bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Bacterial Vaginosis and Its Association with Risk Factors among Nonpregnant Women: A Hospital Based Study
Authors: Ranjit Eliza , Raghubanshi Bijendra Raj , Maskey Smrity , Parajuli Pramila
Published: March 2018

Bacterial vaginosis (BV) is an ecological imbalance of the vaginal microbiota affecting mostly women of reproductive age group. This study was carried out among 160 nonpregnant women registered at the Outpatient Department of Gynaecology/Obstetrics of KIST Medical College Teaching Hospital, Imadol, Lalitpur, Nepal, from November 2014 to May 2015. The aim of the study was to assess the association of the risk factors with BV and analyze the type of bacteria associated with BV. Nugent’s scoring method was used for diagnosis of BV in this study. The overall prevalence of BV was 24.4% among symptomatic patients. Douching was statistically related to BV(P=0.015). Also, BV was significantly associated with consistency(P=0.0001), odor(P=0.02), and amount of abnormal vaginal discharge(P=0.09). Contraceptives users on anatomical sites were found more prone to BV than those who did not use contraceptives on anatomical sites.Pseudomonasspp.,Escherichia coli, Acinetobacterspp., Proteusspp., Klebsiellaspp., Neisseria gonorrhoeae, Enterobacterspp., Citrobacterspp., Staphylococcus aureus,Coagulase-Negative Staphylococci (CoNS),andStreptococcus agalactiaewere associated with BV and out of thoseLactobacillusspp. was the predominant organism. The higher prevalence of BV among symptomatic patients indicates interventions should be applied to reduce the incidence of stillbirth, abortion, and sterility.
Water Pollution and Water Quality Assessment of Major Transboundary Rivers from Banat (Romania)
Authors: Dunca Andreea-Mihaela
Published: March 2018

This study focuses on water resources management and shows the need to enforce the existing international bilateral agreements and to implement the Water Framework Directive of the European Union in order to improve the water quantity and quality received by a downstream country of a common watershed, like Timiş-Bega hydrographical basin, shared by two countries (Romania and Serbia). The spatial trend of water quality index(WQI)and its subindexes are important for determining the locations of major pollutant sources that contribute to water quality depletion in this basin. We compared the values of WQI obtained for 10 sections of the two most important rivers from Banat, which have a great importance for socioeconomic life in southwestern part of Romania and in northeastern part of Serbia. In order to assess the water quality, we calculated theWQIfor a long period of time (2004–2014), taking into account the maximum, minimum, and the mean annual values of physical, chemical, and biological parameters (DO,pH,BOD5,temperature,total P,N-NO2−, andturbidity). This article highlights the importance of using the water quality index which has not been sufficiently explored in Romania and for transboundary rivers and which is very useful in improving rivers water quality.
The Role of Flavonoids in Inhibiting Th17 Responses in Inflammatory Arthritis
Authors: Kelepouri Dimitra , Mavropoulos Athanasios , Bogdanos Dimitrios P. , Sakkas Lazaros I.
Published: March 2018

Flavonoids have been considered powerful anti-inflammatory agents, and their exact immunomodulatory action as therapeutic agents in autoimmune diseases has started to emerge. Their role in the manipulation of immunoregulation is less understood. Several studies attempted to investigate the role of various flavonoids mainly in experimental models of autoimmune diseases, especially in the context of their potential effect on the increase of regulatory T cells (Tregs) and their ability to stimulate an overexpression of anti-inflammatory cytokines, in particular that of IL-10. The emergence of IL-17, a cytokine largely produced by Th17 cells, as a powerful proinflammatory stimulus which attenuates the induction of Tregs has prompted a series of studies investigating the role of flavonoids on Th17 cells in experimental models as well as human autoimmune diseases. This review thoroughly discusses accumulated data on the role of flavonoids on Th17 in rheumatoid arthritis and experimental autoimmune arthritis.
Simulation Analysis of a Multiple‐Vehicle, High‐Speed Train Collision Using a Simplified Model
Authors: Xie Suchao , Yang Weilin , Xu Ping
Published: March 2018

To solve the problems associated with multiple‐vehicle simulations of railway vehicles including large scale modelling, long computing time, low analysis efficiency, need for high performance computing, and large storage space, the middle part of the train where no plastic deformation occurs in the vehicle body was simplified using mass and beam elements. Comparative analysis of the collisions between a single railway vehicle (including head and intermediate vehicles before, and after, simplification) and a rigid wall showed that variations in impact kinetic energy, internal energy, and impact force (after simplification) are consistent with those of the unsimplified model. Meanwhile, the finite element model of a whole high‐speed train was assembled based on the simplified single‐vehicle model. The numbers of nodes and elements in the simplified finite element model of the whole train were 63.4% and 61.6%, respectively, compared to those of the unsimplified model. The simplified whole train model using the above method was more accurate than the multibody model. In comparison to the full‐size finite element model, it is more specific, had more rapid computational speed, and saved a large amount of computational power and storage space. Finally, the velocity and acceleration data for every car were discussed through the analysis of the collision between two simplified trains at various speeds.
The Application of Group Theory in Communication Operation Pipeline System
Authors: Zhang Jianqing , Xiong Feng , Kang Jinsheng
Published: March 2018

To resolve the “pipeline” crisis for telecom operators, this study pioneers the application of Group theory in communication operation pipeline system. The pipeline entity group model was built for information transmission in the pipeline system to analyze operation of pipeline entities. The equations of pipeline system network traffic were established according to the flux conservation principle and matrix of pipeline network. Based on pipeline entity group model, dimensionality of the matrix was reduced. The solution scheme of the flow state transition relationship of the pipeline system is obtained, which will be very useful for the telecom operators to construct high-level mobile e-commerce application model and architecture.
Biomarkers in Cardiorenal Syndromes
Authors: Fu Shihui , Zhao Shaopan , Ye Ping , Luo Leiming
Published: March 2018

