bluuebunny/crossref_metadata_2025 huggingface dataset:
Geochemical Survey and Evaluation Excavations at Alderley Edge: Recognizing Anthropogenic Signatures within a Mining Site‐scape
Authors: Carey Christopher J. , Moles Norman R.
Published: February 2017

Archaeological science and field investigations are making greater use of multi‐element geochemical survey as a tool for site prospection and intra‐excavation analysis. This increasing use of geochemical survey is allowing a new field of geoprospection to develop, a technique that has specific relevance to the investigation of sites containing archaeometallurgical evidence, due to the high geochemical loadings within archaeological contexts produced from past metalworking activities. Correspondingly, there have been relatively few published examples that compare the results of geochemical surveys against excavation data. This study reports the use of geochemical data to investigate a multi‐period mining site‐scape at Alderley Edge, Cheshire, UK. The geochemical data is analysed using principle component analysis, which facilitates the identification of a number of geochemical anomalies. The site taphonomy and stratigraphic evolution of this mining site‐scape is complex, with naturally occurring areas of lead and copper mineralization and a history of exploitation since the early Bronze Age. The geochemical anomalies were compared to the results of excavation within the survey area and this combination of excavation and prospection data allowed the reasons for the different geochemical anomalies to be explained. The article highlights the potential of using multi‐element geochemical survey to investigate sites containing archaeometallurgical remains and provides a discussion of why context specificity is essential to correctly interpret multi‐element geochemical data. Copyright © 2017 John Wiley & Sons, Ltd.
A comparative evaluation of models to predict human intestinal metabolism from nonclinical data
Authors: Yau Estelle , Petersson Carl , Dolgos Hugues , Peters Sheila Annie
Published: February 2017

Extensive gut metabolism is often associated with the risk of low and variable bioavailability. The prediction of the fraction of drug escaping gut wall metabolism as well as transporter‐mediated secretion (Fg) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate Fg and, based on the outcome, to provide recommendations for the prediction of human Fg during drug discovery and early drug development. The use of in vitro intrinsic clearance from human liver microsomes (HLM) in three mechanistic models – the ADAM, Qgut and Competing Rates – was evaluated for drugs whose metabolism is dominated by CYP450s, assuming that the effect of transporters is negligible. The utility of rat as a model for human Fg was also explored. The ADAM, Qgut and Competing Rates models had comparable prediction success (70%, 74%, 69%, respectively) and bias (AFE = 1.26, 0.74 and 0.81, respectively). However, the ADAM model showed better accuracy compared with the Qgut and Competing Rates models (RMSE =0.20 vs 0.30 and 0.25, respectively). Rat is not a good model (prediction success =32%, RMSE =0.48 and AFE = 0.44) as it seems systematically to under‐predict human Fg. Hence, we would recommend the use of rat to identify the need for Fg assessment, followed by the use of HLM in simple models to predict human Fg. © 2017 Merck KGaA. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons, Ltd.
Nucleic‐Acid‐Templated Enzyme Cascades
Authors: Rajendran Arivazhagan , Nakata Eiji , Nakano Shun , Morii Takashi
Published: February 2017

Cellular metabolism involves complex sequences of organized enzymatic reactions, known as metabolic pathways, that convert substrates into readily usable materials. In nature, these enzymatic complexes are organized in a well‐defined manner so that the cascade reactions are more rapid and efficient than they would be if the enzymes were randomly distributed in the cytosol. Development of artificial enzyme cascades that resemble nature's organization of sequentially assembled enzymes is of current interest due to its potential applications, from diagnostics to the production of high‐value chemicals. Nucleic acids and their nanostructures have been used to organize enzyme cascades and have been shown to enhance the efficiencies and rates of sequential reactions. Here we summarize the recent progress in the development of artificial enzyme cascades and sequential reactions by arranging enzymes on various DNA/RNA templates and discuss the future directions of this research endeavour.
TET1 promotes cisplatin‐resistance via demethylating the vimentin promoter in ovarian cancer
Authors: Han Xi , Zhou Yuanyuan , You Yuanyi , Lu Jiaojiao , Wang Lijie , Hou Huilian , Li Jing , Chen Wei , Zhao Le , Li Xu
Published: February 2017

The development of chemo‐resistance impairs the outcome of the first line platinum‐based chemotherapies for ovarian cancer. Deregulation of DNA methylation/demethylation provides a critical mechanism for the occurrence of chemo‐resistance. The ten‐eleven translocation (TET) family of dioxygenases including TET1/2/3 plays an important part in DNA demethylation, but their roles in cisplatin resistance have not been elucidated. Using cisplatin‐sensitive and cisplatin‐resistant ovarian cancer cell models, we found that TET1 was significantly upregulated in cisplatin‐resistant CP70 cells compared with that in cisplatin‐sensitive A2780 cells. Ectopic expression of TET1 in A2780 cells promoted cisplatin resistance and decreased cytotoxicity induced by cisplatin, while inhibition of TET1 by siRNA transfection in CP70 cells attenuated cisplatin resistance and enhanced cytotoxicity of cisplatin. Increased TET1 induced re‐expression of vimentin through active DNA demethylation, and cause partial epithelial‐to‐mesenchymal (EMT) in A2780 cells. Contrarily, knocking down of TET1 in CP70 cells reduced vimentin expression and reversed EMT process. Immunohistochemical analysis of TET1 in human ovarian cancer tissues revealed that TET1 existed in nucleus and cytoplasm in ovarian cancer tissues. And the expression of nuclear TET1 was positively correlated with residual tumor and chemotherapeutic response. Thus, TET1 expression causes resistance to cisplatin and one of the targets of TET1 action is vimentin in ovarian cancer.
Cuvette‐Based Electrogenerated Chemiluminescence Detection System for the Assessment of Polymerizable Ruthenium Luminophores
Authors: Danis Andrew S. , Odette William L. , Perry Samuel C. , Canesi Sylvain , Sleiman Hanadi F. , Mauzeroll Janine
Published: February 2017

