bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of mesenchymal stem cells combined with platelet‐rich plasma on skin wound healing
Authors: Mahmoudian‐Sani Mohammad‐Reza , Rafeei Fatemeh , Amini Razieh , Saidijam Massoud
Published: March 2018

Introduction

Mesenchymal stem cells (MSCs) are multipotent stem cells that have the potential of proliferation, high self‐renewal, and the potential of multilineage differentiation. The differentiation potential of the MSCs in vivo and in vitro has caused these cells to be regarded as potentially appropriate tools for wound healing. After the burn, trauma or removal of the tumor of wide wounds is developed. Although standard treatment for skin wounds is primary healing or skin grafting, they are not always practical mainly because of limited autologous skin grafting.

Evidence Acquisitions

Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO), and Web of Science have been searched.

Evidence Synthesis

For clinical use of the MSCs in wound healing, two key issues should be taken into account: First, engineering biocompatible scaffolds clinical use of which leads to the least amount of side effects without any immunologic response and secondly, use of stem cells secretions with the least amount of clinical complications despite their high capability of healing damage.

Conclusion

In light of the MSCs’ high capability of proliferation and multilineage differentiation as well as their significant role in modulating immunity, these cells can be used in combination with tissue engineering techniques. Moreover, the MSCs’ secretions can be used in cell therapy to heal many types of wounds. The combination of MSCs and PRP aids wound healing which could potentially be used to promote wound healing.
The Importance of Racial Socialization: School‐Based Racial Discrimination and Racial Identity Among African American Adolescent Boys and Girls
Authors: Butler‐Barnes Sheretta T. , Richardson Bridget L. , Chavous Tabbye M. , Zhu Jiaxi
Published: March 2018

This study examined various parental racial socialization messages as mediators between school‐based racial discrimination and racial identity formation over 4 years for African American boys (N = 639) and African American girls (N = 711). Findings indicated that school‐based racial discrimination was associated with racial identity beliefs. For African American boys, behavioral racial socialization messages mediated the relation between school‐based racial discrimination and racial centrality over time. Mediation also resulted for African American girls, but for a different set of race‐related messages (negative messages and racial barriers) and racial identity beliefs. The developmental significance of the findings and implications for future research are discussed.
Equilibrium in Insurance Markets With Adverse Selection When Insurers Pay Policy Dividends
Authors: Picard Pierre
Published: March 2018

We show that an equilibrium always exists in the Rothschild–Stiglitz insurance market model with adverse selection and an arbitrary number of risk types, when insurance contracts include policy dividend rules. The Miyazaki–Wilson–Spence state‐contingent allocation is an equilibrium allocation (defined as a set of type‐dependent lotteries sustained at a symmetric equilibrium of a market game), and it is the only one when out‐of‐equilibrium beliefs satisfy a robustness criterion. It is shown that stock insurers and mutuals may coexist, with stock insurers offering insurance coverage at actuarial price and mutuals cross‐subsidizing risks.
Multiple grouped papules and vesicles on the finger of a 2‐year‐old girl
Authors: Lopez‐Delgado David , Fernandez‐Pugnaire Maria A , Ruiz‐Villaverde Ricardo
Published: March 2018

See Answer
How Does Online Interaction Affect Idea Quality? The Effect of Feedback in Firm‐Internal Idea Competitions
Authors: Zhu Hangzi , Kock Alexander , Wentker Marc , Leker Jens
Published: March 2018

Social media technologies that enable interactive feedback during idea generation can complement existing modes of knowledge exchange in innovation management. Especially large, multinational companies use internal online idea competitions to promote intraorganizational knowledge exchange. Although current studies mainly focus on idea generation through crowdsourcing, little attention has been paid to the effect of online interaction between contributors on idea quality. Building on the organizational knowledge networks theory, this study examines online feedback activities, their contribution to knowledge exchange, and hence, how they increase idea quality. The authors identify three feedback characteristics of online idea generation presumed to affect idea quality: (1) the diversity of commentators (feedback diversity), (2) the extent to which feedback is elaborate and constructive (feedback constructiveness), and (3) the degree of facilitator interaction during idea discussion (feedback integration). This study also investigates how the idea authors' own feedback behavior moderates the relationships between feedback characteristics and idea quality. The results show that all three feedback characteristics relate independently and positively to idea quality. Author feedback shows a positive interaction effect with feedback diversity and a negative interaction effect with feedback constructiveness. The findings suggest that online feedback in idea competitions constitutes an important knowledge exchange process for idea generation. Companies that want to profit from firm‐internal idea competitions should actively support online collaboration—e.g., through facilitators.
Bending strategies of convergently evolved, articulated coralline algae
Authors: Janot Kyra G. , Martone Patrick T.
Published: March 2018

