bluuebunny/crossref_metadata_2025 huggingface dataset:
Do white spruce epicuticular wax monoterpenes follow foliar patterns?
Authors: Despland Emma , Bourdier Thomas , Dion Emilie , Bauce Eric
Published: June 2016

We examine the extent to which foliar monoterpenes are trapped in the epicuticular waxes as part of an investigation into their role in natural defense against folivores. We monitored concentrations in white spruce (Picea glauca (Moench) Voss) previous-year foliage and expanding foliage and their epicuticular waxes over the 2010 (14 trees) and 2011 (25 trees) growing seasons. In 2010, concentrations were low in the spring and increased over the summer; in 2011, they stayed low. The monoterpene profile of individual trees was similar between years and showed a consistent pattern over the growing season; in expanding foliage, δ-3-carene was only present in spring, whereas bornyl acetate increased over the growing season. Individual wax monoterpene profiles correlated with those of foliage, but the total concentration showed a different phenological pattern. Total content remained constant throughout the growing season on previous-year foliage but decreased on expanding foliage. Electron microscopy suggests this is due to changes in stomatal wax plugs and their role in blocking evaporation from the stomata. These findings suggest that insects contacting the leaf surface will receive accurate information from the wax chemical composition about the monoterpene mix but not about overall monoterpene levels.
Muonic X-ray spectroscopy: Effect of the presence of protons on X-ray production
Authors: Mohamadsalehi F. , Rahimi N. , Gheisari R.
Published: June 2016

The paper deals with muonic X-ray generation by a two-layer solid hydrogen structure of [Formula: see text]. The target has a high efficiency for analyzing characteristic X-rays in ion implantation. To predict the effect of the presence of protons on X-ray production, we have proposed a new kinetic schema. Muonic object equations have been written to descibe all muonic processes. In the case of a low concentration of argon (Ar) ions (5 ppm) in the sD2 layer a proton concentration of about 20% leads to a significant drop in the X-ray yield. However, in the case of a high Ar concentration (500 ppm) this effect is negligible.
Dimensional reduction in numerical relativity: Modified Cartoon formalism and regularization
Authors: Cook William G. , Figueras Pau , Kunesch Markus , Sperhake Ulrich , Tunyasuvunakool Saran
Published: June 2016

We present in detail the Einstein equations in the Baumgarte–Shapiro–Shibata–Nakamura formulation for the case of [Formula: see text]-dimensional spacetimes with [Formula: see text] isometry based on a method originally introduced in Ref. 1. Regularized expressions are given for a numerical implementation of this method on a vertex centered grid including the origin of the quasi-radial coordinate that covers the extra dimensions with rotational symmetry. Axisymmetry, corresponding to the value [Formula: see text], represents a special case with fewer constraints on the vanishing of tensor components and is conveniently implemented in a variation of the general method. The robustness of the scheme is demonstrated for the case of a black-hole head-on collision in [Formula: see text] spacetime dimensions with [Formula: see text] symmetry.
Human adipocytes from the subcutaneous superficial layer have greater adipogenic potential and lower PPAR-γ DNA methylation levels than deep layer adipocytes
Authors: Kosaka Kentaro , Kubota Yoshitaka , Adachi Naoki , Akita Shinsuke , Sasahara Yoshitaro , Kira Tomoe , Kuroda Masayuki , Mitsukawa Nobuyuki , Bujo Hideaki , Satoh Kaneshige
Published: June 2016

Human subcutaneous fat tissue consists of two layers, superficial adipose tissue (SAT) and deep adipose tissue (DAT). Some recent reports suggest that a disproportionate accumulation of DAT is related to obesity-associated metabolic complications. However, the differences in adipocyte function between SAT and DAT are unclear. To clarify the differences in human adipocyte characteristics between SAT and DAT, human ceiling culture-derived proliferative adipocytes (ccdPAs) were primary cultured from SAT and DAT of three lean female patients. Differences in adipogenic differentiation potential and sensitivity to exogenous adipogenic factors were examined. Epigenetic modification of the CpG island DNA methylation levels of genes related to adipogenesis was measured. In histological analyses, the mean adipocyte size in SAT was significantly larger than that in DAT (8,741 ± 416 vs. 7,732 ± 213 μm2, P < 0.05). Primary cultured adipocytes from SAT showed significantly greater adipogenesis than did those of DAT. Sensitivity to partial adipogenic stimulation was significantly different between ccdPAs of SAT and DAT. Peroxisome proliferator-activated receptor-γ (PPAR-γ) protein expression and leptin protein secretion from ccdPAs were significantly higher in SAT than DAT. DNA methylation levels of PPAR-γ were significantly lower in ccdPAs of SAT than DAT. Adipocyte size was larger in SAT than DAT in vivo. This is consistent with the findings of an in vitro study that, compared with ccdPAs in DAT, ccdPAs in SAT have higher adipogenic potential and lower DNA methylation levels of PPAR-γ.
Arousal dynamics drive vocal production in marmoset monkeys
Authors: Borjon Jeremy I. , Takahashi Daniel Y. , Cervantes Diego C. , Ghazanfar Asif A.
Published: June 2016