Herein, we validate a novel cuvette‐based approach to measure electrogenerated chemiluminescence (ECL) by employing the hyphenation of a commercial spectrometer and a potentiostat. The new experimental design provides simultaneous acquisition of electrochemical and ECL data, allowing complementary analysis by both techniques. Preliminary analysis of an organometallic ECL standard, tris(2,2′‐bipyridine)ruthenium(II) (Ru(bpy)32+), and tripropylamine (TPA), showed excellent reproducibility both in terms of the electrochemistry and the ECL signal. Equally as important, the acquired electrochemistry and ECL from the Ru(bpy)32+/TPA system served as a baseline for evaluating the ECL response of polymerizable ruthenium luminophores.
Graphene‐Encapsulated Copper tin Sulfide Submicron Spheres as High‐Capacity Binder‐Free Anode for Lithium‐Ion Batteries
Authors: Fu Lin , Wang Xiaogang , Ma Jun , Zhang Chuanjian , He Jianjiang , Xu Hongxia , Chai Jingchao , Li Shizhen , Chai Fenglian , Cui Guanglei
Published: February 2017

Sn‐based sulfides are potential anode materials for lithium‐ion batteries (LIBs); nevertheless, they typically suffer from poor cycle stability resulted from the huge volume variation during lithium‐ion insertion and extraction. Herein, we successfully fabricated the multiphase Cu2Sn3S7/Cu2SnS3/SnS2 (CTS) submicron spheres uniformly incorporated with reduced graphene oxide nanosheets (CTS@RGO). This binder‐free hybrid CTS@RGO paper exhibits favorable capacity retention as an anode of LIBs (965 mAh g−1 after 300 cycles at current density of 500 mA g−1), as well as better rate capability and high initial coulombic efficiency compared with that of a pristine CTS anode. The enhanced electrochemical performance can be ascribed to the introduction of graphene as a buffer to accommodate large volume changes and to maintain structural integrity of electrode.
Cleavage of Dinitrogen from Forming Gas by a Titanium Molecular System under Ambient Conditions
Authors: González‐Moreiras Mariano , Mena Miguel , Pérez‐Redondo Adrián , Yélamos Carlos
Published: February 2017

Simple exposure of a hexane solution of [TiCp*Me3] (Cp*=η5‐C5Me5) to an atmosphere of commercially available and inexpensive forming gas (H2/N2 mixture, 13.5–16.5 % of H2) at room temperature leads to the methylidene–methylidyne–nitrido cube‐type complex [(TiCp*)4(μ3‐CH)(μ3‐CH2)(μ3‐N)2] via dinitrogen cleavage. This paramagnetic compound reacts with [D1]chloroform to give the titanium(IV) methylidyne–nitrido species [(TiCp*)4(μ3‐CH)2(μ3‐N)2], whereas its one‐electron oxidation with AgOTf or [Fe(η5‐C5H5)2](OTf) (OTf=O3SCF3) yields the diamagnetic ionic derivative [(TiCp*)4(μ3‐CH)(μ3‐CH2)(μ3‐N)2](OTf). The μ3‐nitrido ligands of the methylidyne–nitrido cubane complex can be protonated with [LutH](OTf) (Lut=2,6‐lutidine) or hydrogenated with NH3⋅BH3 to afford μ3‐NH imido moieties.
Facile Preparation of Ultrathin Co3O4/Nanocarbon Composites with Greatly Improved Surface Activity as a Highly Efficient Oxygen Evolution Reaction Catalyst
Authors: Chen Yanyan , Hu Jun , Diao Honglin , Luo Wenjing , Song Yu‐Fei
Published: February 2017

The efficient catalytic oxidation of water to dioxygen plays a significant role in solar fuel and artificial photosynthetic systems. It remains highly challenging to develop oxygen evolution reaction (OER) catalysts with high activity and low cost under mild conditions. Here, a new composite material is reported based on ultrathin 2D Co3O4 nanosheets and reduced graphene oxides (rGO) by means of a one‐pot hydrothermal strategy. The ultrathin Co3O4/rGO nanocomposite shows superior stability under alkaline conditions and exhibits an overpotential of 290 mV with a Tafel slope of 68 mA dec−1, which is much smaller than that of bare Co3O4 catalyst. Extensive experiments were also carried out using 0D CS and 1D CNTs (CS=carbon spheres, CNTs=carbon nanotubes) in place of the 2D rGO. The overpotentials of as‐prepared nanocomposites decrease with the increase of the dimension of nanocarbons, suggesting the electrochemistry activity is closely related to the surface area of carbon substrates. In addition, compared with ultrathin 2D Co3O4 nanosheets with a Co2+/Co3+ ratio of 1.2, the as‐prepared ultrathin Co3O4/rGO nanocomposite with a Co2+/Co3+ ratio of 1.4 contributes to the better OER performance as more oxygen vacancies can be formed in the ultrathin Co3O4/rGO nanocomposite under the experimental conditions. Compared with other Co3O4‐containing composite materials reported so far, the ultrathin Co3O4/rGO nanocomposites show excellent OER performance.
Applying search algorithms to obtain the optimal configuration of nDT torus nodes
Authors: Andújar‐Muñoz Francisco‐José , Villar-Ortiz Juan‐Antonio , Sánchez‐García José‐Luis , Alfaro‐Cortés Francisco‐José
Published: February 2017

