bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of Laboratory‐Scale Stirred‐Pulsed Extraction Columns with Different Diameters
Authors: Soboll Sebastian , Hagemann Isabell , Kockmann Norbert
Published: November 2017

Based on a stirred‐pulsed column with 15 mm inner diameter, which was shown to provide a high number of theoretical stages per meter in a previous study, a 32‐mm column of the same type was designed and characterized using the test system water/acetone/n‐butyl acetate. The 32‐mm column shows a lower extraction performance than the 15‐mm column, however, the performance is still nearly twice as high as in conventional extraction columns. Furthermore, the maximum throughput is significantly higher in the 32‐mm column compared to the DN15 column and in the same range as for conventional stirred columns.
Activation and Forming for Improved Properties of Adsorbent Materials from Agricultural By‐Products
Authors: Schaldach Katja , Herdegen Volker , Schröder Hans‐Werner , Repke Jens‐Uwe
Published: November 2017

Um die in großen Mengen anfallenden Agrarreststoffe (z. B. Reis‐/Weizenstroh) stofflich nutzen zu können, wird im Folgenden ein neues Konzept zur Formaktivkohlenerzeugung auf Basis eines Feuchtpelletierverfahrens vorgestellt. Im Rahmen des Konzeptes kann über eine zusätzliche Aktivierung der Biomassen bzw. Aktivkohlen positiv Einfluss auf die spezifischen Eigenschaften genommen werden. Dies spiegelt sich in den vorgestellten Ergebnissen zur Formkohlenerzeugung und zur Aktivierung der nicht‐pelletierten Biomassen/‐kohlen als Grundlage für die spätere Kombination beider Prozessschritte wider.
IR Microimaging of Direction‐Dependent Uptake in MFI‐Type Crystals
Authors: Hwang Seungtaik , Parditka Bence , Cserháti Csaba , Erdélyi Zoltán , Gläser Roger , Haase Jürgen , Kärger Jörg , Schmidt Wolfgang , Chmelik Christian
Published: November 2017

Covering MFI‐type zeolite crystals with Al2O3 by atomic layer deposition is shown to make the external zeolite crystal impermeable for guest molecules. By corresponding manipulations of the crystal certain faces can be opened for guest molecules. In this way, IR microimaging can be applied to record the evolution of transient intracrystalline concentration profiles along the crystals longitudinal extension. The introduced method of covering may provide the possibility of observing fluxes of reactant and product molecules within single zeolite crystals during catalytic reactions.
Model‐free control of a seeded batch crystallizer
Authors: Afsi Nawel , Bakir Toufik , Othman Sami , Sakly Anis
Published: November 2017

As the use of a batch crystallization process in several industrial applications is extensive, finding an effective control strategy is important to improve the product quality, which is typically characterized by a unimodal and narrow crystal size distribution (CSD) with a large mean crystal size. To achieve this requirement, an accurate mathematical model is needed to predict the process comportment and to design an efficient and robust controller. However, due to the highly nonlinear comportment, the difficulties of characterizing several phenomenological effects, the kinetic parameters, uncertainty, and the unknown disturbances, the used model may not describe the real process behaviour, resulting in a poor control strategy. In this work, a model‐free control and its corresponding intelligent PI (iPI), the recently introduced approach, has been proposed to ensure that the desired unimodal CSD with a desired mean size could be reached facing these problems with an easy control structure, choosing the seeded batch crystallizer of adipic acid as a case study. The proposed iPI is compared with the classic PI controller. The simulation results demonstrate the effectiveness and disturbance rejection capability of the iPI controller against the classic PI.
IDK1 is a rat monoclonal antibody against hypoglycosylated bone sialoprotein with application as biomarker and therapeutic agent in breast cancer skeletal metastasis
Authors: Zepp Michael , Kovacheva Marineta , Altankhuyag Munkhtsetseg , Westphal Gabriela , Berger Irina , Gather Katharina S , Hilbig Heidegard , Neuhaus Jochen , Hänsch Gertrud M , Armbruster Franz P , Berger Martin R
Published: November 2017