There is a consensus that cardiorenal syndromes (CRS) are defined as the disorders of heart and kidney where acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in another. Patients with CRS have increased hospitalization and mortality rates, and thus their identification is of great implication. Biomarkers are not only predictive in heart failure or renal diseases, but also useful in identifying cardiac dysfunction in renal diseases and renal injury in heart failure. Thus, they may be applied in order to identify patients with CRS and even assess prognosis and guide therapy in these patients. However, studies on biomarkers have just begun in CRS. Future studies are essential to observe current biomarkers and find novel biomarkers in CRS so as to improve diagnosis, therapy, and prognosis of CRS.
Submerged Groundwater Discharges as Source of Fecal Material in Protected Karstic Coastal Areas
Authors: Kantun Manzano Cristian , Arcega-Cabrera Flor , Derrien Morgane , Noreña-Barroso Elsa , Herrera-Silveira Jorge
Published: March 2018

Coastal zones are vital for their ecosystem services and socioeconomic value. Accordingly, several zones have been protected to limit anthropogenic development and to avoid environmental degradation. Nevertheless, some of these protected areas keep deteriorating probably related with anthropogenic contributions not considered in legislation. Specifically, submerged groundwater discharges (springs) could be releasing anthropogenic materials carried from remote inland areas to the coast. Here we evaluate the role and temporal variation of submerged groundwater discharges as sources of anthropogenic materials using the 5β-stanol C27markers in the natural protected area of Dzilam de Bravo, Yucatán, Mexico. Results demonstrate that (1) submerged groundwater discharge flux velocity and direction vary between hydrological season, exhibiting higher flow rates in Nortes season contrary to dry season and (2) the presence of coprostanol and epicoprostanol (anthropogenic fecal matter markers) in sediments surrounding the submerged groundwater discharges provides proof of allochthonous anthropogenic fecal material in a protected area, probably from remote inland sites. Thus, it is vitally important that inland anthropogenic materials transported in groundwater and released in the coastal environment by submerged groundwater discharges be considered in protection plans, like protection perimeters, for coastal zones.
Effect of Milking Maneuver in Preterm Infants: A Randomized Controlled Trial
Authors: Lago Leal Víctor , Pamplona Bueno Loida , Cabanillas Vilaplana Lucía , Nicolás Montero Estefanía , Martín Blanco Mónica , Fernández Romero Cristina , El Bakkali Sara , Pradillo Aramendi Tamara , Sobrino Lorenzano Lara , Castellano Esparza Paula , Ballesteros Benito Esther , Rayo Navarro Nieves , del Barrio Fernández Pablo , Ocaña Martínez Vanesa , Martínez Cortés Luis
Published: March 2018

Objective: To assess the short and medium-term effects of milking maneuver (MM) compared with early cord clamping for infants born before 37 weeks of pregnancy. Material and Methods: 138 infants between 24+0 and 36+6 weeks of gestation were allocated to MM or early cord clamping. Primary outcomes were the requirement of red blood cell transfusions or phototherapy. Results: Initial hemoglobin was signiﬁcantly higher in the MM group by 1.675 g/dL (p < 0.05) and initial hematocrit by 5.36% (p < 0.05), but no differences in the need of transfusion during the first 30 days after delivery were found (RR 0.8; 95% CI 0.22–2.85). Peak serum bilirubin was similar in both groups (11,097 ± 3.21 vs. 11,247 ± 3.56 mg/dL, p = 0.837). Phototherapy requirements were higher in the MM group (RR 1.62; 95% CI 1.1–2.38). No differences regarding the need of oral iron supplementation, platelet transfusion, respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia, meconium aspiration syndrome, use of surfactant, days of oxygen supplementation, need of vasopressors, length of stay in the neonatal intensive care unit, or postpartum hemorrhage were found. Conclusion: MM does not reduce the need for red blood cell transfusions and increases phototherapy requirements in preterm infants.
A Imagem do Rio de Janeiro Projetada por Turistas em uma Mídia Social: experiência, qualidade e valor
Authors: Mayer Verônica Feder , Silva Andressa Martins da , Bárcia Liana Cid
Published: March 2018

Ocompartilhamento de informações em mídias sociais possibilita que as pessoas tenham acesso de maneira rápida e gratuita a um conteúdo gerado por turistas que já vivenciaram determinada experiência, o que pode influenciar a escolha de outros, e impõe uma nova dinâmica às relações de consumo, afetando a imagem e a competitividade dos destinos. Este estudo investigou a imagem projetada por turistas que visitaram o Rio de Janeiro nos anos de 2015 e 2016 em relação aos seguintes aspectos: experiência nos principais atrativos da cidade, qualidade percebida dos serviços e julgamento de preço e valor. Para tal, foi realizada a análise de conteúdo de 612 comentários postados no site TripAdvisor, a mídia social dedicada ao turismo de maior audiência no mundo. Os resultados mostram que a grande maioria dos turistas relatou experiências favoráveis, avaliou positivamente a qualidade dos serviços e o valor, apresentando altos níveis de satisfação nos principais atrativos da cidade. As dimensões da experiência mais presentes nos comentários foram a estética e o entretenimento, reforçando a importância das belezas naturais e arquitetônicas na formação da imagem do Rio de Janeiro. Quanto aos comentários com teor negativo, a análise do conteúdo revelou pontos que devem ser monitorados e aprimorados por gestores públicos e privados ligados ao turismo.
Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in Mice
Authors: Li Jing , Wang Shuai , Bai Jie , Yang Xiao-Lei , Zhang Yun-Long , Che Yi-Lin , Li Hui-Hua , Yang Yan-Zong
Published: March 2018