The evolution of uncalcified genicula in upright calcified corallines has occurred at least three times independently, resulting in articulated corallines within Corallinoideae, Lithophylloideae, and Metagoniolithoideae. Genicula confer flexibility to otherwise rigid thalli, and the localization of bending at discrete intervals amplifies bending stress in genicular tissue. Genicular morphology must, therefore, be balanced between maintaining flexibility while mitigating or resisting stress. Genicula in the three articulated lineages differ in both cellular construction and development, which may result in different constraints on morphology. By studying the interaction between flexibility and morphological variation in multiple species, we investigate whether representatives of convergently evolving clades follow similar strategies to generate mechanically successful articulated fronds. By using computational models to explore different bending strategies, we show that there are multiple ways to generate flexibility in upright corallines but not all morphological strategies are mechanically equivalent. Corallinoids have many joints, lithophylloids have pliant joints, and metagoniolithoids have longer joints—while these strategies can lead to comparable thallus flexibility, they also lead to different levels of stress amplification in bending. Moreover, genicula at greatest risk of stress amplification are typically the strongest, universally mitigating the trade‐off between flexibility and stress reduction.
Replication in Second Language Research: Narrative and Systematic Reviews and Recommendations for the Field
Authors: Marsden Emma , Morgan‐Short Kara , Thompson Sophie , Abugaber David
Published: March 2018

Despite its critical role for the development of the field, little is known about replication in second language (L2) research. To better understand replication practice, we first provide a narrative review of challenges related to replication, drawing on recent developments in psychology. This discussion frames and motivates a systematic review, building on syntheses of replication in psychology, education, and L2 research. We coded 67 self‐labeled L2 replication studies found across 26 journals for 136 characteristics. We estimated a mean rate of 1 published replication study for every 400 articles, with a mean of 6.64 years between initial and replication studies and a mean of 117 citations of the initial study before a replication was published. Replication studies had an annual mean of 7.3 citations, much higher than averages in linguistics and education. Overlap in authorship between initial and replication studies and the availability of the initial materials both increased the likelihood of a replication supporting the initial findings. Our sample contained no direct (exact) replication attempts, and changes made to initial studies were numerous and wide ranging, which likely obscured, if not undermined, the interpretability of replication studies. To improve the amount and quality of L2 replication research, we propose 16 recommendations relating to rationale, nomenclature, design, infrastructure, and incentivization for collaboration and publication.

Open Practices

This article has been awarded Open Materials and Open Data badges. All materials and data are publicly accessible via the IRIS Repository athttps://www.iris-database.org/iris/app/home/detail?id=york:934328. Learn more about the Open Practices badges from the Center for Open Science:https://osf.io/tvyxz/wiki.
Self‐care agency, lifestyle, and physical condition predict future frailty in community‐dwelling older people
Authors: Tanimura Chika , Matsumoto Hiromi , Tokushima Yasuko , Yoshimura Junko , Tanishima Shinji , Hagino Hiroshi
Published: March 2018

The purpose of this 2 year longitudinal study was to identify the relationship between self‐care agency, lifestyle, physical condition, and frailty among community‐dwelling older people in a rural area of Japan. The participants were 133 older individuals aged 65 years or above. Data collection was conducted via face‐to‐face interviews using self‐administered questionnaires. Background information, such as age, sex, current employment status, family structure, medication use, comorbidities, and knee and lower back pain, were assessed. The definition of frailty was based on the Frailty Checklist. Self‐care agency, lifestyle habits, and locomotive syndrome were assessed using specific assessment scores. Logistic regression analysis showed that locomotive syndrome, knee and lower back pain, and stroke are risk factors for frailty. Among the factors associated with frailty, current employment, regular exercise, and self‐care agency were recognized as preventive factors of depression, decreased cognitive function, and being housebound. Our findings suggest that enhancing self‐care agency, regular exercise, and self‐management skills for chronic illness and disability may decrease the progression of frailty among older people.
Parents’ experiences of their teenage children’s parenthood: An interview study
Authors: Sriyasak Atcharawadee , Almqvist Anna‐Lena , Sridawruang Chaweewan , Häggström‐Nordin Elisabet
Published: March 2018

In this study, we described and analyzed parents’ experiences of teenage parenthood and the provision of support to their teenage children who had recently have become parents. A qualitative method was used. In‐depth interviews with 24 participants were conducted, all parents of teenage parents. Data were analyzed using content analysis; four themes and 11 subthemes were identified. The results show that parents’ norms and values were strongly influenced by their religious beliefs. The participants had mixed emotions and reactions to their teenage children’s parenthood. Also participants were sources of support to the teenage parents and assisted them in their transition to parenthood. However, the participants also expressed the importance that their teenage children continue their education and avoid repeated pregnancies. This study highlights how emotional, instrumental, and informational support provided by parents to their teenagers can assist the latter in their transition to parenthood. In their work with teenage parents, healthcare providers can benefit from teenage parent's own parents involvement and experiences.
Phyllosphere microbiology: at the interface between microbial individuals and the plant host
Authors: Remus‐Emsermann Mitja N. P. , Schlechter Rudolf O.
Published: March 2018