Changes in glycosylation are salient features of cancer cells. Here, we report on the diagnostic and therapeutic properties of IDK1, an antibody against tumour associated, hypoglycosylated bone sialoprotein (hypo‐BSP). The affinity of the rat monoclonal antibody IDK1 for hypo‐BSP, as determined by microscale thermophoresis, was three orders of magnitude higher than for mature BSP, whereas the mouse monoclonal antibody used had similar affinity for both BSP forms. IDK1 showed no activity against the proliferation or migration of normal or cancer cells growing in vitro. In vivo, however, IDK1 caused dose‐dependent regression of soft tissue and skeletal lesions in nude rats harbouring human MDA‐MB‐231 cells. At optimal dose, 80% of the treated rats showed complete remission of all tumour lesions. Analysis of BSP expression in vitro by fluorescence‐activated cell sorting (FACS) and immunocytochemistry showed basal levels of this protein, which were visible only in a fraction of these cells. Cells of the metastatic cell lines MDA‐MB‐231 and PC‐3 were more often positive for hypo‐BSP. In addition, there was co‐expression of both forms in some cells, but almost no co‐localization; rather, hypo‐BSP was present in the nucleus, and mature BSP was detected extra‐cellularly. Normal osteoblasts and osteoclasts were negative for hypo‐BSP. Breast cancer tissue, however, showed strong expression of mature BSP, which was present intra‐cellularly as well as in vesicles outside cells. Hypo‐BSP was present mainly in lesions from skeletal sites, thus explaining the antineoplastic activity of IDK1, which was high in lesions growing in the vicinity of the skeleton but low in lesions growing subcutaneously. Finally, hypo‐BSP was detected in specimens from breast cancer patients, with a significantly greater intensity in skeletal metastases as compared to the respective primary cancers. In conclusion, IDK‐1 is an antibody with diagnostic and therapeutic applications in skeletal metastases of breast cancer.
Expanding Role of Data Science and Bioinformatics in Drug Discovery and Development
Authors: Fingert Howard J.
Published: November 2017

Numerous barriers have been identified which detract from successful applications of clinical trial data and platforms. Despite the challenges, opportunities are growing to advance compliance, quality, and practical applications through top‐down establishment of guiding principles, coupled with bottom‐up approaches to promote data science competencies among data producers. Recent examples of successful applications include modern treatments for hematologic malignancies, developed with support from public–private partnerships, guiding principles for data‐sharing, standards for protocol designs and data management, digital technologies, and quality analytics.
Molecular Tumor Boards: Realizing Precision Oncology Therapy
Authors: Patel Maulik , Kato Shumei M. , Kurzrock Razelle
Published: November 2017

Technological advances in high‐throughput next‐generation sequencing (NGS) along with advances in computational processes have brought about the dawn of the genomic medicine era. NGS has enabled molecular characterization of malignancies, and facilitated the development and approval of gene‐ and immune‐targeted therapies, both of which impact the mutanome. Clinical implementation of this technology, approval of novel targeted agents, and establishment of molecular tumor boards has enabled precision oncology to become a reality.
Commentary on “The Universally Unrecognized Assumption in Predicting Drug Clearance and Organ Extraction Ratio”
Authors: Rowland Malcolm , Pang K. Sandy
Published: November 2017

Among pharmacokinetic concepts, clearance has been the most widely applied in clinical pharmacology and drug development. With so much written on the subject it might be thought that there is nothing more to say. So it is noteworthy that some basic aspects related to hepatic clearance, and specifically the most popular model, the well‐stirred model, have been challenged by Benet et al. This commentary examines the challenge and provides our views.
Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations
Authors: Samant Tanay S. , Dhuria Shyeilla , Lu Yasong , Laisney Marc , Yang Shu , Grandeury Arnaud , Mueller‐Zsigmondy Martin , Umehara Kenichi , Huth Felix , Miller Michelle , Germa Caroline , Elmeliegy Mohamed
Published: November 2017