Angiotensin II (Ang II) and inflammation are associated with pathogenesis of atrial fibrillation (AF), but the underlying molecular mechanisms of these events remain unknown. The immunoproteasome has emerged as a critical regulator of inflammatory responses. Here, we investigated its role in Ang II–induced AF in immunosubunit PSMB10 (also known as β2i or LMP10) knockout (KO) mice. AF was induced by Ang II infusion (2000 ng/min per kg). PSMB10 expression and trypsin-like activity were increased in atrial tissues and serum from Ang II–treated mice or serum from patients with AF. Moreover, Ang II–infused wild-type (WT) mice had a higher AF and increased atrial fibrosis, reactive oxygen species production, and inflammation compared with saline-treated WT animals. These effects were attenuated in PSMB10 KO mice but were aggravated in recombinant adeno-associated virus serotype 9-PSMB10–treated mice. Administration of IKKβ-specific inhibitor IMD 0354 reduced Ang II–induced AF, reactive oxygen species production, inflammation, and NF-kB (nuclear factor-kB) activation. Mechanistically, Ang II infusion upregulated PSMB10 expression to promote PTEN (phosphatase and tensin homolog deleted on chromosome ten) degradation and AKT1 activation, which not only activated TGF-β–Smad2/3 signaling leading to cardiac fibrosis but also induced IKKβ activation and ubiquitin-mediated degradation of IkBα ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1β, IL-6, NOX [NADPH oxidase] 2, NOX4, and CX43 [connexin 43]). Overall, our study identifies immunosubunit PSMB10 as a novel regulator that contributes to Ang II–induced AF and suggests that inhibition of PSMB10 may represent a potential therapeutic target for treating hypertensive AF.
Imaging Expression of Cytosine Deaminase-Herpes Virus Thymidine Kinase Fusion Gene (CD/TK) Expression with [124I]FIAU and PET
Authors: Hackman Trevor , Doubrovin Michail , Balatoni Julius , Beresten Tatiana , Ponomarev Vladimir , Beattie Bradly , Finn Ronald , Bornmann William , Blasberg Ronald , Tjuvajev Juri Gelovani
Published: March 2018

Double prodrug activation gene therapy using the Escherichia coli cytosine deaminase (CD)herpes simplex virus type 1 thymidine kinase ( HSV1-tk) fusion gene ( CD/TK) with 5-fluorocytosine (5FC), ganciclovir (GCV), and radiotherapy is currently under evaluation for treatment of different tumors. We assessed the efficacy of noninvasive imaging with [124I]FIAU (2′-fluoro-2′-deoxy-1-β-d-arabinofuranosyl-5-iodo-uracil) and positron emission tomography (PET) for monitoring expression of the CD/TK fusion gene. Walker-256 tumor cells were transduced with a retroviral vector bearing the CD/TK gene (W256CD/TK cells). The activity of HSV1-TK and CD subunits of the CD/TK gene product was assessed in different single cell-derived clones of W256CD/TK cells using the FIAU radiotracer accumulation assay in cells and a CD enzyme assay in cell homogenates, respectively. A linear relationship was observed between the levels of CD and HSV1-tk subunit expression in corresponding clones in vitro over a wide range of CD/TK expression levels. Several clones of W256CD/TK cells with significantly different levels of CD/TK expression were selected and used to produce multiple subcutaneous tumors in rats. PET imaging of HSV1-TK subunit activity with [124I]FIAU was performed on these animals and demonstrated that different levels of CD/TK expression in subcutaneous W256CD/TK tumors can be imaged quantitatively. CD expression in subcutaneous tumor sample homogenates was measured using a CD enzyme assay. A comparison of CD and HSV1-TK subunit enzymatic activity of the CD/TK fusion protein in vivo showed a significant correlation. Knowing this relationship, the parametric images of CD subunit activity were generated. Imaging with [124I]FIAU and PET could provide pre- and posttreatment assessments of CD/TK-based double prodrug activation in clinical gene therapy trials.
In Vivo Tomographic Imaging of Near-Infrared Fluorescent Probes
Authors: Ntziachristos Vasilis , Bremer Christoph , Graves Edward E. , Ripoll Jorge , Weissleder Ralph
Published: March 2018

Fluorescence imaging is increasingly used to probe protein function and gene expression in live animals. This technology could enhance the study of pathogenesis, drug development, and therapeutic intervention. In this article, we focus on three-dimensional fluorescence observations using fluorescence-mediated molecular tomography (FMT), a novel imaging technique that can resolve molecular function in deep tissues by reconstructing fluorescent probe distributions in vivo. We have compared FMT findings with conventional fluorescence reflectance imaging (FRI) to study protease function in nude mice with subsurface implanted tumors. This validation of FMT with FRI demonstrated the spatial congruence of fluorochrome activation as determined by the two techniques.
Annexin V–CLIO: A Nanoparticle for Detecting Apoptosis by MRI
Authors: Schellenberger Eyk A. , Bogdanov Alexei , Högemann Dagmar , Tait Jonathan , Weissleder Ralph , Josephson Lee
Published: March 2018