An nDT torus is a topology where each node comprises 2 identical (n+1)‐port communication cards interconnected by 1 port. By using the current switches or communication cards, this node architecture allows to build torus networks having a greater number of dimensions than networks including only 1 card per node. There are multiple ways to use the ports of the 2 cards to connect a node to other nodes on the nDT torus, and therefore, checking all the configurations is only an affordable problem for small values of n. In this paper, we use artificial intelligence and data mining techniques to obtain the optimal port configuration of all the nodes in the network. We include a performance evaluation that shows nDT torus effectively increases the performance compared with the equivalent torus in resources, with synthetic and application trace–based workloads. We also apply these techniques to 3DT and 5DT tori to confirm the increase in the number of dimensions that does not affect to performance of the nDT torus.
Quantitation of DNA and RNA with Absorption and Fluorescence Spectroscopy
Authors: Gallagher Sean R.
Published: February 2017

Quantitation of nucleic acids is a fundamental tool in molecular biology that requires accuracy, reliability, and the use of increasingly smaller sample volumes. This unit describes the traditional absorbance measurement at 260 nm and three more sensitive fluorescence techniques employing Hoechst 33258, ethidium bromide, and PicoGreen. The range of the assays covers 25 pg/ml to 50 µg/ml. Absorbance at 260 nm has an effective range from 1 to 50 µg/ml; Hoechst 33258 from 0.01 to 15 µg/ml; ethidium bromide from 0.1 to 10 µg/ml; and PicoGreen from 25 to 1000 pg/ml. © 2017 by John Wiley & Sons, Inc.
Recent Progress in Metal–Organic Frameworks and Their Derived Nanostructures for Energy and Environmental Applications
Authors: Xie Zhiqiang , Xu Wangwang , Cui Xiaodan , Wang Ying
Published: February 2017

Metal–organic frameworks (MOFs), as a very promising category of porous materials, have attracted increasing interest from research communities due to their extremely high surface areas, diverse nanostructures, and unique properties. In recent years, there is a growing body of evidence to indicate that MOFs can function as ideal templates to prepare various nanostructured materials for energy and environmental cleaning applications. Recent progress in the design and synthesis of MOFs and MOF‐derived nanomaterials for particular applications in lithium‐ion batteries, sodium‐ion batteries, supercapacitors, dye‐sensitized solar cells, and heavy‐metal‐ion detection and removal is reviewed herein. In addition, the remaining major challenges in the above fields are discussed and some perspectives for future research efforts in the development of MOFs are also provided.
Distributed fuzzy logic based energy‐aware and coverage preserving unequal clustering algorithm for wireless sensor networks
Authors: Mazumdar Nabajyoti , Om Hari
Published: February 2017

In an energy‐constrained wireless sensor networks (WSNs), clustering is found to be an effective strategy to minimize the energy depletion of sensor nodes. In clustered WSNs, network is partitioned into set of clusters, each having a coordinator called cluster head (CH), which collects data from its cluster members and forwards it to the base station (BS) via other CHs. Clustered WSNs often suffer from the hot spot problem where CHs closer to the BS die much early because of high energy consumption contributed by the data forwarding load. Such death of nodes results coverage holes in the network very early. In most applications of WSNs, coverage preservation of the target area is a primary measure of quality of service. Considering the energy limitation of sensors, most of the clustering algorithms designed for WSNs focus on energy efficiency while ignoring the coverage requirement. In this paper, we propose a distributed clustering algorithm that uses fuzzy logic to establish a trade‐off between the energy efficiency and coverage requirement. This algorithm considers both energy and coverage parameters during cluster formation to maximize the coverage preservation of target area. Further, to deal with hot spot problem, it forms unequal sized clusters such that more CHs are available closer to BS to share the high data forwarding load. The performance of the proposed clustering algorithm is compared with some of the well‐known existing algorithms under different network scenarios. The simulation results validate the superiority of our algorithm in network lifetime, coverage preservation, and energy efficiency.
Quantifying three‐dimensional morphology and RNA from individual embryos
Authors: Green Rebecca M. , Leach Courtney L. , Hoehn Natasha , Marcucio Ralph S. , Hallgrímsson Benedikt
Published: February 2017

Quantitative analysis of morphogenesis aids our understanding of developmental processes by providing a method to link changes in shape with cellular and molecular processes. Over the last decade, many methods have been developed for 3D imaging of embryos using microCT scanning to quantify the shape of embryos during development. These methods generally involve a powerful, cross‐linking fixative such as paraformaldehyde to limit shrinkage during the CT scan. However, the extended time frames that these embryos are incubated in such fixatives prevent use of the tissues for molecular analysis after microCT scanning. This is a significant problem because it limits the ability to correlate variation in molecular data with morphology at the level of individual embryos. Here we outline a novel method that allows RNA, DNA, or protein isolation following CT scan while also allowing imaging of different tissue layers within the developing embryo. We show shape differences early in craniofacial development (E11.5) between common mouse genetic backgrounds, and demonstrate that we are able to generate RNA from these embryos after CT scanning that is suitable for downstream real time PCR (RT‐PCR) and RNAseq analyses. Developmental Dynamics 246:431–436, 2017. © 2017 Wiley Periodicals, Inc.
Impact of low‐weight severity and menstrual status on bone in adolescent girls with anorexia nervosa
Authors: Kandemir Nurgun , Becker Kendra , Slattery Meghan , Tulsiani Shreya , Singhal Vibha , Thomas Jennifer J. , Coniglio Kathryn , Lee Hang , Miller Karen K. , Eddy Kamryn T. , Klibanski Anne , Misra Madhusmita
Published: February 2017