Ribociclib (KISQALI), a cyclin‐dependent kinase 4/6 inhibitor approved for the first‐line treatment of HR+/HER2– advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH‐elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) of clinical trial data, and 4) population PK (PopPK) analysis. This multipronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH‐altering agents on the absorption of ribociclib, without a dedicated drug–drug interaction trial. The bioequivalence of ribociclib exposure with or without a high‐fat meal was demonstrated in a clinical trial. Lack of restrictions on ribociclib dosing may facilitate better patient compliance and therefore clinical benefit.
Role of Bismuth in the Electrokinetics of Silicon Photocathodes for Solar Rechargeable Vanadium Redox Flow Batteries
Authors: Flox Cristina , Murcia‐López Sebastián , Carretero Nina M. , Ros Carles , Morante Juan R. , Andreu Teresa
Published: November 2017

The ability of crystalline silicon to photoassist the V3+/V2+ cathodic reaction under simulated solar irradiation, combined with the effect of bismuth have led to important electrochemical improvements. Besides the photovoltage supplied by the photovoltaics, additional decrease in the onset potentials, high reversibility of the V3+/V2+ redox pair, and improvement in the electrokinetics were attained thanks to the addition of bismuth. In fact, Bi0 deposition has shown to slightly decrease the photocurrent, but the significant enhancement in the charge transfer, reflected in the overall electrochemical performance clearly justifies its use as additive in a photoassisted system for maximizing the efficiency of solar charge to battery.
Impaired secretion of active GLP‐1 in patients with hypertriglyceridaemia: A novel lipotoxicity paradigm?
Authors: Wang Xiangxiang , Liu Jia , Li Chaolin , Zhao Meng , Liu Lu , Guan Qingbo , Zhang Haiqing , Zhang Xu , Gao Ling , Zhao Jiajun , Song Yongfeng
Published: November 2017

Background

Lipotoxicity plays an important role in the pathogenesis of β‐cell dysfunction. Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that exerts beneficial effects on the number and function of islet β cells. However, the effect of lipotoxicity on GLP‐1 secretion is still unknown.

Methods

Twenty‐five patients who were newly diagnosed with diabetes were recruited from 400 subjects based on 75‐g Oral Glucose Tolerance Test. Patients were divided into diabetes (DM) and DM combined with hypertriglyceridaemia (DM + HTG) groups according to their serum triglyceride (TG) levels. Seventy‐one normal controls and 17 patients with isolated hypertriglyceridaemia were matched by age and gender.

Results

Total and active fasting GLP‐1 and 2‐hour GLP‐1 levels were not significantly altered among the 4 groups. However, total and active ΔGLP‐1 levels (the difference between 2‐hour GLP‐1 and fasting GLP‐1 levels) were significantly reduced in the isolated HTG, DM, and DM + HTG groups, particularly the DM + HTG group. The ratio of serum active GLP‐1 (AGLP‐1) to total GLP‐1 (TGLP‐1) levels was also decreased in patients with isolated HTG, suggesting that active GLP‐1 secretion may be more seriously impaired. Both ΔTGLP‐1 and ΔAGLP‐1 levels were negatively correlated with serum TG levels, body mass index and fasting plasma glucose (FPG) levels and positively correlated with HDL‐C levels. According to the multivariate linear regression analysis, only TG and FPG levels were independently associated with ΔTGLP‐1 and ΔAGLP‐1 levels.

Conclusion

Impaired GLP‐1 secretion was associated with hypertriglyceridaemia and diabetes, and a more obvious association was noted in hypertriglyceridaemic patients with diabetes.
Effects of alcohol on plasma glucose and prevention of alcohol‐induced hypoglycemia in type 1 diabetes—A systematic review with GRADE
Authors: Tetzschner R. , Nørgaard K. , Ranjan A.
Published: November 2017