Contents

Summary
1327

I.
Introduction
1327

II.
Individuality and the relevance of scales for the investigation of bacteria
1328

III.
Bacterial aggregation and community patterning at the single‐cell resolution
1329

IV.
What are the effects on the plant host?
1330

V.
Future directions and current questions
1331

Acknowledgements
1332

ORCID
1332

References
1332

Leaf surfaces are home to diverse bacterial communities. Within these communities, every individual cell perceives its unique environment and responds accordingly. In this insight article, the perspective of the bacterial individual is assumed in an attempt to describe how the spatially heterogeneous leaf surface determines the fate of bacteria. To investigate behaviour at scales relevant to bacteria, single‐cell approaches are essential. Single‐cell studies provide important lessons about how current ‘omics’ approaches fail to give an accurate picture of the behaviour of bacterial populations in heterogeneous environments. Upcoming techniques will soon allow us to combine the power of single‐cell and omics approaches.
A targeted approach for routine viral load monitoring in Malawian adults on antiretroviral therapy
Authors: Mungwira Randy G. , Divala Titus H. , Nyirenda Osward M. , Kanjala Maxwell , Muwalo Francis , Mkandawire Felix A. , Choko Augustine , Taylor Terrie E. , Mallewa Jane , van Oosterhout Joep J. , Laufer Miriam K. , Laurens Matthew B.
Published: March 2018

Objectives

WHO recommends HIV viral load (VL) testing 6 months after antiretroviral therapy (ART) initiation and every 12 months thereafter, but cost prohibits routine, universal VL testing in many developing countries. We sought to devise a targeted approach to routine VL monitoring that could reduce cost and identify those at low risk for virologic failure (VF).

Methods

We analysed screening data from a clinical trial enrolling adults on ART in Malawi. We identified risk factors associated with VF and employed the Knill–Jones method to assign summary score identifying persons at lower risk for VF.

Results

Among 957 adults, prevalence of VF was 9.4%. Factors independently associated with VF included age <38 years (OR 3.44, 95% CI 2.01–5.89), ART duration >2.5 years (OR 2.98, 95% CI 1.79–4.96), ART adherence <95% (OR 1.76, 95% CI 1.06–2.94), CD4 count <200 cells/μl (OR 5.94, 95% CI 3.27–10.78), haemoglobin <13 g/dl (OR 2.76, 95% CI 1.70–4.50) and CD8 count >885 cells/μl (OR 2.10, 95% CI 1.28–3.44). Our VF prediction summary score included all factors above except CD8 count and was fairly accurate with validated area under receiver operating characteristic curve of 0.76. Implementation could reduce VL testing by 65%.

Conclusion

A simple score incorporating age, ART duration and adherence, and CD4 count can accurately identify adults at low risk for VF in a sub‐Saharan African setting. In areas with high ART utilisation and limited VL testing capacity, a targeted approach could optimise routine VL monitoring while identifying adults in need of alternate ART regimens.
Three-dimensional analysis of unanticipated behavior of a deep excavation
Authors: Rowe R. Kerry , Mabrouk Ahmed
Published: March 2018

A three-dimensional (3D) effective stress finite element analysis, modified to account for hydrofracturing and gassy soil behavior, is used to examine the potential for the venting of water and gas from a bedrock aquifer and through 13–14 m of low permeability clayey silt between the base of the excavation and the bedrock following excavation to about 24 m in an approximately 40 m thick clayey silt deposit. The clayey deposit contained sand lenses with dissolved gas. The analysis predicts that the exsolution of this dissolved gas, caused by a reduction in total stress due to the excavation, results in liquefaction of the sand in the lenses and consequent lateral deformations of the side slopes. The analysis predicts hydrofracturing through the remaining clayey silt when the excavation reaches its final depth and this explains the venting of water and gas from the underlying aquifer that was observed above a local bedrock high. The presence of gassy sand lenses created weak zones within the clayey deposit that influenced the path of the hydrofracturing. However, the analyses suggest that, for the depth of excavation and bedrock elevation examined, hydrofracturing and subsequent venting would have occurred even if there had been no sand lenses.
Single nucleotide polymorphism (SNP) characterization of drought-responsive genes to estimate genetic variation ofPopulus tremulavar.davidianaand eight otherPopulusspecies
Authors: Kim Yong-Yul , Kwon Soon-Ho , Jo Aruna , Kim Yang-Gil , Lee Jei-Wan , Kang Kyu-Suk
Published: March 2018

To reveal the genetic mechanisms behind drought tolerance, we attempted to identify the drought-responsive genes in Populus tremula var. davidiana (Dode) C.K. Schneid. and eight other species of Populus. Nine drought-responsive genes were assayed by single nucleotide polymorphism (SNP) genotyping using TaqMan probe-based real-time PCR. A total of 346 SNPs were found from the 101 sequences of the nine genes. Among them, 57 primers were selected for SNP genotyping and haplotype determination. For the SNP genotyping, 56 assays were applicable to section Leuce Duby, 53 to section Aigeiros Duby, 50 to Populus maximowiczii Henry, and 52 to Populus simonii Carrière. The expectation maximization algorithm was implemented to determine haplotypes among species and sections. A total of 78 haploid types were estimated from nine drought-responsive gene loci, and the average number of haploid types per locus was 8.67. The analysis of genetic diversity revealed that P. tremula var. davidiana had substantial levels of genetic variation for the nine drought-responsive genes, which was higher than the eight other species. The means of observed number of alleles (NA) and heterozygosity (Ho) were 5.33 and 0.6609, respectively. Analysis of the genetic differentiation of P. tremula var. davidiana showed that 7.52% of genetic variation was among populations and the remaining was within a population.
An improved cellular automata model for train operation simulation with dynamic acceleration
Authors: Li Wen-Jun , Nie Lei
Published: March 2018