Clinicians currently use different low‐weight cut‐offs both to diagnose anorexia nervosa (AN) and to determine AN severity in adolescent girls. The purpose of this study was to evaluate the clinical utility of existing cut‐offs and severity criteria by determining which are most strongly associated with risk for low bone mineral density (BMD). Height adjusted BMD Z scores were calculated for 352 females: 262 with AN and 90 healthy controls (controls) (12–20.5 years), using data from the BMD in Childhood Study, for the lumbar spine, whole body less head, and total hip. For most cut‐offs used to define low weight (5th or 10th BMI percentile, BMI of 17.5 or 18.5, and 85 or 90% of median BMI), AN had lower BMD Z scores than controls. AN at >85 or >90% expected body weight for height (EBW‐Ht) did not differ in BMD Z scores from controls, but differed significantly from AN at ≤85 or ≤90% EBW‐Ht. Among AN, any amenorrhea was associated with lower BMD. AN had lower BMD than controls across DSM‐5 and The Society for Adolescent Health and Medicine (SAHM) severity categories. The SAHM moderate severity classification was differentiated from the mildly malnourished classification by lower BMD at hip and spine sites. Amenorrhea and %EBW‐Ht ≤ 85 or ≤ 90% are markers of severity of bone loss within AN. Among severity categories, BMI Z scores (SAHM) may have the greatest utility in assessing the degree of malnutrition in adolescent girls that corresponds to lower BMD.
Catalytic Water‐Oxidation Activity of a Weakly Coupled Binuclear Ruthenium Polypyridyl Complex
Authors: Matias Tiago A. , Mangoni Ana P. , Toma Sergio H. , Rein Francisca N. , Rocha Reginaldo C. , Toma Henrique E. , Araki Koiti
Published: February 2017

Invited for the cover of this issue is the group of Koiti Araki from the University of São Paulo, Brazil. The cover image shows the oxidation of water to O2 by an angular “Pacman‐like” binuclear Ru complex with weak coupling between catalytic sites.
Triheterometallic Lanthanide Complexes Prepared from Kinetically Inert Lanthanide Building Blocks
Authors: Sørensen Thomas Just , Tropiano Manuel , Kenwright Alan M. , Faulkner Stephen
Published: February 2017

Three molecular structures, each containing three different lanthanide(III) centres, have been prepared by coupling three kinetically inert lanthanide(III) complexes in an Ugi reaction. These 2 kDa molecules were purified by dialysis and characterised by NMR and luminescence techniques. The photophysical properties of these heterotrimetallic complexes were investigated and are discussed by comparison with simpler, but related, heterodimetallic compounds. It was found that an aminonaphthalene unit inhibits the sensitisation of terbium, and that the spatial arrangement of the chromophores and lanthanide(III) centres in these molecules inhibits the efficient sensitisation of europium. We conclude that the intramolecular collisions required for efficient Dexter energy transfer from the sensitiser to the lanthanide(III) centre can be prevented by steric congestion.
Connectivity strength‐weighted sparse group representation‐based brain network construction for MCI classification
Authors: Yu Renping , Zhang Han , An Le , Chen Xiaobo , Wei Zhihui , Shen Dinggang
Published: February 2017

Brain functional network analysis has shown great potential in understanding brain functions and also in identifying biomarkers for brain diseases, such as Alzheimer's disease (AD) and its early stage, mild cognitive impairment (MCI). In these applications, accurate construction of biologically meaningful brain network is critical. Sparse learning has been widely used for brain network construction; however, its l1‐norm penalty simply penalizes each edge of a brain network equally, without considering the original connectivity strength which is one of the most important inherent linkwise characters. Besides, based on the similarity of the linkwise connectivity, brain network shows prominent group structure (i.e., a set of edges sharing similar attributes). In this article, we propose a novel brain functional network modeling framework with a “connectivity strength‐weighted sparse group constraint.” In particular, the network modeling can be optimized by considering both raw connectivity strength and its group structure, without losing the merit of sparsity. Our proposed method is applied to MCI classification, a challenging task for early AD diagnosis. Experimental results based on the resting‐state functional MRI, from 50 MCI patients and 49 healthy controls, show that our proposed method is more effective (i.e., achieving a significantly higher classification accuracy, 84.8%) than other competing methods (e.g., sparse representation, accuracy = 65.6%). Post hoc inspection of the informative features further shows more biologically meaningful brain functional connectivities obtained by our proposed method. Hum Brain Mapp 38:2370–2383, 2017. © 2017 Wiley Periodicals, Inc.
Complementary role of the Memorial Sloan Kettering Cancer Center nomogram to the American Joint Committee on Cancer system for the prediction of relapse of major salivary gland carcinoma after surgery
Authors: Chou Wen‐Chi , Chang Kai‐Ping , Lu Chang‐Hsien , Chen Miao‐Fen , Cheng Yu‐Fan , Yeh Kun‐Yun , Wang Cheng‐Hsu , Lin Yung‐Chang , Yeh Ta‐Sen
Published: February 2017

Background

The purpose of this study was to test the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram in predicting recurrence risk of major salivary gland carcinoma in an Asian cohort.

Methods

We retrospectively enrolled 149 patients who had undergone intended curative resections for major salivary gland carcinoma between 2007 and 2012. The performance of the MSKCC nomogram and the American Joint Committee on Cancer (AJCC) seventh staging system in predicting recurrence risk was compared.