Vocal production is the result of interacting cognitive and autonomic processes. Despite claims that changes in one interoceptive state (arousal) govern primate vocalizations, we know very little about how it influences their likelihood and timing. In this study we investigated the role of arousal during naturally occurring vocal production in marmoset monkeys. Throughout each session, naturally occurring contact calls are produced more quickly, and with greater probability, during higher levels of arousal, as measured by heart rate. On average, we observed a steady increase in heart rate 23 s before the production of a call. Following call production, there is a sharp and steep cardiac deceleration lasting ∼8 s. The dynamics of cardiac fluctuations around a vocalization cannot be completely predicted by the animal's respiration or movement. Moreover, the timing of vocal production was tightly correlated to the phase of a 0.1-Hz autonomic nervous system rhythm known as the Mayer wave. Finally, a compilation of the state space of arousal dynamics during vocalization illustrated that perturbations to the resting state space increase the likelihood of a call occurring. Together, these data suggest that arousal dynamics are critical for spontaneous primate vocal production, not only as a robust predictor of the likelihood of vocal onset but also as scaffolding on which behavior can unfold.
TRPV4: Molecular Conductor of a Diverse Orchestra
Authors: White John P. M. , Cibelli Mario , Urban Laszlo , Nilius Bernd , McGeown J. Graham , Nagy Istvan
Published: June 2016

Transient receptor potential vanilloid type 4 (TRPV4) is a calcium-permeable nonselective cation channel, originally described in 2000 by research teams led by Schultz ( Nat Cell Biol 2: 695 –702, 2000) and Liedtke ( Cell 103: 525–535, 2000). TRPV4 is now recognized as being a polymodal ionotropic receptor that is activated by a disparate array of stimuli, ranging from hypotonicity to heat and acidic pH. Importantly, this ion channel is constitutively expressed and capable of spontaneous activity in the absence of agonist stimulation, which suggests that it serves important physiological functions, as does its widespread dissemination throughout the body and its capacity to interact with other proteins. Not surprisingly, therefore, it has emerged more recently that TRPV4 fulfills a great number of important physiological roles and that various disease states are attributable to the absence, or abnormal functioning, of this ion channel. Here, we review the known characteristics of this ion channel's structure, localization and function, including its activators, and examine its functional importance in health and disease.
The Preventive Effect of Head Injury by Helmet Type in Motorcycle Crashes: A Rural Korean Single-Center Observational Study
Authors: Sung Kang-Min , Noble Jennifer , Kim Sang-Chul , Jeon Hyeok-Jin , Kim Jin-Yong , Do Han-Ho , Park Sang-O , Lee Kyeong-Ryong , Baek Kwang-Je
Published: June 2016

Introduction.The goal of this study was to determine the preventive effect on head injury by helmet type: full face helmet (FFH), open face helmet (OFH), and half-coverage helmet (HCH).Methods.This is a retrospective observational study of motorcycle crash victims between June 2012 and May 2015 in a rural town in Korea. We performed multiple linear regression to predict the effect of each type of helmet compared to unhelmeted status in preventing head injury using dependent variables based on the Abbreviated Injury Scale (AIS) and applied logistic regression modeling to compare the incidence of head injury.Results.Of the 738 patients, the number of FFH patients was 33.5%, followed by unhelmeted (27.8%), OFH (17.6%), and HCH (13.0%) patients. The FFH and OFH group had a lower head maximum AIS than unhelmeted group (coefficient: −0.368, 95% CI: −0.559 to −0.177 and coefficient: −0.235, 95% CI: −0.459 to −0.010, resp.) and only FFHs experienced a reduction effect of severe and minor head injury (OR: 0.206, 95% CI: 0.080 to 0.533 and OR: 0.589, 95% CI: 0.377 to 0.920, resp.).Conclusions.FFHs and OFHs reduce the risk of head injury, and FFHs have a more preventive effect on head injury in motorcycle crashes.
Anticollusion Attack Noninteractive Security Hierarchical Key Agreement Scheme in WHMS
Authors: Mao Kefei , Liu Jianwei , Chen Jie
Published: June 2016

Wireless Health Monitoring Systems (WHMS) have potential to change the way of health care and bring numbers of benefits to patients, physicians, hospitals, and society. However, there are crucial barriers not only to transmit the biometric information but also to protect the privacy and security of the patients’ information. The key agreement between two entities is an essential cryptography operation to clear the barriers. In particular, the noninteractive hierarchical key agreement scheme becomes an attractive direction in WHMS because each sensor node or gateway has limited resources and power. Recently, a noninteractive hierarchical key agreement scheme has been proposed by Kim for WHMS. However, we show that Kim’s cryptographic scheme is vulnerable to the collusion attack if the physicians can be corrupted. Obviously, it is a more practical security condition. Therefore, we proposed an improved key agreement scheme against the attack. Security proof, security analysis, and experimental results demonstrate that our proposed scheme gains enhanced security and more efficiency than Kim’s previous scheme while inheriting its qualities of one-round communication and security properties.
Central Corneal Thickness in Spectral-Domain OCT and Associations with Ocular and Systemic Parameters
Authors: Schuster Alexander Karl-Georg , Fischer Joachim Ernst , Vossmerbaeumer Urs
Published: June 2016