Urban rail transit plays an important role in the urban public traffic because of its advantages of fast speed, large transport capacity, high safety, reliability and low pollution. This study proposes an improved cellular automaton (CA) model by considering the dynamic characteristic of the train acceleration to analyze the energy consumption and train running time. Constructing an effective model for calculating energy consumption to aid train operation improvement is the basis for studying and analyzing energy-saving measures for urban rail transit system operation.
A Triply Selective MIMO Channel Simulator Using GPUs
Authors: Carrasco-Alvarez R. , Carreón-Villal R. , Vázquez Castillo J. , Ortegón Aguilar J. , Longoria-Gandara O. , Castillo Atoche A.
Published: March 2018

A methodology for implementing a triply selective multiple‐input multiple‐output (MIMO) simulator based on graphics processing units (GPUs) is presented. The resulting simulator is based on the implementation of multiple double‐selective single‐input single‐output (SISO) channel generators, where the multiple inputs and the multiple received signals have been transformed in order to supply the corresponding space correlation of the channel under consideration. A direct consequence of this approach is the flexibility provided, which allows different propagation statistics to each SISO channel to be specified and thus more complex environments to be replicated. It is shown that under some specific constraints, the statistics of the triply selective MIMO simulator are the same as those reported in the state of art. Simulation results show the computational time improvement achieved, up to 650‐fold for an 8 × 8 MIMO channel simulator when compared with sequential implementations. In addition to the computational improvement, the proposed simulator offers flexibility for testing a variety of scenarios in vehicle‐to‐vehicle (V2V) and vehicle‐to‐infrastructure (V2I) systems.
Design Method of ADAS for Urban Electric Vehicle Based on Virtual Prototyping
Authors: Jezierska-Krupa Katarzyna , Skarka Wojciech
Published: March 2018

Since 2012, the Smart Power Team has been actively participating in the Shell Eco-marathon, which is a worldwide competition. From the very beginning, the team has been working to increase driver’s safety on the road by developing Advanced Driver Assistance Systems. This paper presents unique method for designing ADAS systems in order to minimize the costs of the design phase and system implementation and, at the same time, to maximize the positive effect the system has on driver and vehicle safety. The described method is based on using virtual prototyping tool to simulate the system performance in real-life situations. This approach enabled an iterative design process, which resulted in reduction of errors with almost no prototyping and testing costs.
Research on Clustering Method of Improved Glowworm Algorithm Based on Good-Point Set
Authors: Li Yaping , Ni Zhiwei , Jin Feifei , Li Jingming , Li Fenggang
Published: March 2018

As an important data analysis method in data mining, clustering analysis has been researched extensively and in depth. Aiming at the limitation of K-means clustering algorithm that it is sensitive to the distribution of initial clustering center, Glowworm Swarm Optimization (GSO) Algorithm is introduced to solve clustering problems. Firstly, this paper introduces the basic ideas of GSO algorithm, K-means algorithm, and good-point set and analyzes the feasibility of combining them for clustering optimization. Next, it designs a clustering method of improved GSO algorithm based on good-point set which combines GSO algorithm and classical K-means algorithm together, searches data object space, and provides initial clustering centers for K-means algorithm by means of improved GSO algorithm and thus obtains better clustering results. Major improvement of GSO algorithm is to optimize the initial distribution of glowworm swarm by introducing the theory and method of good-point set. Finally, the new clustering algorithm is applied to UCI data sets of different categories and numbers for clustering test. The advantages of the improved clustering algorithm in terms of sum of squared errors (SSE), clustering accuracy, and robustness are explained through comparison and analysis.
Robust Solution Approach for the Dynamic and Stochastic Vehicle Routing Problem
Authors: Bernardo Marcella , Pannek Jürgen
Published: March 2018

The dynamic and stochastic vehicle routing problem (DSVRP) can be modelled as a stochastic program (SP). In a two-stage SP with recourse model, the first stage minimizes the a priori routing plan cost and the second stage minimizes the cost of corrective actions, performed to deal with changes in the inputs. To deal with the problem, approaches based either on stochastic modelling or on sampling can be applied. Sampling-based methods incorporate stochastic knowledge by generating scenarios set on realizations drawn from distributions. In this paper we proposed a robust solution approach for the capacitated DSVRP based on sampling strategies. We formulated the problem as a two-stage stochastic program model with recourse. In the first stage the a priori routing plan cost is minimized, whereas in the second stage the average of higher moments for the recourse cost calculated via a set of scenarios is minimized. The idea is to include higher moments in the second stage aiming to compute a robust a priori routing plan that minimizes transportation costs while permitting small changes in the demands without changing solution structure. Additionally, the approach allows managers to choose between optimality and robustness, that is, transportation costs and reconfiguration. The computational results on a generic dynamic benchmark dataset show that the robust routing plan can cover unmet demand while incurring little extra costs as compared to the preplanning. We observed that the plan of routes is more robust; that is, not only the expected real cost, but also the increment within the planned cost is lower.
A Web-Based Platform to Collect Data from ESRD Patients Undergoing Dialysis: Methods and Preliminary Results from the Brazilian Dialysis Registry
Authors: Lugon Jocemir R. , Gordan Pedro A. , Thomé Fernando S. , Lopes Antonio A. , Watanabe Yoshimi J. A. , Tzanno Carmen , Sesso Ricardo C.
Published: March 2018

