theorem. Furthermore, abundant results of numerical simulations are given by choosing two different and concrete functional responses, which indicate that impulsive effects, stage-structure, and functional responses are vital to the dynamical properties of this system. Finally, the biological meanings of the main results and some control strategies are given.
Safety and Biocompatibility of a New High-Density Polyethylene-Based Spherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits
Authors: Fernandez-Bueno Ivan , Di Lauro Salvatore , Alvarez Ivan , Lopez Jose Carlos , Garcia-Gutierrez Maria Teresa , Fernandez Itziar , Larra Eva , Pastor Jose Carlos
Published: November 2015

Purpose. To evaluate clinically and histologically the safety and biocompatibility of a new HDPE-based spherical porous orbital implants in rabbits.Methods. MEDPOR (Porex Surgical, Inc., Fairburn, GA, USA), OCULFIT I, and OCULFIT II (AJL Ophthalmic S.A., Vitoria, Spain) implants were implanted in eviscerated rabbis. Animals were randomly divided into 6 groups (n=4each) according to the 3 implant materials tested and 2 follow-up times of 90 or 180 days. Signs of regional pain and presence of eyelid swelling, conjunctival hyperemia, and amount of exudate were semiquantitatively evaluated. After animals sacrifice, the implants and surrounding ocular tissues were processed for histological staining and polarized light evaluation. Statistical study was performed by ANOVA and Kaplan-Meier analysis.Results. No statistically significant differences in regional pain, eyelid swelling, or conjunctival hyperemia were shown between implants and/or time points evaluated. However, amount of exudate differed, with OCULFIT I causing the smallest amount. No remarkable clinical complications were observed. Histological findings were similar in all three types of implants and agree with minor inflammatory response.Conclusions. OCULFIT ophthalmic tolerance and biocompatibility in rabbits were comparable to the clinically used MEDPOR. Clinical studies are needed to determine if OCULFIT is superior to the orbital implants commercially available.
Incidence Trends and Geographical Variability of Pediatric Inflammatory Bowel Disease in Slovenia: A Nationwide Study
Authors: Urlep Darja , Blagus Rok , Orel Rok
Published: November 2015

Background. The aims of the study were to determine the incidence rate of pediatric inflammatory bowel disease (PIBD) and its trends for the period of 2002–2010 and to assess the geographical distribution of PIBD in Slovenia.Materials and Methods. Medical records of patients (0–18 years) with newly diagnosed IBD during the study period were retrospectively reviewed.Results. The mean incidence rate for IBD in 2002–2010 was 7.6 per 100,000 children and adolescents per year, 4.5 for Crohn’s disease (CD), 2.9 for ulcerative colitis (UC), and 0.2 for IBD-unclassified, respectively. The incidence rate increased from 5.8 per 100,000 per year in 2002–2004 to 8.6 in 2005–2007 and remained stable afterwards. Statistically significant difference in the incidence rate between the Northeastern and Southwestern parts of the country was observed (p=0.025).Conclusion. This nationwide study demonstrates that Slovenia is among the European countries with the highest PIBD incidence. During the study period a substantial rise of PIBD incidence was observed during the first half of the study and it seems to have stabilized in the second half. The significant difference in PIBD incidence between Northeastern and Southwestern parts of the country merits further exploration of the possible environmental factors.
QoS Routing RPL for Low Power and Lossy Networks
Authors: Mohamed Belghachi , Mohamed Feham
Published: November 2015

Energy conservation, while ensuring an adequate level of service, is a major concern in Low power and Lossy Networks (LLNs), because the nodes are typically deployed and are not replaced in case of failure. Several efforts have recently led to the standardization of a routing protocol for LLNs. The standard provides several criteria that can be used as a routing metric. The working group RoLL of the IETF developed a routing protocol for 6LoWPAN sensor network (IPv6 over IEEE 802.15.4) (Ko et al., 2011), RPL, recently standardized. Using this protocol could become common and standard in IPv6 sensor networks in the future. Most implementation of the protocol makes use of the transmission rate successfully (ETX) as metric and focuses on the reliability of links. In this paper we present the use of the residual energy and the transmission delay as routing metric in the next hop selection process for the RPL protocol. We design an objective function for this metric based on ant colony optimization (ACO), and then we compare the results of experiments realized with the RPL based on ETX.
Confounding of the Association between Radiation Exposure from CT Scans and Risk of Leukemia and Brain Tumors by Cancer Susceptibility Syndromes
Authors: Meulepas Johanna M. , Ronckers Cécile M. , Merks Johannes , Weijerman Michel E. , Lubin Jay H. , Hauptmann Michael
Published: November 2015

Background: Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of CT scans performed in children.