Annexin V, which recognizes the phosphatidylserine of apoptotic cells, was conjugated to crosslinked iron oxide (CLIO) nanoparticles, a functionalized superparamagnetic preparation developed for target-specific magnetic resonance imaging (MRI). The resulting nanoparticle had an average of 2.7 annexin V proteins linked per CLIO nanoparticle through disulfide bonds. Using camptothecin to induce apoptosis, a mixture of Jurkat T cells (69% healthy and 31% apoptotic) was incubated with annexin V–CLIO and was applied to magnetic columns. The result was an almost complete removal of the apoptotic cells (>99%). In a phantom MRI experiment, untreated control cells (12% apoptotic cells, 88% healthy cells) and camptothecin-treated cells (65% apoptotic cells, 35% healthy cells) were incubated with either annexin V–CLIO (1.0, 0.5, and 0.1 μg Fe/mL) or with unlabeled CLIO. A significant signal decrease of camptothecin-treated cells relative to untreated cells was observed even at the lowest concentration tested. Unmodified CLIO failed to cause a significant signal change of apoptotic cells. Hence, annexin V–CLIO allowed the identification of cell suspensions containing apoptotic cells by MRI even at very low concentrations of magnetic substrate. Conjugation of annexin V to CLIO affords a strategy for the development of a MRI imaging probe for detecting apoptosis.
Microarray Gene Expression Analysis of Murine Tumor Heterogeneity Defined by Dynamic Contrast-Enhanced MRI
Authors: Costouros Nick G. , Lorang Dominique , Zhang Yantian , Miller Marshall S. , Diehn Felix E. , Hewitt Stephen M. , Knopp Michael V. , Li King C. P. , Choyke Peter L. , Alexander H. Richard , Libutti Steven K.
Published: March 2018

Current methods of studying angiogenesis are limited in their ability to serially evaluate in vivo function throughout a target tissue. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and pharmacokinetic modeling provide a useful method for evaluating tissue vasculature based on contrast accumulation and washout. While it is often assumed that areas of high contrast enhancement and washout comprise areas of increased angiogenesis and tumor activity, the actual molecular pathways that are active in such areas are poorly understood. Using DCE-MRI in a murine subcutaneous tumor model, we were able to perform pharmacokinetic functional analysis of a tumor, coregistration of MRI images with histological cross-sections, immunohistochemistry, laser capture microdissection, and genetic profiling of tumor heterogeneity based on pharmacokinetic parameters. Using imaging as a template for biologic investigation, we have not found evidence of increased expression of proangiogenic modulators at the transcriptional level in either distinct pharmacokinetic region. Furthermore, these regions show no difference on histology and CD31 immunohistochemistry. However, the expression of ribosomal proteins was greatly increased in high enhancement and washout regions, implying increased protein translation and consequent increased cellular activity. Together, these findings point to the potential importance of posttranscriptional regulation in angiogenesis and the need for the development of angiogenesis-specific contrast agents to evaluate in vivo angiogenesis at a molecular level.
A Novel Method of Imaging Lysosomes in Living Human Mammary Epithelial Cells
Authors: Glunde Kristine , Guggino Sandra E. , Ichikawa Yoshitaka , Bhujwalla Zaver M.
Published: March 2018

Cancer cells invade by secreting degradative enzymes which, under normal conditions, are sequestered in lysosomal vesicles. The ability to noninvasively label lysosomes and track lysosomal trafficking would be extremely useful to understand the mechanisms by which degradative enzymes are secreted in the presence of pathophysiological environments, such as hypoxia and acidic extracellular pH, which are frequently encountered in solid tumors. In this study, a novel method of introducing a fluorescent label into lysosomes of human mammary epithelial cells (HMECs) was evaluated. Highly glycosylated lysosomal membrane proteins were labeled with a newly synthesized compound, 5-dimethylamino-naphthalene-1-sulfonic acid 5-amino-3,4,6-trihydroxy-tetrahydro-pyran-2-ylmethyl ester (6- O-dansyl-GlcNH2). The ability to optically image lysosomes using this new probe was validated by determining the colocalization of the fluorescence from the dansyl group with immunofluorescent staining of two well-established lysosomal marker proteins, LAMP-1 and LAMP-2. The location of the dansyl group in lysosomes was also verified by using an anti-dansyl antibody in Western blots of lysosomes isolated using isopycnic density gradient centrifugation. This novel method of labeling lysosomes biosynthetically was used to image lysosomes in living HMECs perfused in a microscopy-compatible cell perfusion system.
Image-guided Control of Transgene Expression Based on Local Hyperthermia
Authors: Guilhon E. , Quesson B. , Moraud-Gaudry F. , de Verneuil H. , Canioni P. , Salomir R. , Voisin P. , Moonen C. T. W.
Published: March 2018

Spatial and temporal control of transgene expression is one of the major prerequisites of efficient gene therapy. Recently, a noninvasive, physical approach has been presented based on local heat in combination with a heat-sensitive promoter. This strategy requires tight temperature control in vivo. Here, we use MRI-guided focused ultrasound (MRI-FUS) with real-time feedback control on a whole-body clinical MRI system for a completely automatic execution of a predefined temperature-time trajectory in the focal point. Feasibility studies on expression control were carried out on subcutaneously implanted rat tumors. A stable modified C6 glioma cell line was used carrying a fused gene coding for thymidine kinase (TK) and green fluorescent protein (GFP) under control of the human heat-shock protein 70 (HSP70) promoter. In vitro studies showed strong induction of the TK-GFP gene expression upon heat shock under various conditions and localization of the protein product in the nucleus. In vivo tumors were subjected to a 3-min temperature elevation using MRI-FUS with a constant temperature, and were analysed 24 hr after the heat shock with respect to GFP fluorescence. Preliminary results showed strong local induction in regions heated above 40°C, and a good correspondence between temperature maps at the end of the heating period and elevated expression of TK-GFP.
Fluorescence Imaging Analysis of Upstream Regulators and Downstream Targets of STAT3 in Melanoma Precursor Lesions Obtained from Patients Before and After Systemic Low-Dose Interferon-α Treatment
Authors: Smith Amanda Pfaff , Kirkwood John M. , Edington Howard D. , Jukic Drazen M. , Farkas Daniel L. , Becker Dorothea
Published: March 2018