Background. Optical coherence tomography (OCT) allows quantitative analysis of the anterior segment of the eye with a noncontact examination. The aim of this study is to analyze associations of central corneal thickness (CCT) as measured by OCT with ocular and systemic cardiovascular parameters.Methods. A cross-sectional study of 734 persons was performed in a working age population. Only healthy eyes were included. A comprehensive ophthalmological examination including refraction, noncontact tonometry, and imaging of the anterior segment by SD-OCT was performed. In parallel, a broad range of systemic cardiovascular parameters were measured. Associations were analyzed using a generalized estimating equations’ model.Results. CCT measurements showed a significant association with corneal curvature and intraocular pressure: a thinner CCT was associated with a flatter cornea and with lower intraocular pressure (p<0.001). Age was positively associated with CCT (p<0.001); all other cardiovascular parameters were not associated.Conclusion. A thinner cornea is associated with a flatter surface and with lower intraocular pressure readings, while there are no independent associations with refraction and systemic cardiovascular parameters. Our findings highlight the value of SD-OCT CCT measurements as a standard tool in anterior segment analysis.
An Application of Self-Organizing Map for Multirobot Multigoal Path Planning with Minmax Objective
Authors: Faigl Jan
Published: June 2016

In this paper, Self-Organizing Map (SOM) for the Multiple Traveling Salesman Problem (MTSP) with minmax objective is applied to the robotic problem of multigoal path planning in the polygonal domain. The main difficulty of such SOM deployment is determination of collision-free paths among obstacles that is required to evaluate the neuron-city distances in the winner selection phase of unsupervised learning. Moreover, a collision-free path is also needed in the adaptation phase, where neurons are adapted towards the presented input signal (city) to the network. Simple approximations of the shortest path are utilized to address this issue and solve the robotic MTSP by SOM. Suitability of the proposed approximations is verified in the context of cooperative inspection, where cities represent sensing locations that guarantee to “see” the whole robots’ workspace. The inspection task formulated as the MTSP-Minmax is solved by the proposed SOM approach and compared with the combinatorial heuristic GENIUS. The results indicate that the proposed approach provides competitive results to GENIUS and support applicability of SOM for robotic multigoal path planning with a group of cooperating mobile robots. The proposed combination of approximate shortest paths with unsupervised learning opens further applications of SOM in the field of robotic planning.
Constitutive Equations of Yield Stress Sensitivity to Strain Rate of Metals: A Comparative Study
Authors: Al Salahi Ammar A. , Othman Ramzi
Published: June 2016

Several constitutive equations have proposed to model the strain rate sensitivity of metals to strain rate. This paper presents a comparative of six equations reported in the open literature. All equations are used to fit the yield stress of three copper materials and one steel material at two different temperatures. A specific cost function and an optimization problem are defined. The authors recommend the use of the Cowper-Symonds equation or a modified-Eyring equation as both of them fit well the experimental data while using only three material constants. A modified flow stress Johnson-Cook equation is then proposed for metallic materials.
Self-Monitoring Strengthening System Based on Carbon Fiber Laminate
Authors: Krzywon Rafal , Gorski Marcin , Dawczynski Szymon , Szojda Leszek , Castro Gomes Joao , Salvado Rita
Published: June 2016

Externally bonded composites reinforced with high-strength fibers are increasingly popular in construction, especially in structures’ strengthening, where the best possible mechanical properties are required. At the same time the ability to autodetect threats is one of the most desirable features of contemporary structures. The authors of the paper have developed an intelligent fabric, wherein the carbon fibers play the role of not only tensile reinforcement but also strain sensor. The idea is based on the construction of the strain gauge, where the thread of carbon fibers arranged in zig-zag pattern works as electrical conductor and is insulated by parallel thread of glass or acrylic fibers. Preliminary laboratory tests were designed to create effective measurement techniques and assess the effectiveness of the strengthening of selected building structures, as reinforced concrete and timber beams. Presented in the paper, selected results of these studies are very promising, although there were some noted problems to be considered in next steps. The main problem here is the control of the cross section of the fibers tow, affecting the total resistance of the fabric. One of the main deficiencies of the proposed solution is also sensitivity to moisture.
Pigtail Catheter: A Less Invasive Option for Pleural Drainage in Egyptian Patients with Recurrent Hepatic Hydrothorax
Authors: Sharaf-Eldin Mohamed , Bediwy Adel Salah , Kobtan Abdelrahman , Abd-Elsalam Sherief , El-Kalla Ferial , Mansour Loai , Elkhalawany Walaa , Elhendawy Mohamed , Soliman Samah
Published: June 2016

Background and Aims. Treatment of hepatic hydrothorax is a clinical challenge. Chest tube insertion for hepatic hydrothorax is associated with high complication rates. We assessed the use of pigtail catheter as a safe and practical method for treatment of recurrent hepatic hydrothorax as it had not been assessed before in a large series of patients.Methods. This study was conducted on 60 patients admitted to Tanta University Hospital, Egypt, suffering from recurrent hepatic hydrothorax. The site of pigtail catheter insertion was determined by ultrasound guidance under complete aseptic measures and proper local anesthesia. Insertion was done by pushing the trocar and catheter until reaching the pleural cavity and then the trocar was withdrawn gradually while inserting the catheter which was then connected to a collecting bag via a triple way valve.Results. The use of pigtail catheter was successful in pleural drainage in 48 (80%) patients with hepatic hydrothorax. Complications were few and included pain at the site of insertion in 12 (20%) patients, blockage of the catheter in only 2 (3.3%) patients, and rapid reaccumulation of fluid in 12 (20%) patients. Pleurodesis was performed on 38 patients with no recurrence of fluid within three months of observation.Conclusions. Pigtail catheter insertion is a practical method for treatment of recurrent hepatic hydrothorax with a low rate of complications. This trial is registered with ClinicalTrials.gov Identifier:NCT02119169.
A Comprehensive Single Institutional Review of 2 Years in a Designated Fast-Track Sarcoma Diagnostic Clinic Linked with a Sarcoma Specialist Advisory Group: Meeting the Target but Failing the Task?
Authors: Szucs Zoltan , Davidson Dochka , Wong Han Hsi , Horan Gail , Bearcroft Philip W. P. , Grant Ian , Grimer Robert , Hopper Melanie A. , Hatcher Helen , Earl Helena
Published: June 2016