Introduction. The methods and initial results of a web-based platform to collect data from patients receiving maintenance dialysis in Brazil are reported. Methods. Companies providing management software for dialysis centers adapted their system to comply with a formulary of the Brazilian Society of Nephrology. Baseline and follow-up individual patients’ data were transmitted via Internet on monthly bases to the coordinating center from 2011 to 2017. Results. 73 dialysis centers provided information of 24,930 patients: 57% were male, 28% were 64 years old or older, and 13% were overweight/obese. Median dialysis vintage was 28 months. Hemodialysis was the most frequent initial therapy (93%) with venous catheters used in 64% of cases. Conventional hemodialysis remained the main current therapy (90%). Seropositivity for hepatitis C, hepatitis B, and HIV was 2.7%, 1.1%, and 0.5%, respectively. Erythropoietin (53.9%), iron (35.1%), and sevelamer (23.4%) were the most used medications. Hemoglobin < 100 g/L and serum P > 1.74 mmol/L were present in 33.1% and 36.6% of the cases, respectively. The 5-year survival of incident cases (n=7,538) was 57%. Conclusion. The initiative represents an innovative strategy to collect clinical and epidemiologic data of dialysis patients which may be applied to other settings and provides information that can contribute to guiding clinical practice and health care policy.
Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non–Small Cell Lung Cancer Patients
Authors: Yang Zhe , Yang Nong , Ou Qiuxiang , Xiang Yi , Jiang Tao , Wu Xue , Bao Hua , Tong Xiaoling , Wang Xiaonan , Shao Yang W. , Liu Yunpeng , Wang Yan , Zhou Caicun
Published: March 2018

Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non–small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown.

Experimental Design: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified.

Results: EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC50) of osimertinib in vitro, among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS, and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations.

Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo, and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097–107. ©2018 AACR.
A Importância do Posicionamento Internacional do Bosque de Pedras Marcahuasi como Destino Turístico no Peru
Authors: Gonzáles Mantilla Pedro G. , Bahl Miguel
Published: March 2018

O bosque de pedras Marcahuasi, localizado nos Andes centrais do Peru, é um imponente planalto que apresenta vestígios de uma cultura pré-incaica, onde o intemperismo modelou rochas gigantes com figuras antropomórficas e zoomórficas, criando uma paisagem singular. Seu valor cientifico, cênico e cultural, assim como sua acessibilidade desde a capital peruana, Lima, colocam-o como um lugar de grande potencial turístico. Este ensaio é um trabalho reflexivo que justifica a importância do posicionamento internacional deste patrimônio geológico como destino turístico no país andino por meio de uma pesquisa bibliográfica e documental e observação dire
Kinetic Analysis of 2-[11C]Thymidine PET Imaging Studies of Malignant Brain Tumors: Preliminary Patient Results
Authors: Wells Joanne M. , Mankoff David A. , Eary Janet F. , Spence Alexander M. , Muzi Mark , O'Sullivan Finbarr , Vernon Cheryl B. , Link Jeanne M. , Krohn Kenneth A.
Published: March 2018

2-[11C]Thymidine (TdR), a PET tracer for cellular proliferation, may be advantageous for monitoring brain tumor progression and response to therapy. Kinetic analysis of dynamic TdR images was performed to estimate the rate of thymidine transport ( K1t) and thymidine flux ( KTdR) into brain tumors and normal brain. These estimates were compared to MRI and pathologic results. Methods: Twenty patients underwent sequential [11C]CO2 (major TdR metabolite) and TdR PET studies with arterial blood sampling and metabolite analysis. The data were fitted using the five-compartment model described in the companion article. Results: Comparison of model estimates with clinical and pathologic data shows that K1t is higher for MRI contrast enhancing tumors ( p > .001), and KTdR increases with tumor grade ( p > .02). On average, TdR retention was lower after treatment in high-grade tumors. The model was able to distinguish between increased thymidine transport due to blood–brain barrier breakdown and increased tracer retention associated with tumor cell proliferation. Conclusion: Initial analysis of model estimates of thymidine retention and transport show good agreement with the clinical and pathological features of a wide range of brain tumors. Ongoing studies will evaluate its role in measuring response to treatment and predicting outcome.
Pan and Sentinel Lymph Node Visualization Using a Near-Infrared Fluorescent Probe
Authors: Josephson Lee , Mahmood Umar , Wunderbaldinger Patrick , Tang Yi , Weissleder Ralph
Published: March 2018