Atypical nevi are the precursors and risk markers of melanoma. Apart from persistently monitoring these nevocytic lesions and resecting them at the earliest signs of clinical changes, there is as yet no systemic clinical treatment available to interfere with their progression to melanoma. To explore clinical treatments that might interfere with and possibly prevent atypical nevus progression, a previous study documented that 3 months systemic low-dose interferon-α (IFN-α) treatment of patients with a clinical history of melanoma and numerous atypical nevi, led to inactivation of the STAT1 and STAT3 transcription factors in atypical nevi. Based upon this finding, we initiated a second study to determine whether systemic low-dose IFN-α treatment also impairs the expression of upstream regulators and downstream targets of STAT1 and STAT3 in atypical nevi. Using cyanine dye-conjugated antibodies, fluorescence imaging analysis revealed expression of JAK2, JNK1, AKT1, NF-κB, and IFN-αβ receptor in benign and atypical nevi, and early- and advanced-stage melanomas. To determine possible changes in the level of expression of these molecules in atypical nevi, excised before and after 3 months of systemic low-dose IFN-α treatment, newly designed optical imaging software was used to quantitate the captured fluorescent hybridization signals on a cell-by-cell basis and across an entire nevus section. The results of this analysis did not provide evidence that systemic low-dose IFN-α treatment alters the level of expression of upstream regulators or downstream targets of STAT1 and STAT3.
Dendrimer-based Macromolecular MRI Contrast Agents: Characteristics and Application
Authors: Kobayashi Hisataka , Brechbiel Martin W.
Published: March 2018

Numerous macromolecular MRI contrast agents prepared employing relatively simple chemistry may be readily available that can provide sufficient enhancement for multiple applications. These agents operate using a ~100-fold lower concentration of gadolinium ions in comparison to the necessary concentration of iodine employed in CT imaging. Herein, we describe some of the general potential directions of macromolecular MRI contrast agents using our recently reported families of dendrimer-based agents as examples. Changes in molecular size altered the route of excretion. Smaller-sized contrast agents less than 60 kDa molecular weight were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Hydrophilic and larger-sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants formed with polypropylenimine diaminobutane dendrimer cores created liver contrast agents. Larger hydrophilic agents are useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents, which also might be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.
Synthesis and Properties of Sulfhydryl-Reactive Near-Infrared Cyanine Fluorochromes for Fluorescence Imaging
Authors: Lin Yuhui , Weissleder Ralph , Tung Ching-Hsuan
Published: March 2018

Near-infrared fluorochromes (NIRF) are useful compounds for diverse biotechnology applications and for in vivo biomedical imaging. Such NIRF must have high quantum yield, be biocompatible, and be conjugatable to a wide variety of proteins, peptides, and other affinity ligands. Here, we describe the synthesis of four new nonsymmetrical sulfhydryl-reactive cyanine NIRF with excellent optical and chemical properties. Each fluorochrome was designed to contain an iodoacetamido group that reacts specifically with sulfhydryl-containing molecules. The synthesized fluorochromes were used to label model peptides and sulfhydryl-containing biomolecules.
Mouse Reporter Strain for Noninvasive Bioluminescent Imaging of Cells that have Undergone Cre-Mediated Recombination
Authors: Safran Michal , Kim William Y. , Kung Andrew L. , Horner James W. , DePinho Ron A. , Kaelin William G.
Published: March 2018

Conditional alleles containing LoxP recombination sites, in conjunction with Cre recombinase delivered by a variety of means, allows for spatial and temporal control of gene expression in mouse models. Here we describe a mouse strain in which a luciferase (Luc) cDNA, preceded by a LoxP-stop-LoxP (L-S-L) cassette, was introduced into the ubiquitously expressed ROSA26 locus. Mouse embryo fibroblasts derived from this strain expressed luciferase after Cre-mediated recombination in vitro. ROSA26 L-S-L-Luc/+ mice expressed luciferase in a diffuse or liver-restricted pattern, as determined by noninvasive, bioluminescent imaging, when crossed to transgenic mice in which Cre was under the control of a zygotically expressed (EIIA-Cre), or a liver-restricted (albumin-Cre), promoter, respectively. Organ-specific luciferase expression was also seen after intraparenchymal administration of an adenovirus encoding Cre. The ROSA26 L-S-L-Luc/+ strain should be useful for characterizing Cre mouse strains and for following the fate of cells that have undergone Cre-mediated recombination in vivo.
Miniaturized Multichannel Near Infrared Endoscope for Mouse Imaging
Authors: Funovics Martin A. , Alencar Herlen , Su Henry S. , Khazaie Khashayarsha , Weissleder Ralph , Mahmood Umar
Published: March 2018