Results

The MSKCC nomogram and the AJCC staging system both accurately predicted the 5‐year recurrence probabilities, with the concordance index (c‐index = 0.82; 95% confidence interval [CI], 0.75–0.89 vs c‐index, 0.77; 95% CI, 0.68–0.87; p = .45) in patients with major salivary gland carcinomas after curative surgeries. Comparing to the actual observed events, the calibration plot indicated that the MSKCC nomogram accurately estimated the recurrence in low‐risk groups but tended to overestimate in high‐risk groups. When using the MSKCC nomogram to predict the 5‐year recurrence‐free probability in each AJCC stage, the prediction was very good for patients with AJCC stages I and II disease (c‐index = 0.92 and 0.90, respectively) and modest for those of AJCC stages III and IVa (c‐index = 0.51 and 0.62, respectively).

Conclusion

The MSKCC nomogram and the AJCC staging system each had its value in predicting recurrence of major salivary gland cancers. When using the MSKCC nomogram to predict the 5‐year recurrence‐free probability in each AJCC stage, the MSKCC nomogram was more accurate in predicting recurrence risks in those patients with AJCC stage I and II diseases than those with late‐stage diseases. © 2017 Wiley Periodicals, Inc. Head Neck 39: 860–867, 2017
Effect of prophylactic percutaneous endoscopic gastrostomy tube on swallowing in advanced head and neck cancer: A randomized controlled study
Authors: Axelsson Lars , Silander Ewa , Nyman Jan , Bove Mogens , Johansson Leif , Hammerlid Eva
Published: February 2017

Background

Dysphagia is common in head and neck cancer. A percutaneous endoscopic gastrostomy (PEG) tube is used to facilitate nutrition; however, some retrospective studies have indicated that the PEG tube causes dysphagia.

Methods

A randomized study of patients with head and neck cancer was conducted with up to 10 years of follow‐up. Patients were randomized to either the prophylactic PEG tube group (study group) or the common clinical nutritional support group (control group). At each follow‐up, a dietician assessed the oral intake, noted the patients' weight, and if the patients used a PEG tube. Dysphagia was also assessed by the quality of life questionnaire, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 Head and Neck 35‐questions (EORTC‐QLQ‐H&N35).

Results

One hundred thirty‐four patients were included in this study. There was no significant difference in swallowing function between the groups after 12 months, 24 months, and 8 years based on the EORTC‐QLQ‐H&N35, the oral intake scale, tube dependence, esophageal intervention, weight, body mass index (BMI), and overall survival.

Conclusion

A prophylactic PEG tube can be used without an increased risk of long‐term dysphagia in patients with head and neck cancer. © 2017 Wiley Periodicals, Inc. Head Neck 39: 908–915, 2017
microRNA‐577 suppresses tumor growth and enhances chemosensitivity in colorectal cancer
Authors: Jiang Haiping , Ju Hui , Zhang Lin , Lu Haijun , Jie Kan
Published: February 2017

In this work, we aimed to determine the expression and biological functions of microRNA (miR)‐577 in colorectal cancer (CRC). The results showed that miR‐577 was downregulated in CRC specimens and cell lines. Restoration of miR‐577 significantly suppressed the proliferation and colony formation and induced a G0/G1 cell cycle arrest in CRC cells. 5‐Fluorouracil (5‐FU)‐resistant SW480 cells (SW480/5‐FU) were found to have elevated levels of miR‐577. Ectopic expression of miR‐577 enhanced 5‐FU sensitivity in SW480/5‐FU cells. Heat shock protein 27 (HSP27) was identified as a target gene of miR‐577. Enforced expression of HSP27 reversed the effects of miR‐577 on CRC cell growth and 5‐FU sensitivity. Xenograft tumors derived from miR‐577‐overexpressing SW480 cells exhibited significantly slower growth than control tumors. In conclusion, our results support that miR‐577 acts as a tumor suppressor in CRC likely through targeting HSP27. Therefore, miR‐577 may have therapeutic potential in the treatment of CRC.
Can diffusion‐weighted imaging serve as a biomarker of fibrosis in pancreatic adenocarcinoma?
Authors: Hecht Elizabeth M. , Liu Michael Z. , Prince Martin R. , Jambawalikar Sachin , Remotti Helen E. , Weisberg Stuart W. , Garmon Donald , Lopez‐Pintado Sara , Woo Yanghee , Kluger Michael D. , Chabot John A.
Published: February 2017

Purpose

To assess the relationship between diffusion‐weighted imaging (DWI) and intravoxel incoherent motion (IVIM)‐derived quantitative parameters (apparent diffusion coefficient [ADC], perfusion fraction [f], Dslow, diffusion coefficient [D], and Dfast, pseudodiffusion coefficient [D*]) and histopathology in pancreatic adenocarcinoma (PAC).

Materials and Methods

Subjects with suspected surgically resectable PAC were prospectively enrolled in this Health Insurance Portability and Accountability Act (HIPAA)‐compliant, Institutional Review Board‐approved study. Imaging was performed at 1.5T with a respiratory‐triggered echo planar DWI sequence using 10 b values. Two readers drew regions of interest (ROIs) over the tumor and adjacent nontumoral tissue. Monoexponential and biexponential fits were used to derive ADC2b, ADCall, f, D, and D*, which were compared to quantitative histopathology of fibrosis, mean vascular density, and cellularity. Two biexponential IVIM models were investigated and compared: 1) nonlinear least‐square fitting based on the Levenberg–Marquardt algorithm, and 2) linear fit using a fixed D* (20 mm2/s). Statistical analysis included Student's t‐test, Pearson correlation (P < 0.05 was considered significant), intraclass correlation, and coefficients of variance.

Results

Twenty subjects with PAC were included in the final cohort. Negative correlation between D and fibrosis (Reader 2: r = –0.57 P = 0.01; pooled P = –0.46, P = 0.04) was observed with a trend toward positive correlation between f and fibrosis (r = 0.44, P = 0.05). ADC2b was significantly lower in PAC with dense fibrosis than with loose fibrosis ADC2b (P = 0.03). Inter‐ and intrareader agreement was excellent for ADC, D, and f.