A number of different types of agents have been employed to aid in the visualization of lymph nodes, particularly the sentinel lymph node, and to decrease the tissue destruction associated with the diagnosis of nodal metastases. The current study was performed to see if a novel macromolecular near-infrared fluorescent (NIRF) probe could be used to visualize lymph nodes after intravenous administration (pan-node visualization) or subcutaneous administration (sentinel node visualization), and serve as method for guiding dissection with interventional radiologic and surgical procedures. Cy5.5-PGC, the near-infrared dye Cy5.5 coupled to a protected graft copolymer (PGC), was injected (iv or sc) into nude mice. Twenty-four hours later white light and NIRF images were obtained on (i) the live animal, (ii) a partially dissected animal, and (iii) tissue specimens. With Cy5.5-PGC administered intravenously, axillary nodes were visualized from outside a living mouse. With partial dissection, iliac and aortic nodes were visible as concentrated foci of high-intensity NIRF signals. With subcutaneous injection in the front extremity, axillary and brachial nodes draining the injection site were easily visualized. NIRF imaging provides a nonradioactive method of visualizing lymph nodes through layers of tissue that can be employed with intravenous or subcutaneous injection.
Selection of Quantum Dot Wavelengths for Biomedical Assays and Imaging
Authors: Lim Yong Taik , Kim Sungjee , Nakayama Akira , Stott Nathan E. , Bawendi Moungi G. , Frangioni John V.
Published: March 2018

Fluorescent semiconductor nanocrystals (quantum dots [QDs]) are hypothesized to be excellent contrast agents for biomedical assays and imaging. A unique property of QDs is that their absorbance increases with increasing separation between excitation and emission wavelengths. Much of the enthusiasm for using QDs in vivo stems from this property, since photon yield should be proportional to the integral of the broadband absorption. In this study, we demonstrate that tissue scatter and absorbance can sometimes offset increasing QD absorption at bluer wavelengths, and counteract this potential advantage. By using a previously validated mathematical model, we explored the effects of tissue absorbance, tissue scatter, wavelength dependence of the scatter, water-to- hemoglobin ratio, and tissue thickness on QD performance. We conclude that when embedded in biological fluids and tissues, QD excitation wavelengths will often be quite constrained, and that excitation and emission wavelengths should be selected carefully based on the particular application. Based on our results, we produced near-infrared QDs optimized for imaging surface vasculature with white light excitation and a silicon CCD camera, and used them to image the coronary vasculature in vivo. Taken together, our data should prove useful in designing fluorescent QD contrast agents optimized for specific biomedical applications.
Synthesis and Characterization of a Gd-DOTA-D-Permeation Peptide for Magnetic Resonance Relaxation Enhancement of Intracellular Targets
Authors: Prantner Andrew M. , Sharma Vijay , Garbow Joel R. , Piwnica-Worms David
Published: March 2018

Many MR contrast agents have been developed and proven effective for extracellular nontargeted applications, but exploitation of intracellular MR contrast agents has been elusive due to the permeability barrier of the plasma membrane. Peptide transduction domains can circumvent this permeability barrier and deliver cargo molecules to the cell interior. Based upon enhanced cellular uptake of permeation peptides with D-amino acid residues, an all-D Tat basic domain peptide was conjugated to DOTA and chelated to gadolinium. Gd-DOTA-D-Tat peptide in serum at room temperature showed a relaxivity of 7.94 ± 0.11 mM−1 sec−1 at 4.7 T. The peptide complex displayed no significant binding to serum proteins, was efficiently internalized by human Jurkat leukemia cells resulting in intracellular T1 relaxation enhancement, and in preliminary T1-weighted MRI experiments, significantly enhanced liver, kidney, and mesenteric signals.
Thermoacoustic Molecular Imaging of Small Animals
Authors: Kruger Robert A. , Kiser William L. , Reinecke Daniel R. , Kruger Gabe A. , Miller Kathy D.
Published: March 2018

We have designed, constructed, and tested a thermoacoustic computed tomography (TCT) scanner for imaging optical absorption in small animals in three dimensions. The device utilizes pulsed laser irradiation (680–1064 nm) and a unique, 128-element transducer array. We quantified the isotropic spatial resolution of this scanner to be 0.35 mm. We describe a dual-wavelength subtraction technique for isolating optical dyes with TCT. Phantom experiments demonstrate that we can detect 5 fmol of a near-infrared dye (indocyanine green, ICG) in a 1-ML volume using dual-wavelength subtraction. Initial TCT imaging in phantoms and in two sacrificed mice suggests that three-dimensional, optical absorption patterns in small animals can be detected with an order of magnitude better spatial resolution and an order of magnitude better low-contrast detectability in small animals when compared to fluorescence imaging or diffusion optical tomography.
Advancing Molecular Therapies through In Vivo Bioluminescent Imaging
Authors: McCaffrey Anton , Kay Mark A. , Contag Christopher H.
Published: March 2018