We describe the design and construction of a miniaturized multichannel near infrared (NIR) endoscopic imaging system developed for high-resolution imaging of mice. The device allows for simultaneous real-time video images in white light and two independent NIR channels. Testing demonstrated independent acquisition of nanomolar concentrations of fluorochromes Cy5.5 and Cy7. Cross-talk between the NIR channels, partially a result of broad tails in the spectra of commonly used organic fluorochromes, was assessed, modeled for the linear range of the concentration/signal intensity function, and compensated. The calculated compensation was 5.5% and 22% of the total signal intensity in the two channels NIR700 and NIR780, respectively, at equal concentrations of the two fluorochromes. Using a mouse model of colonic adenomatosis, we show that both perfusion and protease activity can be detected simultaneously, independently, and repeatedly in live mice. The developed device should be useful for in vivo imaging of diverse molecular targets.
Direct Comparison of Radiolabeled Probes FMAU, FHBG, and FHPG as PET Imaging Agents for HSV1-tk Expression in a Human Breast Cancer Model
Authors: Alauddin Mian M. , Shahinian Atranik , Gordon Erlinda M. , Conti Peter S.
Published: March 2018

2′-Deoxy-2′-fluoro-5-methyl-1-β-d-arabinofuranosyluracil (FMAU), 9-(4-fluoro-3-hydroxy-methyl-butyl)guanine (FHBG) and 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]-guanine (FHPG) have been evaluated in a human breast cancer model as potential radiotracers for PET imaging of HSV1-tk gene expression. In vitro accumulation of [14C]FMAU, [18F]FHBG, and [18F]FHPG in HSV1-tk-expressing cells was 14- to 16-fold ( p < .001), 9- to 13-fold ( p < .001), and 2- to 3-fold ( p < .05) higher than tk-negative control cells, respectively, between 30 and 240 min. Accumulation of FMAU and FHBG in vector-transduced cells was 10- to 14-fold and 6- to 10-fold higher than wild-type cells, respectively. At 2 hr, uptake of [14C]FMAU in tk-positive cells was 6.3-fold and 60-fold higher than [18F]FHBG and [18F]FHPG, respectively. In vivo, tumor uptake of [14C]FMAU in HSV1-tk-expressing cells was 3.7-fold and 5.5-fold ( p < .001) higher than tk-negative control cells at 1 and 2 hr, respectively. Tumor uptake of [18F]FHBG was 4.2-fold and 12.6-fold higher ( p < .001) than tk-negative cells at the same time points. Incorporation of [14C]FMAU in tk-positive tumor was 18-fold and 24-fold higher ( p < .001) than [18F]FHBG at 1 and 2 hr, respectively. Micro-PET images support the biodistribution results and indicate that both [18F]FMAU and [18F]FHBG are useful for imaging HSV1-tk expression in breast cancer. Although FMAU demonstrates higher total incorporation (%dose/g) in tumor tissue compared with the other tracers, FHBG is superior in terms of specific accumulation in transfected cells at later time points.
Validating Bioluminescence Imaging as a High-Throughput, Quantitative Modality for Assessing Tumor Burden
Authors: Paroo Zain , Bollinger Robert A. , Braasch Dwaine A. , Richer Edmond , Corey David R. , Antich Peter P. , Mason Ralph P.
Published: March 2018

Bioluminescence imaging (BLI) is a highly sensitive tool for visualizing tumors, neoplastic development, metastatic spread, and response to therapy. Although BLI has engendered much excitement due to its apparent simplicity and ease of implementation, few rigorous studies have been presented to validate the measurements. Here, we characterize the nature of bioluminescence output from mice bearing subcutaneous luciferase-expressing tumors over a 4-week period. Following intraperitoneal or direct intratumoral administration of luciferin substrate, there was a highly dynamic kinetic profile of light emission. Although bioluminescence was subject to variability, strong correlations ( r > .8, p < .001) between caliper measured tumor volumes and peak light signal, area under light signal curve and light emission at specific time points were determined. Moreover, the profile of tumor growth, as monitored with bioluminescence, closely resembled that for caliper measurements. The study shows that despite the dynamic and variable nature of bioluminescence, where appropriate experimental precautions are taken, single time point BLI may be useful for noninvasive, high-throughput, quantitative assessment of tumor burden.
In Vivo Respiratory-Gated Micro-CT Imaging in Small-Animal Oncology Models
Authors: Cavanaugh Dawn , Johnson Evan , Price Roger E. , Kurie Jonathan , Travis Elizabeth L. , Cody Dianna D.
Published: March 2018

Micro-computed tomography (micro-CT) is becoming an accepted research tool for the noninvasive examination of laboratory animals such as mice and rats, but to date, in vivo scanning has largely been limited to the evaluation of skeletal tissues. We use a commercially available micro-CT device to perform respiratory gated in vivo acquisitions suitable for thoracic imaging. The instrument is described, along with the scan protocol and animal preparation techniques. Preliminary results confirm that lung tumors as small as 1 mm in diameter are visible in vivo with these methods. Radiation dose was evaluated using several approaches, and was found to be approximately 0.15 Gy for this respiratory-gated micro-CT imaging protocol. The combination of high-resolution CT imaging and respiratory-gated acquisitions appears well-suited to serial in vivo scanning.
Comparison of Transfection Agents in Forming Complexes with Ferumoxides, Cell Labeling Efficiency, and Cellular Viability
Authors: Arbab Ali Syed , Yocum Gene Thomus , Wilson Lindsey Bashaw , Parwana Ashari , Jordan Elaine Kay , Kalish Heather , Frank Joseph Alan
Published: March 2018