Conclusion

In PAC, D negatively correlates with fibrosis, with a trend toward positive correlation with f suggesting both perfusion and diffusion effects contribute to stromal desmoplasia. ADC2b is significantly lower in tumors with dense fibrosis and may serve as a biomarker of fibrosis architecture.

Level of Evidence: 1

Technical Efficacy: Stage 2

J. MAGN. RESON. IMAGING 2017;46:393–402
Spatiotemporal alignment of in utero BOLD‐MRI series
Authors: Turk Esra Abaci , Luo Jie , Gagoski Borjan , Pascau Javier , Bibbo Carolina , Robinson Julian N. , Grant P. Ellen , Adalsteinsson Elfar , Golland Polina , Malpica Norberto
Published: February 2017

Purpose

To present a method for spatiotemporal alignment of in‐utero magnetic resonance imaging (MRI) time series acquired during maternal hyperoxia for enabling improved quantitative tracking of blood oxygen level‐dependent (BOLD) signal changes that characterize oxygen transport through the placenta to fetal organs.

Materials and Methods

The proposed pipeline for spatiotemporal alignment of images acquired with a single‐shot gradient echo echo‐planar imaging includes 1) signal nonuniformity correction, 2) intravolume motion correction based on nonrigid registration, 3) correction of motion and nonrigid deformations across volumes, and 4) detection of the outlier volumes to be discarded from subsequent analysis. BOLD MRI time series collected from 10 pregnant women during 3T scans were analyzed using this pipeline. To assess pipeline performance, signal fluctuations between consecutive timepoints were examined. In addition, volume overlap and distance between manual region of interest (ROI) delineations in a subset of frames and the delineations obtained through propagation of the ROIs from the reference frame were used to quantify alignment accuracy. A previously demonstrated rigid registration approach was used for comparison.

Results

The proposed pipeline improved anatomical alignment of placenta and fetal organs over the state‐of‐the‐art rigid motion correction methods. In particular, unexpected temporal signal fluctuations during the first normoxia period were significantly decreased (P < 0.01) and volume overlap and distance between region boundaries measures were significantly improved (P < 0.01).

Conclusion

The proposed approach to align MRI time series enables more accurate quantitative studies of placental function by improving spatiotemporal alignment across placenta and fetal organs.

Level of Evidence: 1

Technical Efficacy: Stage 1

J. MAGN. RESON. IMAGING 2017;46:403–412
Imaging of the rabbit supraspinatus enthesis at 7 Tesla: a 4‐week time course after repair surgery and effect of channeling
Authors: Trudel Guy , Melkus Gerd , Cron Greg O. , Louati Hakim , Sheikh Adnan , Larson Peder E.Z. , Schweitzer Mark , Lapner Peter , Uhthoff Hans K. , Laneuville Odette
Published: February 2017

Purpose

To image the supraspinatus enthesis reformation of rabbit shoulders by magnetic resonance at 7 Tesla (T) using T2 mapping after surgical repair and to assess the effects of channeling aimed at enhancing enthesis reformation.

Materials and Methods

In 112 rabbits, the distal supraspinatus (SSP) tendon was unilaterally detached and reattached after 1 week. At the first surgery, channeling was performed at the footprint in 64 rabbits. At the second surgery, the SSP tendon of all rabbits was re‐attached to the greater tuberosity. The shoulders were harvested at 0, 1, 2, or 4 weeks after the repair surgery and were imaged at 7T. Quantitative T2 mapping was performed using multi slice two‐dimensional multi‐echo spin‐echo sequence with fat saturation. Enthesis regions of interests were drawn on three slices at the footprint to measure T2 relaxation times.

Results

Tendon repair (F(2, 218) = 44; P < 2.2e‐16) and postoperative duration (F(3, 218) = 4.8; P = 0.006) both affected significantly the T2 values while channeling had no significant effect. For the time effect, the only pair with a statistical difference was the 0‐week and 4‐week for the channeling groups (P = 0.023).

Conclusion

Enthesis reformation early after surgical repair of the SSP distal tendon was characterized by increasing T2 values.

Level of Evidence: 2

Technical Efficacy: Stage 1

J. MAGN. RESON. IMAGING 2017;46:461–467
Intravoxel incoherent motion MRI in the brain: Impact of the fitting model on perfusion fraction and lesion differentiability
Authors: Keil Vera C. , Mädler Burkhard , Gielen Gerrit H. , Pintea Bogdan , Hiththetiya Kanishka , Gaspranova Alisa R. , Gieseke Jürgen , Simon Matthias , Schild Hans H. , Hadizadeh Dariusch R.
Published: February 2017

Purpose

To investigate the effect of the choice of the curve‐fitting model on the perfusion fraction (fIVIM) with regard to tissue type characterization, correlation with microvascular anatomy, and dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) parameters. Several curve‐fitting models coexist in intravoxel incoherent motion (IVIM) MRI to derive the (fIVIM).

Materials and Methods

In all, 29 patients with brain lesions (12 gliomas, 11 meningiomas, three metastases, two gliotic scars, one multiple sclerosis) underwent IVIM‐MRI (32 b‐values, 0 to 2000 s/mm2) at 3T. fIVIM was determined by classic monoexponential, biexponential, and a novel nonnegative least squares (NNLS) fitting in 352 regions of interest (lesion‐containing and normal‐appearing tissue) and tested their correlation with DCE‐MRI kinetic parameters and microvascular anatomy derived from 57 region of interest (ROI)‐based biopsies and their capacities to differentiate histologically different lesions.