Effective development of therapeutics that target the molecular basis of disease is dependent on testing new therapeutic moieties and delivery strategies in animal models of human disease. Accelerating the analyses of these models and improving their predictive value through whole animal imaging methods, which provide data in real time and are sensitive to the subtle changes, are crucial for rapid advancement of these approaches. Modalities based on optics are rapid, sensitive, and accessible methods for in vivo analyses with relatively low instrumentation costs. In vivo bioluminescent imaging (BLI) is one of these optically based imaging methods that enable rapid in vivo analyses of a variety of cellular and molecular events with extreme sensitivity. BLI is based on the use of light-emitting enzymes as internal biological light sources that can be detected externally as biological indicators. BLI has been used to test spatio-temporal expression patterns of both target and therapeutic genes in living laboratory animals where the contextual influences of whole biological systems are preserved. BLI has also been used to analyze gene delivery, immune cell therapies, and the in vivo efficacy of inhibitory RNAs. New tools for BLI are being developed that will offer greater flexibility in detection and analyses. BLI can be used to accelerate the evaluation of experimental therapeutic strategies and whole body imaging offers the opportunity of revealing the effects of novel approaches on key steps in disease processes.
Development of a New Reporter Gene System-dsRed/Xanthine Phosphoribosyltransferase-Xanthine for Molecular Imaging of Processes Behind the Intact Blood-Brain Barrier
Authors: Doubrovin Mikhail , Ponomarev Vladimir , Serganova Inna , Soghomonian Suren , Myagawa Tadashi , Beresten Tatiana , Ageyeva Lyudmila , Sadelain Michel , Koutcher Jason , Blasberg Ronald G , Tjuvajev Juri G. Gelovani
Published: March 2018

We report the development of a novel dual-modality fusion reporter gene system consisting of Escherichia coli xanthine phosphoribosyltransferase (XPRT) for nuclear imaging with radiolabeled xanthine and Discosoma red fluorescent protein for optical fluorescent imaging applications. The dsRed/XPRT fusion gene was successfully created and stably transduced into RG2 glioma cells, and both reporters were shown to be functional. The level of dsRed fluorescence directly correlated with XPRT enzymatic activity as measured by ribophosphorylation of [14C]-xanthine was in vitro ( Ki = 0.124 ± 0.008 vs. 0.00031 ± 0.00005 mL/min/g in parental cell line), and [*]-xanthine octanol/water partition coefficient was 0.20 at pH = 7.4 (log P = 0.69), meeting requirements for the blood-brain barrier (BBB) penetrating tracer. In the in vivo experiment, the concentration of [* C]-xanthine in the normal brain varied from 0.20 to 0.16 + 0.05% dose/g under 0.87 + 0.24% dose/g plasma radiotracer concentration. The accumulation in vivo in the transfected flank tumor was to 2.4 ± 0.3% dose/g, compared to 0.78 ± 0.02% dose/g and 0.64 ± 0.05% dose/g in the control flank tumors and intact muscle, respectively. [14C]-Xanthine appeared to be capable of specific accumulation in the transfected infiltrative brain tumor (RG2-dsRed/XPRT), which corresponded to the 585 nm fluorescent signal obtained from the adjacent cryosections. The images of endogenous gene expression with the “sensory system” have to be normalized for the transfection efficiency based on the “beacon system” image data. Such an approach requires two different “reporter genes” and two different “reporter substrates.” Therefore, the novel dsRed/XPRT fusion gene can be used as a multimodality reporter system in the biological applications requiring two independent reporter genes, including the cells located behind the BBB.
Repetitive Imaging of Reporter Gene Expression in the Lung
Authors: Richard Jean-Christophe , Factor Philip , Ferkol Thomas , Ponde Datta E. , Zhou Zhaohui , Schuster Daniel P.
Published: March 2018

Positron emission tomographic imaging is emerging as a powerful technology to monitor reporter transgene expression in the lungs and other organs. However, little information is available about its usefulness for studying gene expression over time. Therefore, we infected 20 rats with a replication-deficient adenovirus containing a fusion gene encoding for a mutant Herpes simplex virus type-1 thymidine kinase and an enhanced green fluorescent protein. Five additional rats were infected with a control virus. Pulmonary gene transfer was performed via intratracheal administration of vector using a surfactant-based method. Imaging was performed 4–6 hr, and 4, 7, and 10 days after gene transfer, using 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine, an imaging substrate for the mutant kinase. Lung tracer uptake assessed with imaging was moderately but significantly increased 4–6 hr after gene transfer, was maximal after 4 days, and was no longer detectable by 10 days. The temporal pattern of transgene expression measured ex vivo with in vitro assays of thymidine kinase activity and green fluorescent protein was similar to imaging. In conclusion, positron emission tomography is a reliable new tool to evaluate the onset and duration of reporter gene expression noninvasively in the lungs of intact animals.
Multi-modality Imaging Identifies Key Times for Annexin V Imaging as an Early Predictor of Therapeutic Outcome
Authors: Mandl Stefanie J. , Mari Carina , Edinger Matthias , Negrin Robert S. , Tait Jonathan F. , Contag Christopher H. , Blankenberg Francis G.
Published: March 2018