Because ethanol is thought to be a risk factor for severe hypoglycemia, patients with type 1 diabetes (T1D) are recommended to limit ethanol intake. However, little is known on how ethanol affects plasma glucose and how ethanol‐induced hypoglycemia can be prevented. In this study, we systematically reviewed the literature for ethanol effects on plasma glucose and for prevention strategies on ethanol‐induced hypoglycemia. Electronic searches on PubMed and Google were conducted in February 2017. Randomized clinical trials and observational studies were included. Studies involved patients with T1D with no history of ethanol abuse. The primary aims were changes in plasma glucose after ethanol intake and prevention strategies for ethanol‐induced hypoglycemia. Quality of the studies was assessed by GRADE. Additionally, we searched for guidelines from diabetes associations on their suggested prevention strategies. We included 13 studies. Eight studies reported that ethanol, regardless of administration intravenously or orally, were associated with an increased risk of hypoglycemia due to decrease in plasma glucose, impaired counter‐regulatory response, awareness of hypoglycemia, and cognitive function. Five studies did not report an increased risk of hypoglycemia. None of the studies investigated prevention strategies for ethanol‐induced hypoglycemia. Recommendations from 13 diabetes associations were included. All associations recommend that ethanol should only be consumed with food intake. The majority of included studies showed that ethanol intake increased the risk of hypoglycemia in patients with T1D. However, the evidence for how to prevent ethanol‐induced hypoglycemia is sparse, and further investigations are needed to establish evidence‐based recommendations.
Identifying suitable reference genes for developing and injured mouse CNS tissues
Authors: Xu Dongchao , Liu Ajuan , Wang Xuan , Zhang Ming , Zhang Zunyi , Tan Zhou , Qiu Mengsheng
Published: November 2017

Accurate quantification of gene expression is fundamental for understanding the molecular, genetic and functional bases of tissue development and diseases. Quantitative real‐time PCR (qPCR) is now the most widely used method of quantifying gene expression due to its simplicity, specificity, sensitivity, and wide quantification range. The use of appropriate reference genes to ensure accurate normalization is crucial for the correct quantification of gene expression from the early development, maturation, aging to injury processes in the central nervous system (CNS). In this study, we have determined the expression profiles of 12 candidate housekeeping genes (ACTB, CYC1, HMBS, GAPDH, HPRT1, RPL13A, YWHAZ, PPIA, RPLP0, TFRC, GUS, and 18S rRNA) in developing mouse brain and spinal cord. Throughout development, there was a significant degree of fluctuations in their expression levels, indicating the importance and complexity of finding appropriate reference genes. Three software including BestKeeper, geNorm and NormFinder were used to evaluate the stability of potential reference genes. GUS was the most stable gene and GUS/YWHAZ were the most stable reference gene pair across different developmental stages in different CNS regions, whereas HPRT1 and GAPDH were the most variable genes and thus inappropriate to use as reference genes. Therefore, our results identified GUS and YWHAZ as the best combination of two reference genes for expression data normalization in CNS developmental studies. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 39–50, 2018
Direct Metal‐Free C–H Functionalization of Cyclic Ethers with Schiff Bases Through an Azobisisobutyronitrile‐Initiated Radical Chain Process
Authors: Zeng Haipeng , Lu Dengfu , Gong Yuefa
Published: November 2017

The radical‐initiated C–H bond functionalization of cyclic ethers with imines represents an efficient way to form C–C bonds and construct 1,2‐amino ethers. Despite being a net redox‐neutral process, most examples require excess amounts of radical reagents or oxidants to continuously generate the radical species. Herein, we report an atom‐economic protocol for the radical addition of cyclic ethers to imines without the need for any oxidant, metal salt, delicate catalyst, or UV irradiation. In the presence of small amounts of AIBN (2 mol‐%), tetrahydrofuran smoothly undergoes the reaction with a variety of imines to afford 1,2‐amino ethers in moderate to good yields. Preliminary mechanistic studies suggest that this transformation likely proceeds through a radical chain process with the hydrogen atom abstraction as the rate‐determining step.
New Method for Carbohydrates Determination in Sugarcane Bagasse by HPAEC‐RPAD Using Glassy Carbon Electrode Modified with Carbon Nanotubes and Nickel Nanoparticles
Authors: Cardoso de Sá Acelino , Cristina Sedenho Graziela , Paim Leonardo Lataro , Ramos Stradiotto Nelson
Published: November 2017