Results

fIVIM differed significantly between all three models and all tissue types (monoexponential confidence interval in percent [CI 3.4–3.8]; biexponential [CI 11.21–12.45]; NNLS [CI 2.06–2.60]; all P < 0.001). For all models an increase in fIVIM was associated with a shift to larger vessels and higher vessel area / tissue area ratio (regression coefficient 0.07–0.52; P = 0.04–0.001). Correlation with kinetic parameters derived from DCE‐MRI was usually not significant. Only biexponential fitting allowed differentiation of both gliosis from edema and high‐ from low‐grade glioma (both P < 0.001).

Conclusion

The curve‐fitting model has an important impact on fIVIM and its capacity to differentiate tissues. fIVIM may possibly be used to assess microvascular anatomy and is weakly correlated with DCE‐MRI kinetic parameters.

Level of Evidence: 2

Technical Efficacy: Stage 1

J. Magn. Reson. Imaging 2017;46:1187–1199.
Vessel wall and adventitial DCE‐MRI parameters demonstrate similar correlations with carotid plaque microvasculature on histology
Authors: van Hoof Raf H.M. , Vöö Stefan A. , Sluimer Judith C. , Wijnen Nicky J.A. , Hermeling Evelien , Schreuder Floris H.B.M. , Truijman Martine T.B , Cleutjens Jack P.M. , Daemen Mat J.A.P. , Daemen Jan‐Willem H. , van Oostenbrugge Robert J. , Mess Werner H. , Wildberger Joachim E. , Heeneman Sylvia , Kooi M. Eline
Published: February 2017

Purpose

To assess parameter agreement of volume transfer coefficient (Ktrans) between two vascular regions and to study the correlation with microvessel density on histology. The dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) parameter Ktrans is frequently used to study atherosclerotic plaque microvasculature. Ktrans has been reported using different descriptive statistics (mean, median, 75th percentile) either for the whole vessel wall or the adventitia in previous studies.

Materials and Methods

DCE‐MRI parameter agreement was analyzed in 110 symptomatic patients with ≥2 mm carotid plaque that underwent a 3T carotid DCE‐MRI examination. Ktrans was estimated in the entire vessel wall and adventitia. Twenty‐three patients underwent carotid endarterectomy and were used for comparison with histological quantification of microvessel density of the plaque using CD31 immunohistochemistry. DCE‐MRI parameters in the vessel wall regions were compared using Pearson's correlation coefficient, Bland–Altman analysis, and a two‐sided paired samples t‐test. Correlation of the DCE‐MRI parameters with histology was studied using the Pearson's correlation coefficient.

Results

Median adventitial Ktrans was 5% higher (P = 0.003) than entire vessel wall Ktrans, with no differences for other descriptive statistics. Vessel wall and adventitial Ktrans showed similar moderately strong correlations with plaque microvessel density on histology (Pearson's ρ: 0.59–0.65 [P < 0.003] and 0.52–0.64 [P < 0.011], respectively).

Conclusion

The similar moderately strong correlations for vessel wall and adventitial Ktrans with microvessel density on histology suggested that both regions reflected plaque microvessel density. Care should to be taken when comparing absolute values between studies. Future studies incorporating thresholds for risk stratification need to agree upon standardization of DCE‐MRI parameters.

Level of Evidence: 2

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2017;46:1053–1059.
Evaluation of relative MS response factors of drug metabolites for semi‐quantitative assessment of chemical liabilities in drug discovery
Authors: Blanz Joachim , Williams Gareth , Dayer Jerôme , Délémonté Thierry , Gertsch Werner , Ramstein Philippe , Aichholz Reiner , Trunzer Markus , Pearson David
Published: February 2017

Drug metabolism studies are performed in drug discovery to identify metabolic soft spots, detect potentially toxic or reactive metabolites and provide an early insight into potential species differences. The relative peak area approach is often used to semi‐quantitatively estimate the abundance of metabolites. Differences in the liquid chromatography‐mass spectrometry responses result in an underestimation or overestimation of the metabolite and misinterpretation of results. The relative MS response factors (RF) of 132 structurally diverse drug candidates and their 233 corresponding metabolites were evaluated using a capillary‐liquid chromatography/high‐resolution mass spectrometry system. All of the synthesized metabolites discussed here were previously identified as key biotransformation products in discovery investigations or predicted to be formed. The most commonly occurring biotransformation mechanisms such as oxygenation, dealkylation and amide cleavage are represented within this dataset. However, relatively few phase II metabolites were evaluated because of the limited availability of authentic standards. Approximately 85% of these metabolites had a relative RF in the range between 0.2 (fivefold under‐prediction) and 2.0 (twofold over‐prediction), and the median MS RF was 0.6. Exceptions to this included very small metabolites that were hardly detectable. Additional experiments performed to understand the impact of the MS platform, flow rate and concentration suggested that these parameters do not have a significant impact on the RF of the compounds tested. This indicates that the use of relative peak areas to semi‐quantitatively estimate the abundance of metabolites is justified in the drug discovery setting in order to guide medicinal chemistry efforts. Copyright © 2017 John Wiley & Sons, Ltd.
From blast to bench: A translational mini‐review of posttraumatic headache
Authors: Moye Laura S. , Pradhan Amynah A.
Published: February 2017