Background. National guidelines prompted the implementation of a designated two-week wait referral pathway to facilitate the early diagnosis of sarcomas, to improve treatment outcomes.Methods. Patients referred to the Cambridge Sarcoma Diagnostic Clinic between January 2013 and December 2014 were identified through the electronic appointments system. Information was retrospectively retrieved about patient characteristics and details of the diagnostic pathway.Results. 17.3% of patients referred (69/397) were diagnosed with a malignancy. Of these, 59.3% (41/69) had primary sarcomas, 17.4% (12/69) had metastatic cancer, and 23.2% (16/69) had a different primary malignancy. 15% of the 41 sarcomas were <5 cm, 34% in the 5–10 cm range, and 51% >10 cm. Sarcomas diagnosed through this clinic represented 13% (41/315) of sarcomas managed at the centre during the same 2 years.Conclusion. While we achieved the target of 10% (41/397) sarcoma diagnosis rate in the rapid access clinic, only 15% of these were <5 cm better prognosis lesions. This calls into question the “real world” impact of such diagnostic clinics on early diagnosis of sarcomas. In order to enhance generic cancer diagnostic skills, training in these diagnostic clinics could be usefully integrated into national training curricula for both surgical and nonsurgical oncologists.
Assessment of Functional EST-SSR Markers (Sugarcane) in Cross-Species Transferability, Genetic Diversity among Poaceae Plants, and Bulk Segregation Analysis
Authors: Ul Haq Shamshad , Kumar Pradeep , Singh R. K. , Verma Kumar Sambhav , Bhatt Ritika , Sharma Meenakshi , Kachhwaha Sumita , Kothari S. L.
Published: June 2016

Expressed sequence tags (ESTs) are important resource for gene discovery, gene expression and its regulation, molecular marker development, and comparative genomics. We procured 10000 ESTs and analyzed 267 EST-SSRs markers through computational approach. The average density was one SSR/10.45 kb or 6.4% frequency, wherein trinucleotide repeats (66.74%) were the most abundant followed by di- (26.10%), tetra- (4.67%), penta- (1.5%), and hexanucleotide (1.2%) repeats. Functional annotations were done and after-effect newly developed 63 EST-SSRs were used for cross transferability, genetic diversity, and bulk segregation analysis (BSA). Out of 63 EST-SSRs, 42 markers were identified owing to their expansion genetics across 20 different plants which amplified 519 alleles at 180 loci with an average of 2.88 alleles/locus and the polymorphic information content (PIC) ranged from 0.51 to 0.93 with an average of 0.83. The cross transferability ranged from 25% for wheat to 97.22% for Schlerostachya, with an average of 55.86%, and genetic relationships were established based on diversification among them. Moreover, 10 EST-SSRs were recognized as important markers between bulks of pooled DNA of sugarcane cultivars through BSA. This study highlights the employability of the markers in transferability, genetic diversity in grass species, and distinguished sugarcane bulks.
Platelet‐Rich Plasma Obtained with Different Anticoagulants and Their Effect on Platelet Numbers and Mesenchymal Stromal Cells Behavior In Vitro
Authors: do Amaral Ronaldo José Farias Corrêa , da Silva Nemias Pereira , Haddad Natália Ferreira , Lopes Luana Siqueira , Ferreira Fábio Dias , Filho Ricardo Bastos , Cappelletti Paola Alejandra , de Mello Wallace , Cordeiro-Spinetti Eric , Balduino Alex
Published: June 2016

There are promising results in the use of platelet‐rich plasma (PRP) for musculoskeletal tissue repair. However, the variability in the methodology for its obtaining may cause different and opposing findings in the literature. Particularly, the choice of the anticoagulant is the first definition to be made. In this work, blood was collected with sodium citrate (SC), ethylenediaminetetraacetic acid (EDTA), or anticoagulant citrate dextrose (ACD) solution A, as anticoagulants, prior to PRP obtaining. Hematological analysis and growth factors release quantification were performed, and the effects on mesenchymal stromal cell (MSC) culture, such as cytotoxicity and cell proliferation (evaluated by MTT method) and gene expression, were evaluated. The use of EDTA resulted in higher platelet yield in whole blood; however, it induced an increase in the mean platelet volume (MPV) following the blood centrifugation steps for PRP obtaining. The use of SC and ACD resulted in higher induction of MSC proliferation. On the other hand, PRP obtained in SC presented the higher platelet recovery after the blood first centrifugation step and a minimal change in MSC gene expression. Therefore, we suggest the use of SC as the anticoagulant for PRP obtaining.
Application of Vehicle Mounted Accelerometers to Measure Pavement Roughness
Authors: Du Yuchuan , Liu Chenglong , Wu Difei , Li Siyu
Published: June 2016