Methods: We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk estimates. Because there is virtually no empirical evidence in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about the current and previous patterns of CT scans among CSS patients.

Results: We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome, or other CSS. In contrast, RRs for brain tumors may be overestimated due to confounding by tuberous sclerosis complex (TSC) while von Hippel–Lindau disease, neurofibromatosis type 1, or other CSS do not meaningfully confound. Empirical data on the use of CT scans among CSS patients are urgently needed.

Conclusions: Our assessment indicates that associations with leukemia reported in previous studies are unlikely to be substantially confounded by unmeasured CSS, whereas brain tumor risks might have been overestimated due to confounding by TSC.

Impact: Future studies should identify TSC patients in order to avoid overestimation of brain tumor risks due to radiation exposure from CT scans. Cancer Epidemiol Biomarkers Prev; 25(1); 114–26. ©2015 AACR.
Optimal Dosing for Targeted Therapies in Oncology: Drug Development Cases Leading by Example
Authors: Sachs Jeffrey R. , Mayawala Kapil , Gadamsetty Satvik , Kang Soonmo Peter , de Alwis Dinesh P.
Published: November 2015

One of the key objectives of oncology first-in-human trials has often been to establish the maximum tolerated dose (MTD). However, targeted therapies might not exhibit dose-limiting toxicities (DLT) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events. Thus, while MTD-based determination of recommended phase II dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies and/or immunotherapies) sometimes need alternative or complementary strategies to help identify dose ranges for a randomized dose-ranging study. One complementary strategy is to define a biologically efficacious dose (BED) using an “effect marker.” An effect marker could be a target engagement, pharmacodynamic, or disease progression marker (change in tumor size for solid tumors or bone marrow blast count for some hematologic tumors). Although the concept of BED has been discussed extensively, we review specific examples in which the approach influenced oncology clinical development. Data extracted from the literature and the examples support improving dose selection strategies to benefit patients, providers, and the biopharmaceutical industry. Although the examples illustrate key contributions of effect markers in dose selection, no one-size-fits-all approach to dosing can be justified. Higher-than-optimal dosing can increase toxicity in later trials (and in clinical use), which can have a negative impact on efficacy (via lower adherence or direct sequelae of toxicities). Proper dose selection in oncology should follow a multifactorial decision process leading to a randomized, dose-ranging study instead of a single phase II dose. Clin Cancer Res; 22(6); 1318–24. ©2015 AACR.
Mechanisms of Protective Effect of Ramulus Mori Polysaccharides on Renal Injury in High-Fat Diet/Streptozotocin-Induced Diabetic Rats
Authors: Li Xi , Wang Ling , Gao Xingxin , Li Guoping , Cao Honghua , Song Dezhi , Cai Shuangqi , Liang Tao , Zhang Bo , Du Gang
Published: November 2015

Background: Diabetic nephropathy (DN) is the most important complication of diabetes and the most common cause of end-stage renal disease (ESRD). Aims: A recent study established that the Ramulus mori polysaccharides (RMP) exert antioxidant effects on DN in rats. Methods: The diabetic rats which induced by high-fat diet and streptozotocin injection were orally administered RMP by doses of 250, 500 and 1000 mg/kg daily for 8 weeks. The effects of RMP on hyperglycemia and other biochemical changes were examined in the sera and kidney tissues. Additionally, the pathological and ultrastructural changes and expressions of nuclear-factor kappa B (NF-κB) and transforming growth factor-ß1 (TGF-ß1) were assessed. Results: The results revealed that the serum levels of blood glucose, total cholesterol (TC) and triglycerides (TG) were significantly decreased by RMP. Furthermore, the blood urea nitrogen (BUN), serum creatinine (SCr) and 24-hour urine protein levels in the RMP-medicated rats were lower than those in untreated diabetic rats. Moreover, treatment of the DN rats with RMP normalized all biochemical changes, including the malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels in the serum and kidney tissues. In contrast, the protein expression levels of NF-κB and TGF-ß1, which were enhanced in the kidneys of DN rats, were reduced by RMP. Conclusion: These results suggest that RMP improving the renal function of diabeitc rats possibly via its ameliorating antioxidant activities.
Esophageal Cancer Specific Risk Score Is Associated with Postoperative Complications Following Open Ivor-Lewis Esophagectomy for Adenocarcinoma
Authors: Lindner Kirsten , Palmes Daniel , Grübener Amelie , Senninger Norbert , Haier Jörg , Hummel Richard
Published: November 2015