Radiolabeled annexin V may provide an early indication of the success or failure of anticancer therapy on a patient-by-patient basis as an in vivo marker of tumor cell killing. An important question that remains is when, after initiation of treatment, should annexin V imaging be performed. To address this issue, we obtained simultaneous in vivo measurements of tumor burden and uptake of radiolabeled annexin V in the syngeneic orthotopic murine BCL1 lymphoma model using in vivo bioluminescence imaging (BLI) and small animal single-photon emission computed tomography (SPECT). BCL1 cells labeled for fluorescence and bioluminescence assays (BCL1− gfp/luc) were injected into mice at a dose that leads to progressive disease within two to three weeks. Tumor response was followed by BLI and SPECT before and after treatment with a single dose of 10 mg/kg doxorubicin. Biodistribution analyses revealed a biphasic increase of annexin V uptake within the tumor-bearing tissues of mice. An early peak occurring before actual tumor cells loss was observed between 1 and 5 hr after treatment, and a second longer sustained rise from 9 to 24 hr after therapy, which heralds the onset of tumor cell loss as confirmed by BLI. Multimodality imaging revealed the temporal patterns of tumor cell loss and annexin V uptake revealing a better understanding of the timing of radiolabeled annexin V uptake for its development as a marker of therapeutic efficacy.
Bioluminescence Detection of Cells Having Stabilized p53 in Response to a Genotoxic Event
Authors: Rehemtulla Alnawaz , Taneja Neelam , Ross Brian D.
Published: March 2018

Inactivation of p53 is one of the most frequent molecular events in neoplastic transformation. Approximately 60% of all human tumors have mutations in both p53 alleles. Wild-type p53 activity is regulated in large part by the proteosome-dependent degradation of p53, resulting in a short p53 half-life in unstressed and untransformed cells. Activation of p53 by a variety of stimuli, including DNA damage induced by genotoxic drugs or radiation, is accomplished by stabilization of wild-type p53. The stabilized and active p53 can result in either cell-cycle arrest or apoptosis. Surprisingly, the majority of tumor-associated, inactivating p53 mutations also result in p53 accumulation. Thus, constitutive elevation of p53 levels in cells is a reliable measure of p53 inactivation, whereas transiently increased p53 levels reflect a recent genotoxic stress. In order to facilitate noninvasive imaging of p53 accumulation, we here describe the construction of a p53-luciferase fusion protein. Induction of DNA damage in cells expressing the fusion protein resulted in a time-dependent accumulation of the fusion that was noninvasively detected using bioluminescence imaging and validated by Western blot analysis. The p53-Luc protein retains p53 function because its expression in HCT116 cells lacking functional p53 resulted in activation of p21 expression as well as induction of apoptosis in response to a DNA damaging event. Employed in a transgenic animal model, the proposed p53-reporter fusion protein will be useful for studying p53 activation in response to exposure to DNA-damaging carcinogenic agents. It could also be used to study p53 stabilization as a result of inactivating p53 mutations. Such studies will further our understanding of p53's role as the “guardian of the genome” and its function in tumorigenesis.
Cellular Imaging at 1.5 T: Detecting Cells in Neuroinflammation using Active Labeling with Superparamagnetic Iron Oxide
Authors: Oweida Ayman J. , Dunn Elizabeth A. , Foster Paula J.
Published: March 2018

The ability to visualize cell infiltration in experimental autoimmune encephalomyelitis (EAE), a well-known animal model for multiple sclerosis in humans, was investigated using a clinical 1.5-T magnetic resonance imaging (MRI) scanner, a custom-built, high-strength gradient coil insert, a 3-D fast imaging employing steady-state acquisition (FIESTA) imaging sequence and a superparamagnetic iron oxide (SPIO) contrast agent. An “active labeling” approach was used with SPIO administered intravenously during inflammation in EAE. Our results show that small, discrete regions of signal void corresponding to iron accumulation in EAE brain can be detected using FIESTA at 1.5 T. This work provides early evidence that cellular abnormalities that are the basis of diseases can be probed using cellular MRI and supports our earlier work which indicates that tracking of iron-labeled cells will be possible using clinical MR scanners.
Micro-PET Imaging of αvβ3-Integrin Expression with 18F-Labeled Dimeric RGD Peptide
Authors: Chen Xiaoyuan , Tohme Michel , Park Ryan , Hou Yingping , Bading James R. , Conti Peter S.
Published: March 2018

The αv integrins, which act as cell adhesion molecules, are closely involved with tumor invasion and angiogenesis. In particular, αvβ3 integrin, which is specifically expressed on proliferating endothelial cells and tumor cells, is a logical target for development of a radiotracer method to assess angiogenesis and anti-angiogenic therapy. In this study, a dimeric cyclic RGD peptide E[c(RGDyK)]2 was labeled with 18F ( t1/2 = 109.7 min) by using a prosthetic 4-[18F]fluorobenzoyl moiety to the amino group of the glutamate. The resulting [18F]FB-E[c(RGDyK)]2, with high specific activity (200–250 GBq/μmol at the end of synthesis), was administered to subcutaneous U87MG glioblastoma xenograft models for micro-PET and autoradiographic imaging as well as direct tissue sampling to assess tumor targeting efficacy and in vivo kinetics of this PET tracer. The dimeric RGD peptide demonstrated significantly higher tumor uptake and prolonged tumor retention in comparison with a monomeric RGD peptide analog [18F]FB-c(RGDyK). The dimeric RGD peptide had predominant renal excretion, whereas the monomeric analog was excreted primarily through the biliary route. Micro-PET imaging 1 hr after injection of the dimeric RGD peptide exhibited tumor to contralateral background ratio of 9.5 ± 0.8. The synergistic effect of polyvalency and improved pharmacokinetics may be responsible for the superior imaging characteristics of [18F]FB-E[c(RGDyK)]2.