By complexing ferumoxides or superparamagnetic iron oxide (SPIO) to transfection agents (TAs), it is possible to magnetically label mammalian cells. There has been no systematic study comparing TAs complexed to SPIO as far as cell labeling efficiency and viability. This study investigates the toxicity and labeling efficiency at various doses of FEs complexed to different TAs in mammalian cells. Different classes of TAs were used, such as polycationic amines, dendrimers, and lipid-based agents. Cellular toxicity was measured using doses of TAs from 1 to 50 μg/mL in incubation media. Iron incorporation efficiency was measured by combining various amounts of FEs and different doses of TAs. Lipofectamine2000 showed toxicity at lowest dose (1 μg/mL), whereas FuGENE6 and low molecular weight poly-L-lysine (PLI.) showed the least toxicity. SPIO labeling efficiency was similar with high-molecular-weight PIX (388.1 kDa) and superfect, whereas FuGENE6 and low-molecular-weight PLL were inefficient in labeling cells. Concentrations of 25 to 50 μg/mL of FEs complexed to TAs in media resulted in sufficient endocytosis of the SPIO into endosomes to detect cells on cellular magnetic resonance imaging.
Loss of P53 Function in Colon Cancer Cells Results in Increased Phosphocholine and Total Choline
Authors: Mori Noriko , Delsite Robert , Natarajan Kshama , Kulawiec Mariola , Bhujwalla Zaver M. , Singh Keshav K.
Published: March 2018

Mutations in the p53 gene are the most frequently observed genetic lesions in human cancers. Human cancers that contain a p53 mutation are more aggressive, more apt to metastasize, and more often fatal. p53 controls numerous downstream targets that can influence various outcomes such as apoptosis, growth arrest, and DNA repair. Based on previous observations using 1H magnetic resonance spectroscopy (MRS), we have identified choline phospholipid metabolite intensities typical of increased malignancy. Here we have used 1H MRS to characterize the choline phospholipid metabolite levels of p53+/+ and p53−/– cells, and demonstrated that loss of p53 function results in increased phosphocholine and total choline. These data suggest that the increased malignancy of cancer cells resulting from loss of p53 may be mediated, in part, through the choline phospholipid pathway.
Nanotechnology and Tumor Imaging: Seizing an Opportunity
Authors: Sullivan Daniel C. , Ferrari Mauro
Published: March 2018

Nanoparticles, labeled with a signaling moiety for in vivo imaging, and one or more ligands for molecularly targeted specificity, hold considerable promise in oncology. Nanoparticles can serve as modular platforms, from which a wide variety of highly sensitive and specific imaging agents can be created. For example, many hundreds or thousands of atoms that provide imaging signals, such as radioisotopes, lanthanides, or fluorophores, can be attached to each nanoparticle, to form imaging agents that would provide higher sensitivity that can be obtained from agents based on small molecules. Similarly, many copies of targeted ligands can be attached to nanoparticles to markedly inrease specific binding. Drugs or therapeutic isotopes can be added to create multifunctional nanoparticles. Appropriately labeled and targeted nanoparticles could lead to a paradigm change in which cancer detection, diagnosis, and therapy are combined in a single molecular complex.
Development of a Single Detector Ring Micro Crystal Element Scanner: QuickPET II
Authors: Miyaoka Robert S. , Janes Marie L. , Lee Kisung , Park Byungki , Kinahan Paul E. , Lewellen Tom K.
Published: March 2018

This article describes a single ring version of the micro crystal element scanner (MiCES) and investigation of its spatial resolution imaging characteristics for mouse positron emission tomography (PET) imaging. This single ring version of the MiCES system, referred to as QuickPET II, consists of 18 MiCE detector modules mounted as a single ring in a vertical gantry. The system has a 5.76-cm transverse field of view and a 1.98-cm axial field of view. In addition to the scanner and data acquisition system, we have developed an iterative reconstruction that includes a model of the system's detector response function. Evaluation images of line sources and mice have been acquired. Using filtered backprojection, the resolution for a reconstructed line source has been measured at 1.2 mm full width at half maximum. F-18-2-fluoro-2-deoxyglucose mouse PET images are provided. The result shows that QuickPET II has the imaging characteristics to support high-resolution, static mouse PET studies using 18-F labeled compounds.
An Interventional Magnetic Resonance Imaging Technique for the Molecular Characterization of Intraprostatic Dynamic Contrast Enhancement
Authors: Ménard Cynthia , Susil Robert C. , Choyke Peter , Coleman Jonathan , Grubb Robert , Gharib Ahmed , Krieger Axel , Guion Peter , Thomasson David , Ullman Karen , Gupta Sandeep , Espina Virginia , Liotta Lance , Petricoin Emanuel , Fitchtinger Gabor , Whitcomb Louis L. , Atalar Ergin , Coleman C. Norman , Camphausen Kevin
Published: March 2018

The biological characterization of an individual patient's tumor by noninvasive imaging will have an important role in cancer care and clinical research if the molecular processes that underlie the image data are known. Spatial heterogeneity in the dynamics of magnetic resonance imaging contrast enhancement (DCE-MRI) is hypothesized to reflect variations in tumor angiogenesis. Here we demonstrate the feasibility of precisely colocalizing DCE-MRI data with the genomic and proteomic profiles of underlying biopsy tissue using a novel MRI-guided biopsy technique in patients with prostate cancer.
Transfection Agent Induced Nanoparticle Cell Loading
Authors: Montet-Abou Karin , Montet Xavier , Weissleder Ralph , Josephson Lee
Published: March 2018