Background/Aims: Surgery for esophageal cancer is associated with a high morbidity and mortality. With this study, we investigated if a validated preoperative risk score correlates with overall morbidity, mortality, anastomotic insufficiency, respiratory complications and with the severity of complications after open Ivor-Lewis esophagectomy. Methods: A total of 94 patients undergoing esophageal resection for adenocarcinoma between 2005 and 2009 were included. Patients were assigned using the preoperative risk score according to Schröder et al. [Langenbecks Arch Surg 2006;391:455-460] and the Dindo classification regarding the severity of complications. Results: Of all the patients, 12% had a ‘normal', 54% a ‘moderateʼ and 34% a ‘high' preoperative risk score. Postoperative complications occurred in 79%. Furthermore, 36 or 21 or 14 or 7% of patients experienced complications of category I/II or III or IV or V, respectively. There was a significant association between preoperative risk score and overall morbidity (p = 0.010), mortality (p = 0.035) and anastomotic insufficiency (p = 0.023). Furthermore, higher preoperative risk score was significant related to increasing severity of postoperative complications (grade IV according to the Dindo classification: p = 0.018, Dindo grade V: p = 0.035). Neoadjuvant therapy consisting of cisplatin and 5-fluorouracil had no influence. Conclusion: As we demonstrated, a significant association between preoperative risk score and occurrence and severity of postoperative complications after open Ivor-Lewis esophagectomy, standardized, organ-specific pre- and postoperative categorizations might be useful for individual clinical decision making in this group of patients.
Early Recruitment of Cerebral Microcirculation by Neuronal Nitric Oxide Synthase Inhibition in a Juvenile Ischemic Rat Model
Authors: Leger P.L. , Bonnin P. , Moretti R. , Tanaka S. , Duranteau J. , Renolleau S. , Baud O. , Charriaut-Marlangue C.
Published: November 2015

Background: The development of collateral circulation is proposed as an inherent compensatory mechanism to restore impaired blood perfusion after ischemia, at least in the penumbra. We have studied the dynamic macro- and microcirculation after ischemia-reperfusion in the juvenile rat brain and evaluated the impact of neuronal nitric oxide synthase (nNOS) inhibition on the collateral flow. Methods: Fourteen-day-old (P14) rats were subjected to ischemia-reperfusion and treated with either PBS or 7-nitroindazole (7-NI, an nNOS inhibitor, 25 mg/kg). Arterial blood flow (BF) was measured using 2D-color-coded pulsed ultrasound imaging. Laser speckle contrast (LSC) imaging and sidestream dark-field videomicroscopy were used to measure cortical and microvascular BF, respectively. Results: In basal conditions, 7-NI reduced BF in the internal carotids (by ∼25%) and cortical (by ∼30%) BF, as compared to PBS. During ischemia, the increased mean BF velocity in the basilar trunk after both PBS and 7-NI demonstrated the establishment of collateral support and patency. Upon re-flow, BF immediately recovered to basal values in the internal carotid arteries under both conditions. The 7-NI group showed increased collateral flow in the penumbral tissue during early re-flow compared to PBS, as shown with both LSC imaging and side-stream dark-field videomicroscopy. The proportion of perfused capillaries was significantly increased under 7-NI as compared to PBS when given before ischemia (67.0 ± 3.9 vs. 46.8 ± 8.8, p < 0.01). Perfused capillaries (63.1 ± 17.7 vs. 81.1 ± 20.7, p < 0.001) and the BF index (2.4 ± 0.6 vs. 1.3 ± 0.1, p < 0.001) significantly increased under 7-NI given at the re-flow onset. Conclusions: Collateral support in the penumbra is initiated during ischemia, and may be increased during early re-flow by neuronal NOS inhibition (given in pre- and post-treatment), which may preserve brain tissue in juvenile rats.
TCD-Profiling Using AVERAGE. A New Technique to Evaluate Transcranial Doppler Ultrasound Flow Spectra of Subjects with Cerebral Small Vessel Disease
Authors: Fisse Anna Lena , Pueschel Johannes , Deppe Michael , Ringelstein E. Bernd , Ritter Martin A.
Published: November 2015