To enhance the efficiency of pavement roughness measurement and reduce the cost, an integrated and wireless transfer based measuring system was developed. The proposed system can obtain vehicles status and location data via wireless acceleration sensors and GPS, calculate the international roughness index (IRI) by power spectral density analysis, and provide reports automatically. This paper presents the architecture of the proposed system, consisting of data collector, car mounted terminal, and information platform. Two wireless communication systems (ZigBee and 3G modules) were utilized to transfer the data and construct network between the components. The information platform implemented an acceleration-IRI model to calculate IRI, and a GPS based distance algorithm was employed to segment the measured road per 1 km. The various results are saved in an Oracle database, displayed on the digital map and made available to the mobile terminal. Several field tests of the prototype system were conducted in Huzhou, Zhejiang province in China. The results show that, compared to the laser roughness testing method, the relative error of this proposed system is less than 10%, which verifies the accuracy, effectiveness, and reliability of the proposed measuring system.
Serum Gelatinases Levels in Multiple Sclerosis Patients during 21 Months of Natalizumab Therapy
Authors: Castellazzi Massimiliano , Bellini Tiziana , Trentini Alessandro , Delbue Serena , Elia Francesca , Gastaldi Matteo , Franciotta Diego , Bergamaschi Roberto , Manfrinato Maria Cristina , Volta Carlo Alberto , Granieri Enrico , Fainardi Enrico
Published: June 2016

Background. Natalizumab is a highly effective treatment approved for multiple sclerosis (MS). The opening of the blood-brain barrier mediated by matrix metalloproteinases (MMPs) is considered a crucial step in MS pathogenesis. Our goal was to verify the utility of serum levels of active MMP-2 and MMP-9 as biomarkers in twenty MS patients treated with Natalizumab.Methods. Serum levels of active MMP-2 and MMP-9 and of specific tissue inhibitors TIMP-1 and TIMP-2 were determined before treatment and for 21 months of therapy.Results. Serum levels of active MMP-2 and MMP-9 and of TIMP-1 and TIMP-2 did not differ during the treatment. The ratio between MMP-9 and MMP-2 was increased at the 15th month compared with the 3rd, 6th, and 9th months, greater at the 18th month than at the 3rd and 6th months, and higher at the 21st than at the 3rd and 6th months.Discussion. Our data indicate that an imbalance between active MMP-9 and active MMP-2 can occur in MS patients after 15 months of Natalizumab therapy; however, they do not support the use of serum active MMP-2 and active MMP-9 and TIMP-1 and TIMP-2 levels as biomarkers for monitoring therapeutic response to Natalizumab.
Multiagent Semantical Annotation Enhancement Model for IoT-Based Energy-Aware Data
Authors: Razzaq Malik Kaleem , Ahmad Tauqir , Farhan Muhammad , Ullah Farhan , Amjad Kashif , Khalid Shehzad
Published: June 2016

The Internet of Things (IoT) is involved in dealing with physical items, gadgets, vehicles, structures, and different things that are inserted into hardware, programming, sensors, and system availability, which empowers these items to gather and trade information. Improving extraction of sensor-based data for energy awareness and then annotating it and converting it into semantically enabled form for analyzing results with the use of improved tools and applications are the focus of this research. However, as the amount of real time data gets huge, it becomes difficult to track results when needed at once. Reconciliation of heterogeneous information sources into an interlinked data is a standout among the most pertinent difficulties for some learning based systems these days. This paper forms suitable elements by a methodology for adjustment of heterogeneous sensor-based Web assets, where different tools and applications like weather detection for self-observing and self-diagnostics use dispersed human specialists and learning. The proposed general model uses a capability of the Semantic Web innovation and concentrates on the part of a semantic adjustment of existing broadly utilized models of information representation to Resource Description Framework (RDF) based semantically rich arrangement. This work is valuable for sorting out and inquiry of the detecting information in the Internet of Things.
Association oflincRNA-p21Haplotype with Coronary Artery Disease in a Chinese Han Population
Authors: Tang Sai-sai , Cheng Jie , Cai Meng-yun , Yang Xi-li , Liu Xin-guang , Zheng Bi-ying , Xiong Xing-dong
Published: June 2016

lincRNA-p21 plays an important role in the pathogenesis and progression of coronary artery disease (CAD). To date, the biological significance of polymorphisms inlincRNA-p21on CAD risk remains unknown. Here we aimed to evaluate the influence oflincRNA-p21polymorphisms on individual susceptibility to CAD. Genotyping of four tagSNPs (rs9380586, rs4713998, rs6930083, and rs6931097) withinlincRNA-p21gene was performed in 615 CAD and 655 controls. The haplotype analysis showed that the haplotype G-A-A-G (rs9380586-rs4713998-rs6930083-rs6931097) was statistically significantly associated with the reduced risk for CAD (OR = 0.78,P= 0.023). Stratified analysis revealed that G-A-A-G haplotype was at a significantly lower risk for myocardial infarction (MI) (OR = 0.68,P= 0.010). We also found that haplotype G-A-A-G had a more pronounced decreased risk for premature CAD or MI subjects (OR = 0.67,P= 0.017 for premature CAD, and OR = 0.65,P= 0.041 for premature MI, resp.). Our data provide the first evidence that the G-A-A-G haplotype oflincRNA-p21is associated with decreased risk of CAD and MI, particularly among premature CAD/MI in the Chinese Han population. Further studies with more subjects and in diverse ethnic populations are warranted to clarify the general validity of our findings.
Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors
Authors: Ortiz-Cuaran Sandra , Scheffler Matthias , Plenker Dennis , Dahmen llona , Scheel Andreas H. , Fernandez-Cuesta Lynnette , Meder Lydia , Lovly Christine M. , Persigehl Thorsten , Merkelbach-Bruse Sabine , Bos Marc , Michels Sebastian , Fischer Rieke , Albus Kerstin , König Katharina , Schildhaus Hans-Ulrich , Fassunke Jana , Ihle Michaela A. , Pasternack Helen , Heydt Carina , Becker Christian , Altmüller Janine , Ji Hongbin , Müller Christian , Florin Alexandra , Heuckmann Johannes M. , Nuernberg Peter , Ansén Sascha , Heukamp Lukas C. , Berg Johannes , Pao William , Peifer Martin , Buettner Reinhard , Wolf Jürgen , Thomas Roman K. , Sos Martin L.
Published: June 2016

Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).

Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.

Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS.

Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837–47. ©2016 AACR.
Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor–Positive Lymph Node–Negative Early-Stage Breast Cancer
Authors: Sestak Ivana , Zhang Yi , Schroeder Brock E. , Schnabel Catherine A. , Dowsett Mitch , Cuzick Jack , Sgroi Dennis
Published: June 2016

Purpose: Previous results from the TransATAC study demonstrated that both the Breast Cancer Index (BCI) and the OncotypeDX Recurrence Score (RS) added significant prognostic information to clinicopathologic factors over a 10-year period. Here, we examined cross-stratification between BCI and RS to directly compare their prognostic accuracy at the individual patient level.

Experimental Design: A total of 665 patients with hormone receptor–positive (HR+) and lymph node–negative disease were included in this retrospective analysis. BCI and RS risk groups were determined using predefined clinical cut-off points. Kaplan–Meier estimates of 10-year risk of distant recurrence (DR) and log-rank tests were used to examine cross-stratification between BCI and RS.

Results: As previously reported, both RS and BCI were significantly prognostic in years 0 to 10. BCI provided significant additional prognostic information to the Clinical Treatment Score (CTS) plus RS (ΔLR-χ2 = 11.09; P < 0.001), whereas no additional prognostic information was provided by RS to CTS plus BCI (ΔLR-χ2 = 2.22; P = 0.1). Restratification by BCI of the low and intermediate RS risk groups led to subgroups with significantly different DR rates (P < 0.001 and P = 0.003, respectively). In contrast, restratified subgroups created by RS of BCI risk groups did not differ significantly.

Conclusions: In this retrospective analysis, BCI demonstrated increased prognostic accuracy versus RS. Notably, BCI identified subsets of RS low and RS intermediate risk patients with significant and clinically relevant rates of DR. These results indicate that additional subsets of women with HR+, lymph node–negative breast cancer identified by BCI may be suitable candidates for adjuvant chemotherapy or extended endocrine therapy. Clin Cancer Res; 22(20); 5043–8. ©2016 AACR.

See related commentary by Brufsky and Davidson, p. 4963
The Vulnerable Newborn Brain: Imaging Patterns of Acquired Perinatal Injury
Authors: Ferriero Donna M.
Published: June 2016

Background: Over the past two decades, imaging techniques have allowed for better visualization of the newborn brain. This has enabled us to detect patterns, understand mechanisms and guide diagnosis and treatment. Objectives: The purpose of this review is to discuss imaging characteristics of acquired perinatal brain injury. Methods: Through literature review and the author's research, this review assesses published data on the distinct imaging patterns that occur in the neonatal period due to acquired brain insults. Results: In the term brain, susceptibility to hypoxia-ischemia, hypoglycemia and hyperbilirubinemia results in unique patterns of injury. Stroke commonly occurs in the newborn period. Infections, especially viral, have distinct patterns of white matter injury. In the preterm brain, white matter injury occurs commonly and is affected by postnatal growth, stress and infection. The cerebellum is uniquely vulnerable during this period, with resultant hemorrhages in almost half of preterm infants. Cerebellar growth is affected by intraventricular hemorrhage, drugs and placental pathology. Periventricular hemorrhagic infarction is the most serious consequence of the spectrum of intraventricular hemorrhage and results in profound disabilities. Conclusions: Taken together, the acquired perinatal brain injuries can have lifelong devastating consequences, so the search for therapies must continue.
Stem Cells for Neonatal Brain Disorders
Authors: Ahn So Yoon , Chang Yun Sil , Park Won Soon
Published: June 2016

Despite recent advances in neonatal intensive care medicine, neonatal brain injury resulting from intraventricular hemorrhage or hypoxic-ischemic encephalopathy remains a major cause of neonatal mortality and neurologic morbidities in survivors. Several studies have indicated that stem cell therapy is a promising novel therapy for neonatal brain injury resulting from these disorders. This review summarizes recent advances in stem cell research for treating neonatal brain injury due to intraventricular hemorrhage or hypoxic-ischemic encephalopathy with a particular focus on preclinical data, covering important issues for clinical translation such as optimal cell type, route, dose and timing of stem cell therapy, and translation of these preclinical results into a clinical trial.
Normal Newborn Heart Rate in the First Five Minutes of Life Assessed by Dry-Electrode Electrocardiography
Authors: Linde Jørgen Erland , Schulz Jörn , Perlman Jeffrey M. , Øymar Knut , Francis Fortunata , Eilevstjønn Joar , Ersdal Hege Langli
Published: June 2016