Current events within the military and professional sports have resulted in an increased recognition of the long‐term and debilitating consequences of traumatic brain injury. Mild traumatic brain injury accounts for the majority of head injuries, and posttraumatic headache is the most common adverse effect. It is estimated that between 30% to 90% of traumatic brain injuries result in posttraumatic headache, and for a significant number of people this headache disorder can continue for up to and over a year post injury. Often, the most severe and chronic posttraumatic headache has a migraine‐like phenotype and is difficult to resolve. In this review we discuss the preclinical findings from animal models of posttraumatic headache. We also describe potential mechanisms by which traumatic brain injury leads to chronic posttraumatic headache, including neuroinflammatory mediators and migraine‐associated neuropeptides. There are surprisingly few preclinical studies that have investigated overlapping mechanisms between posttraumatic headache and migraine, especially considering the prevalence and debilitating nature of posttraumatic headache. Given this context, posttraumatic headache is a field with many emerging opportunities for growth. The frequency of posttraumatic headache in the general and military population is rising, and further preclinical research is required to understand, ameliorate, and treat this disabling disorder. © 2017 Wiley Periodicals, Inc.
Activity‐dependent modulation of intracellular ATP in cultured cortical astrocytes
Authors: Winkler Ulrike , Seim Pauline , Enzbrenner Yvonne , Köhler Susanne , Sicker Marit , Hirrlinger Johannes
Published: February 2017

Brain function is absolutely dependent on an appropriate supply of energy. A shortfall in supply—as occurs, for instance, following stroke—can lead rapidly to irreversible damage to this vital organ. While the consequences of pathophysiological energy depletion have been well documented, much less is known about the physiological energy dynamics of brain cells, although changes in the intracellular concentration of adenosine triphosphate (ATP), the major energy carrier of cells, have been postulated to contribute to cellular signaling. To address this issue more closely, we have investigated intracellular ATP in cultured primary cortical astrocytes by time‐lapse microscopy using a genetically encoded fluorescent sensor for ATP. The cytosolic ATP sensor signal decreased after application of the neurotransmitter glutamate in a manner dependent on both glutamate concentration and glutamate transporter activity, but independent of glutamate receptors. The application of dopamine did not affect ATP levels within astrocytes. These results confirm that intracellular ATP levels in astrocytes do indeed respond to changes in physiological activity and pave the way for further studies addressing factors that affect regulation of ATP. © 2017 Wiley Periodicals, Inc.
Probing nano‐organization of astroglia with multi‐color super‐resolution microscopy
Authors: Heller Janosch P. , Michaluk Piotr , Sugao Kohtaroh , Rusakov Dmitri A.
Published: February 2017

Astroglia are essential for brain development, homeostasis, and metabolic support. They also contribute actively to the formation and regulation of synaptic circuits, by successfully handling, integrating, and propagating physiological signals of neural networks. The latter occurs mainly by engaging a versatile mechanism of internal Ca2+ fluctuations and regenerative waves prompting targeted release of signaling molecules into the extracellular space. Astroglia also show substantial structural plasticity associated with age‐ and use‐dependent changes in neural circuitry. However, the underlying cellular mechanisms are poorly understood, mainly because of the extraordinary complex morphology of astroglial compartments on the nanoscopic scale. This complexity largely prevents direct experimental access to astroglial processes, most of which are beyond the diffraction limit of optical microscopy. Here we employed super‐resolution microscopy (direct stochastic optical reconstruction microscopy; dSTORM), to visualize astroglial organization on the nanoscale, in culture and in thin brain slices, as an initial step to understand the structural basis of astrocytic nano‐physiology. We were able to follow nanoscopic morphology of GFAP‐enriched astrocytes, which adapt a flattened shape in culture and a sponge‐like structure in situ, with GFAP fibers of varied diameters. We also visualized nanoscopic astrocytic processes using the ubiquitous cytosolic astrocyte marker proteins S100β and glutamine synthetase. Finally, we overexpressed and imaged membrane‐targeted pHluorin and lymphocyte‐specific protein tyrosine kinase (N‐terminal domain) ‐green fluorescent protein (lck‐GFP), to better understand the molecular cascades underlying some common astroglia‐targeted fluorescence imaging techniques. The results provide novel, albeit initial, insights into the cellular organization of astroglia on the nanoscale, paving the way for function‐specific studies. © 2017 Wiley Periodicals, Inc.
Meta‐analysis of dorsolateral nigral hyperintensity on magnetic resonance imaging as a marker for Parkinson's disease
Authors: Mahlknecht Philipp , Krismer Florian , Poewe Werner , Seppi Klaus
Published: February 2017

Background

Dorsolateral nigral hyperintensity on iron‐sensitive magnetic resonance imaging (MRI) sequences seems to be a typical finding in Parkinson's disease (PD), but most studies have involved small samples and have had heterogeneous control populations.

Objectives

The objective of this study was to perform a meta‐analysis on dorsolateral nigral hyperintensity as an imaging marker for PD.

Methods

The methods included a systematic literature search and a hierarchical summary receiver operating characteristics curve approach.

Results

Of the 16 identified studies, 10 were suitable for analysis, including 364 PD and 231 control cases. The meta‐analysis showed an overall sensitivity and specificity of the absence of dorsolateral nigral hyperintensity for PD versus controls of 97.7% and 94.6% (3 and 7 Tesla) and of 94.6% and 94.4% (3 Tesla only). Descriptive analysis among the 4 studies including patients with non‐PD parkinsonism showed that dorsolateral nigral hyperintensity was absent in 89.4% of cases with atypical parkinsonian disorders (n = 74), but only in 21.7% of cases with non‐neurodegenerative parkinsonism (n = 69). Moreover, in 2 of these studies, the absence of dorsolateral nigral hyperintensity predicted ipsilateral dopamine‐transporter deficiency with 87.5% sensitivity and 83.6% specificity.

Conclusions

Visual assessment of dorsolateral nigral hyperintensity on iron‐sensitive MRI sequences provides excellent diagnostic accuracy for PD versus controls. Moreover, its loss appears to be a marker of nigral pathology and holds the potential for the differentiation of neurodegenerative from non‐neurodegenerative parkinsonian disorders. © 2017 International Parkinson and Movement Disorder Society