Background: There is an unmet need for screening methods to detect and quantify cerebral small vessel disease (SVD). Transcranial Doppler ultrasound (TCD) flow spectra of the larger intracranial arteries probably contain relevant information about the microcirculation. However, it has not yet been possible to exploit this information as a valuable biomarker. Methods: We developed a technique to generate normalized and averaged flow spectra during middle cerebral artery Doppler ultrasound examinations. Second, acceleration curves were calculated, and the absolute amount of the maximum positive and negative acceleration was calculated. Findings were termed ‘TCD-profiling coefficient' (TPC). Validation study: we applied this noninvasive method to 5 young adults for reproducibility. Degenerative microangiopathy study: we also tested this new technique in 30 elderly subjects: 15 free of symptoms but with MRI-verified presence of cerebral SVD, and 15 healthy controls. SVD severity was graded according to a predefined score. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) study: TPC values of 10 CADASIL patients were compared with those of 10 healthy controls. Pulse wave analysis and local measurements of carotid stiffness were also performed. CADASIL patients were tested for cognitive impairment with the Montreal Cognitive Assessment scale. White matter and basal ganglia lesions in their cerebral MRI were evaluated according to the Wahlund score. Results: Validation study: the technique delivered reproducible results. Degenerative microangiopathy study: patients with SVD had significantly larger TPCs compared with controls (SVD: 2,132; IQR 1,960-2,343 %/s vs. controls: 1,935; IQR 1,782-2,050 %/s, p = 0.01). TPC values of subjects with SVD significantly correlated with SVD severity scores (R = 0.58, n = 15, p < 0.05). CADASIL study: TPC values of CADASIL patients were significantly higher than values of the controls (CADASIL: 2,504; IQR 2,308-2,930 %/s vs. controls 2,084; 1,839-2,241 %/s, p = 0.008), and also significantly higher than the TPC values of the patients with SVD from the degenerative microangiopathy study (p = 0.007). CADASIL patients had significantly worse cognitive test results than healthy controls. Conclusion: TCD-profiling detects impairment of the cerebral microcirculatory state. The suitability of the TCD-profiling for the evaluation of cerebral microangiopathy was confirmed.
Weight Management in Phenylketonuria: What Should Be Monitored?
Authors: Rocha Julio César , van Rijn Margreet , van Dam Esther , Ahring Kirsten , Bélanger-Quintana Amaya , Dokoupil Katharina , Gokmen Ozel Hulya , Lammardo Anna Maria , Robert Martine , Heidenborg Carina , MacDonald Anita
Published: November 2015

Background: Severe intellectual disability and growth impairment have been overcome by the success of early and continuous treatment of patients with phenylketonuria (PKU). However, there are some reports of obesity, particularly in women, suggesting that this may be an important comorbidity in PKU. It is becoming evident that in addition to acceptable blood phenylalanine control, metabolic dieticians should regard weight management as part of routine clinical practice. Summary: It is important for practitioners to differentiate the 3 levels for overweight interpretation: anthropometry, body composition and frequency and severity of associated metabolic comorbidities. The main objectives of this review are to suggest proposals for the minimal standard and gold standard for the assessment of weight management in PKU. While the former aims to underline the importance of nutritional status evaluation in every specialized clinic, the second objective is important in establishing an understanding of the breadth of overweight and obesity in PKU in Europe. Key Messages: In PKU, the importance of adopting a European nutritional management strategy on weight management is highlighted in order to optimize long-term health outcomes in patients with PKU.
CDKN2B
Regulates
TGF
β Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels
Authors: Nanda Vivek , Downing Kelly P. , Ye Jianqin , Xiao Sophia , Kojima Yoko , Spin Joshua M. , DiRenzo Daniel , Nead Kevin T. , Connolly Andrew J. , Dandona Sonny , Perisic Ljubica , Hedin Ulf , Maegdefessel Lars , Dalman Jessie , Guo Liang , Zhao XiaoQing , Kolodgie Frank D. , Virmani Renu , Davis Harry R. , Leeper Nicholas J.
Published: November 2015

Rationale:

Genetic variation at the chromosome 9p21 cardiovascular risk locus has been associated with peripheral artery disease, but its mechanism remains unknown.