Loading cells with magnetic nanoparticles, and tracking their fate in vivo by high resolution MRI, is an attractive approach for enhancing the efficacy of cell-based therapies including those utilizing hematopoietic stem cells, neuroprogenitor cells, and T cells. The transfection agent (internalization agent) assisted loading with the Feridex IV® nanoparticle is an attractive method of loading because of the low cost of materials, and possible low regulatory barriers for eventual clinical use. We therefore explored the interaction between Feridex IV® and three internalization agents protamine (PRO), polylysine (PLL), and lipofectamine (LFA). Feridex reacted with internalization agents to form aggregates, except when either the internalization agent or Feridex was present in large excess. When Jurkat T cells were incubated with Feridex/LFA or Feridex/PRO mixtures, and washed by centrifugation, nanoparticle aggregates co-purified with cells. With C17.2 cells large iron oxide particles adhered to the cell surface. At 30 μg/mL Feridex and 3 μg/mL LFA, internalization was largely mediated by LFA and was largely cytoplasmic. However, we found that the conditions used to label cells with Feridex and transfection agents need to be carefully selected to avoid the problems of surface adsorption and nanoparticle precipitation.
The “ḥadīṯ literature”: What is it and where is it?
Authors: Burge Stephen R.
Published: March 2018

This article seeks to explore what the ḥadīṯ literature is from a theoretical perspective. Developing ideas first formulated by Andrew Newman, it will be argued that the “ḥadīṯ literature” is an abstract concept, which, subsequently, raises a number of issues and questions. Using a comparison of two works on ǧihād as a case study—al-Biqāʿī’s (d. 885/1480) Ḏayl al-istišhād bi-āyāt al-ǧihād and al-Suyūṭī’s (d. 911/1505) Arbaʿūn ḥadīṯan fī faḍl al-ǧihād—questions around the “ḥadīṯ literature” and what it is will be raised. The discussion will focus on the way in which the ḥadīṯ found in ḥadīṯ collections are affected by a compiler’s own personal discourse and historical context. It will be argued that a paradox emerges in which ḥadīṯ are both part of an abstract, atemporal “ḥadīṯ literature,” but, at the same time, rooted in the theological and historical context of the compiler.
Faculty Workshop on Using Instructional Technologies and Satellite Data for College-Level Education in the Atmospheric and Earth Sciences
Authors: Wetzel Melanie , Dempsey David , Nilsson Sandra , Ramamurthy Mohan , Koch Steve , Moody Jennie , Knight David , Murphy Charles , Fulker David , Marlino Mary , Morgan Michael , Yarger Doug , Vietor Dan , Cox Greg
Published: March 2018

An education-oriented workshop for college faculty in the atmospheric and related sciences was held in Boulder, Colorado, during June 1997 by three programs of the University Corporation for Atmospheric Research. The objective of this workshop was to provide faculty with hands-on training in the use of Web-based instructional methods for specific application to the teaching of satellite remote sensing in their subject areas. More than 150 faculty and associated scientists participated, and postworkshop evaluation showed it to have been a very successful integration of information and activities related to computer-based instruction, educational principles, and scientific lectures.
Linear Predictability: A Sea Surface Height Case Study
Authors: Sonnewald Maike , Wunsch Carl , Heimbach Patrick
Published: March 2018

A benchmark of linear predictability of sea surface height (SSH) globally is presented, complementing more complicated studies of SSH predictability. Twenty years of the Estimating the Circulation and Climate of the Ocean (ECCOv4) state estimate (1992–2011) are used, fitting autoregressive moving average [ARMA([Formula: see text])] models where the order of the coefficients is chosen by the Akaike information criteria (AIC). Up to 50% of the ocean SSH variability is dominated by the seasonal signal. The variance accounted for by the nonseasonal SSH is particularly distinct in the Southern and Pacific Oceans, containing >95% of the total SSH variance, and the expected prediction error growth takes a few months to reach a threshold of 1 cm. Isolated regions take 12 months or more to cross an accuracy threshold of 1 cm. Including the trend significantly increases the time taken to reach the threshold, particularly in the South Pacific. Annual averaging has expected prediction error growth of a few years to reach a threshold of 1 cm. Including the trend mainly increases the time taken to reach the threshold, but the time series is short and noisy.
Intensification of Convective Rain Cells at Warmer Temperatures Observed from High-Resolution Weather Radar Data
Authors: Peleg Nadav , Marra Francesco , Fatichi Simone , Molnar Peter , Morin Efrat , Sharma Ashish , Burlando Paolo
Published: March 2018

This study contributes to the understanding of the relationship between air temperature and convection by analyzing the characteristics of rainfall at the storm and convective rain cell scales. High spatial–temporal resolution (1 km, 5 min) estimates from a uniquely long weather radar record (24 years) were coupled with near-surface air temperature over Mediterranean and semiarid regions in the eastern Mediterranean. In the examined temperature range (5°–25°C), the peak intensity of individual convective rain cells was found to increase with temperature, but at a lower rate than the 7%°C−1 scaling expected from the Clausius–Clapeyron relation, while the area of the individual convective rain cells slightly decreases or, at most, remains unchanged. At the storm scale, the areal convective rainfall was found to increase with warmer temperatures, whereas the areal nonconvective rainfall and the stormwide area decrease. This suggests an enhanced moisture convergence from the stormwide extent toward the convective rain cells. Results indicate a reduction in the total rainfall amounts and an increased heterogeneity of the spatial structure of the storm rainfall for temperatures increasing up to 25°C. Thermodynamic conditions, analyzed using convective available potential energy, were determined to be similar between Mediterranean and semiarid regions. Limitations in the atmospheric moisture availability when shifting from Mediterranean to semiarid climates were detected and explain the suppression of the intensity of the convective rain cells when moving toward drier regions. The relationships obtained in this study are relevant for nearby regions characterized by Mediterranean and semiarid climates.