Background: There is limited evidence regarding the heart rate (HR) during the first minutes of life. Nonetheless, resuscitative actions within the first minute are partly guided by different HR levels. The advent of an electrocardiographic (ECG) HR sensor with early HR detection has provided the opportunity to study changes immediately following delivery. Objective: The objectives were to determine immediately following delivery: (i) the time to achievement of reliable ECG signals using dry electrodes, (ii) changes in HR, and (iii) the influence of the onset of breathing and cord clamping on the HR. Methods: Healthy term neonates were randomly included between July and October 2013. The HR was recorded by the ECG sensor, placed over the abdomen immediately after birth. Results: Fifty-five newborns were included. The median time from birth to placement of the HR sensor was 3 s (quartiles: 2 and 5), and the median time to the start of breathing was 6 s (quartiles: 2 and 15). The HR was around 120 beats/min (bpm) in the first seconds of life. As determined via breakpoint analysis, the HR increased by 1 beat in the first 40 s to 149 ± 33 bpm, followed by a moderate increase until 130 s and stabilization thereafter. After the onset of breathing, the HR decreased for 10 s and then increased. Minimal HR changes were observed after cord clamping. Conclusion: A dry-electrode ECG sensor detected reliable ECG signals almost immediately after birth. The normal HR increased significantly in spontaneously breathing infants during the first minute, influenced by the onset of breathing. Delayed cord clamping had a minimal impact on the HR, likely reflecting an earlier onset of breathing.
Ligation-Assisted Endoscopic Enucleation for the Resection of Gastrointestinal Tumors Originating from the Muscularis Propria: Analysis of Efficacy and Facility
Authors: Zheng Zhongqing , Jiao Guohui , Wang Tao , Chen Xin , Wang Bangmao
Published: June 2016

Background: Gastrointestinal tumors originating from the muscularis propria are believed to have the potential to progress to malignant tumors. The efficacy of ‘pre-management' with elastic band or endoloop assistant ligation after initial submucosal dissection in endoscopic enucleation procedure of these tumors was investigated and evaluated. Methods: The study included 21 patients with small gastric stromal tumors arising in the gastric muscularis propria as determined by endoscopy (endoscopic ultrasonography). A standard endoscope with a transparent cap attached to the tip was used. The cap was placed over the lesion, after incision of the surrounding tissue, maximum sustained suction was applied. Then the elastic band or endoloop was released around the base. Circumference resection was performed with clips strengthening the defect closure. Results: The 22 gastrointestinal stromal tumors sloughed completely. The mean time required for the full-thickness resection was 48 min. Minor perforation occurred with metal clips closing the defect of the gastric wall. Follow-up ranged from 13 to 42 months, during which time no recurrence was observed postoperatively. Conclusions: The band or endoloop assistant endoscopic ligation technique is effective for the enucleation of deep gastric tumors. It may help avoiding disturbance the abdominal cavity hemostasis in traditional full-thickness enucleation procedure.
Non-Descemet Stripping Automated Endothelial Keratoplasty for Bullous Keratopathy in Buphthalmic Eye
Authors: Hirano Koji , Kachi Shu , Matsuura Masako , Kawase Kazuhide , Park Won Sun
Published: June 2016

Purpose: To report the 2-year follow-up findings in a patient with buphthalmic bullous keratopathy (BK) who was successfully treated with non-Descemet stripping automated endothelial keratoplasty (nDSAEK). Methods: A 39-year-old man had an endothelial graft of 8.0 mm diameter placed uneventfully using the nDSAEK method for phakic BK with buphthalmos of the left eye. He had had a penetrating keratoplasty in the right eye due to aphakic BK 5 years earlier, which, however, resulted in the invasion of blood vessels and graft failure. Since the left eye was phakic, Descemetorhexis was not performed because the instruments might touch the crystalline lens. The best-corrected visual acuity (BCVA), intraocular pressure (IOP), and endothelial cell density (ECD) were determined at 2 weeks, and at 1, 3, 6, 12, 18 and 24 months after nDSAEK. Results: Twenty-four months after nDSAEK, his left cornea and lens remained clear, and the decimal BCVA was 0.8. However, the ECD of the graft had decreased from 2,274 cells/mm2 before nDSAEK to 539 cells/mm2 24 months after the surgery, and the rate of decrease appeared to be slightly faster than that of former reports. An IOP of >30 mm Hg was recorded at around 2 months after the surgery, but was well controlled by tapering the topical steroids and the addition of topical brinzolamide and latanoprost. Conclusion: Our findings show that nDSAEK can be successfully used to treat buphthalmic BK. We recommend that nDSAEK be considered especially in phakic eyes with a smooth posterior surface around the pupillary area.
Review of Cytology Practice at Thomas Jefferson University Hospital before and after High-Risk Human Papillomavirus Testing
Authors: Bibbo Marluce , Wang Zi-Xuan , Jones Krister , Solomides Charalambos , Draganova-Tacheva Rossitza , Stapp Robert
Published: June 2016