Objective:

To determine whether this association is secondary to an increase in atherosclerosis, or it is the result of a separate angiogenesis-related mechanism.

Methods and Results:

Quantitative evaluation of human vascular samples revealed that carriers of the 9p21 risk allele possess a significantly higher burden of immature intraplaque microvessels than carriers of the ancestral allele, irrespective of lesion size or patient comorbidity. To determine whether aberrant angiogenesis also occurs under nonatherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking the 9p21 candidate gene,
Cdkn2b
. These animals developed advanced hindlimb ischemia and digital autoamputation, secondary to a defect in the capacity of the
Cdkn2b
-deficient smooth muscle cell to support the developing neovessel. Microarray studies identified impaired transforming growth factor β (
TGF
β) signaling in cultured cyclin-dependent kinase inhibitor 2B (
CDKN2B
)–deficient cells, as well as
TGF
β
1
upregulation in the vasculature of 9p21 risk allele carriers. Molecular signaling studies indicated that loss of
CDKN2B
impairs the expression of the inhibitory factor,
SMAD-7
, which promotes downstream
TGF
β activation. Ultimately, this manifests in the upregulation of a poorly studied effector molecule,
TGF
β
1-induced-1
, which is a
TGF
β-rheostat known to have antagonistic effects on the endothelial cell and smooth muscle cell. Dual knockdown studies confirmed the reversibility of the proposed mechanism, in vitro.

Conclusions:

These results suggest that loss of
CDKN2B
may not only promote cardiovascular disease through the development of atherosclerosis but may also impair
TGF
β signaling and hypoxic neovessel maturation.
Evidence for a Prognostic Role of Orthostatic Hypertension on Survival in a Very Old Institutionalized Population
Authors: Agnoletti Davide , Valbusa Filippo , Labat Carlos , Gautier Sylvie , Mourad Jean-Jacques , Benetos Athanase
Published: November 2015

Abstract—

In old individuals, regulation of blood pressure during postural changes is impaired. Several studies have assessed the clinical impact of orthostatic hypotension (OHypoT) during the aging process. By contrast, the prevalence and prognostic role of the increase in blood pressure in upright position (orthostatic hypertension, OHyperT) in old adults remain unknown. We investigated the association of OHyperT with cardiovascular morbidity and mortality in a population of old institutionalized subjects. A 2-year follow-up longitudinal study was conducted on 972 subjects (mean age [SD] 88 [5]) from the PARTAGE (Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population) study, able to maintain a standing position. OHyperT was defined as an increase in systolic blood pressure ≥20 mm Hg during the first and third minute of standing. Three groups of subjects were compared: orthostatic normotension (n=540), OHypoT (n=157), and OHyperT (n=275). OHyperT prevalence (28%) was higher than OHypoT (16%). Sitting systolic blood pressure was higher in OHypoT compared with orthostatic normotension and OHyperT groups (146 [23] versus 136 [21] and 136 [20] mm Hg, respectively,
P
<0.001). The OHyperT group was associated with a greater risk of cardiovascular morbidity and mortality than orthostatic normotension (hazard ratio 1.51 [1.09–2.08],
P
<0.01) and remained unchanged after adjustment for age, sex, sitting systolic blood pressure, and comorbidities. No difference in cardiovascular morbidity and mortality was observed between OHyperT and OHypoT groups. In conclusion, in a old frail population, the increase in systolic blood pressure during upright position occurs frequently and is associated with higher cardiovascular morbidity and mortality independently of sitting blood pressure levels and major comorbidities. Health professional should take into account not only the decrease but also the increase in blood pressure when standing up.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00901355.