Objective: We performed a retrospective review of Papanicolaou (Pap) testing to assess whether the cytology practice in our institution was affected by the introduction of high-risk (HR) human papillomavirus (HPV) assays over time. Study Design: Cytology, HPV and histopathology records were retrieved from our laboratory information system from 2003 to 2015. Records for Digene Hybrid Capture 2®, Hologic Cervista® and Roche Cobas® HPV assays were obtained. A 3-month follow-up for HPV detected cases was performed, and results were correlated with cytology and biopsies. A 1-year follow-up of HPV 16/18 and other HR HPV detected cases was also performed. Results: From 2008 to 2015, a noticeable decrease in Pap testing volume occurred, from 11,792 to 4,664, while the percentage of HPV testing increased from 19 to 59%. Similar HPV detection rates and follow-up results for both reflex and cotesting were observed in the 3 HPV assays. Conclusions: The decrease in Pap testing was due to the lengthening of the test interval when cotesting results were negative. Practitioners adhering to guidelines accounts for increased molecular testing volume. A trend towards higher-grade cervical intraepithelial neoplasia in the follow-up of detected HPV 16/18 was noted. So far there has been no demand for HPV as a stand-alone test.
Cardiac Findings in the Fetus with Cerebral Arteriovenous Malformation Are Associated with Adverse Outcome
Authors: Godfrey Max E. , Tworetzky Wayne , Morash Donna , Friedman Kevin G.
Published: June 2016

Objectives: To assess cardiac sequelae of fetal cerebral arteriovenous malformations (CAVMs) and evaluate any association with outcomes. Methods: We retrospectively analyzed cardiac structure and function in fetuses with CAVMs who underwent fetal echocardiography (October 1999 to August 2015, n = 11), and compared them with normal controls. Results: The median gestational age was 36 weeks (range 18-38). Common abnormal findings included dilated superior vena cava (100%) and right atrium (82%), reduced middle cerebral artery pulsatility index (86%), tricuspid regurgitation (82%), and right ventricular (RV) dysfunction (64%). Hydrops was present in 1 fetus, who did not survive. The median cardiothoracic ratio (CTR) was 0.36 (0.29-0.45, n = 10); the median combined cardiac output indexed to estimated fetal weight (iCCO) was 565 ml/kg/min (379-1,565, n = 7). Of the 11 fetuses, 1 patient elected for termination, and 5 suffered neonatal demise. Comparing survivors (n = 5) and nonsurvivors (n = 6), a larger tricuspid valve (TV) z-score (p = 0.009) and RV dysfunction (p = 0.015) were associated with nonsurvival, and nonsurvivors had a higher iCCO than controls (990 vs. 550 ml/kg/min, p = 0.035). A larger difference between the TV and mitral valve z-scores (surrogate for RV dilation, p = 0.052), and CTR >0.38 (p = 0.0762) tended towards nonsurvival. Conclusion: CAVMs impose volume load on the fetal circulation, mainly affecting right heart structures. Increased right heart dilation and dysfunction are associated with nonsurvival.
The Medical Management of Gastro-Oesophageal Reflux Disease
Authors: Sharma Neel , Ho Khek Yu
Published: June 2016

Background: Gastro-oesophageal reflux disease (GORD) is a common global phenomenon. It is associated with the backflow of gastric contents proximally, typically due to transient relaxations of the lower oesophageal sphincter. Various factors contribute to GORD, including obesity, smoking, alcohol and pregnancy. The primary concern of GORD is its association with the development over time of Barrett's oesophagus and, ultimately, oesophageal adenocarcinoma. Summary: This review focuses on the various medical interventions that are useful in the treatment of GORD. Key Messages: Various lifestyle interventions such as weight loss and smoking cessation are useful in the treatment of GORD. Medical therapy relies on the use of acid suppressants such as proton pump inhibitors and histamine H2 receptor antagonists.
Effects of 22 CYP2D6 Genetic Variations Newly Identified in Chinese Population on Olanzapine Metabolism in vitro
Authors: Zhou Hong-Yu , Gu Er-Min , Chen Qiu-lei , Zhan Yun-Yun , Wang Shuang-Hu , Liang Bing-Qing , Dai Da-Peng , Cai Jian-Ping , Hu Guo-Xin
Published: June 2016

The objective of this study was to assess the catalytic activity of 22 novel CYP2D6 allelic variants (2D6*87-*98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C and R497C) to olanzapine in vitro. Their protein products expressed in Spodoptera frugiperda 21 (Sf21) insect cells were incubated with olanzapine 100-2,000 μmol/l for 30 min. The kinetic parameters of Km, Vmax and intrinsic clearance were determined by 2-hydroxymethylolanzapine, the metabolite of olanzapine mediated by CYP2D6, using ultra-performance liquid chromatography tandem mass spectrometry. Results showed that the kinetic parameters of 2 alleles, CYP2D6*92 and 2D6*96, could not be detected; 17 allelic variants, CYP2D6*87-*88, 2D6*90-*91, 2D6*93-*95, 2D6*97, R25Q, F164L, E215K, F219S, V327M, V342M, R344Q, R440C and R497C, significantly reduced the intrinsic clearance of olanzapine; 2 variants, CYP2D6*89 and 2D6*98, increased the intrinsic clearance of olanzapine; no difference was found in intrinsic clearance of D336N. Furthermore, 6 alleles, CYP2D6*87, 2D6*88, 2D6*91, 2D6*93, 2D6*97 and R497C, exhibited higher Km values in a range of 120.80-217.56% relative to wild-type CYP2D6*1. The research demonstrated the metabolic phenotype of the 22 novel CYP2D6 variants for olanzapine that were different from probe drugs we used previously and might provide beneficial information to the personalized medicine of olanzapine.