Second generation ethanol can be produced from carbohydrates released from both sugarcane bagasse cell wall and sugarcane straw. The development of new method for the analysis of carbohydrates is, in this sense, seen as extremely relevant in the area of bioenergy. Based on the above considerations, the scope of this work encompasses the identification and quantification of carbohydrates composition in sugarcane bagasse without the need of sample derivatization, developing a novel analytical method using a glassy carbon electrode modified with multi‐walled carbon nanotubes containing nickel oxyhydroxide nanoparticles (GCE/MWCNT/NiOOH) and applying the modified electrode as a detector in HPAEC (High Performance Anion‐Exchange Chromatography) with reverse pulsed amperometric detection (RPAD) towards the determination of arabinose, galactose, glucose and xylose in hydrolyzed sugarcane bagasse. The carbohydrates concentrations determined in the hydrolyzed sugarcane bagasse were 6.1×10−4 mol L−1, 1.0×10−2 mol L−1 and 2.8×10−3 mol L−1 for arabinose, glucose, and xylose respectively. Our results showed that the present method is, in essence, attractive for analysis in the course of the production process of second generation ethanol production in that it does not require sample derivatization, has rapid run time, satisfactory separation, and can be used for the detection of carbohydrates without the interference of other electroactive species.
Determination of Diazepam and Clonazepam in Natural Water – a Voltammetric Study
Authors: Nogueira Nunes Chalder , Egéa dos Anjos Vanessa , Pércio Quináia Sueli
Published: November 2017

The differential pulse adsorptive cathodic stripping voltammetry (DP‐AdsCSV) employing the hanging mercury drop electrode (HMDE) was used towards the determination of two psychotropic drugs in environmental samples. Voltammetric and experimental conditions to Clonazepam (CLO) and diazepam (DIAZ) were optimized and the methods were in‐house validated. Accumulation potentials were −0.3 V to CLO and −0.6 V to DIAZ at 120 s of accumulation time. Pulse amplitude, pulse time and scan rate were 80 mV, 20 ms and 25 mV s−1 to CLO and 100 mV, 20 ms and 40 mV s−1 to DIAZ, respectively. Recovery tests were done in three different concentrations to evaluate methods’ accuracy and the results were from 88±6 to 120±13 %. In precision tests, standard deviations were lower than 15 % for both methods. Goods limits of quantification 0.65 and 0.27 μg L−1 to CLO and DIAZ respectively were achieved without pre‐concentration steps such as SPE, etc. Voltammetry employing HMDE was first used for the determination of CLO and DIAZ in natural water. Natural samples were spiked and recovery tests confirmed the applicability of the methods developed. Nine samples from Parana state, Brazil, were analyzed and CLO and DIAZ values were below the limits of detection in all samples.
Stripping Voltammetric Determination of Mercury in Fish Oil Capsules Using a Screen‐printed Gold Electrode
Authors: Squissato André L. , Rocha Diego P. , Almeida Eduardo S. , Richter Eduardo M. , Munoz Rodrigo A. A.
Published: November 2017

This work presents a simple electrochemical method for Hg determination in fish oil capsules using anodic stripping voltammetry (ASV) on a screen‐printed gold electrode (SPGE). Samples were treated in an ultrasonic bath for 15 min in the presence of a 1 : 1 (v/v) concentrated HCl/H2O2 mixture at room temperature. The limit of detection (LOD) was estimated as 0.25 μg L−1 (corresponding to 7.6 μg kg−1 of oil) with a linear range between 5 and 400 μg L−1 (90 s of deposition time). The analyzed fish oil samples presented Hg concentration below the LOD value. Recovery values for samples spiked with oil standard containing Hg ranged from 95 to 105 %. The method is precise (inter‐day and intra‐day RSD<4 % for n=3) as well as the SPGE sensors (RSD=4.3 %, n=3), which were used continuously (around 100 analyses without replacement) under such oxidation media. The proposed method is feasible to be applied for on‐site determinations due to the portability of sensing and sample treatment approaches.
Does the design of spot markets matter for the success of futures markets? Evidence from dairy futures
Authors: Białkowski Jędrzej , Koeman Jan
Published: November 2017

This study provides evidence of the importance of a well‐defined and functioning spot market for the success of the associated futures market. Our analysis of hedging effectiveness and hedge ratio persistence shows that none of the United States (US) spot market indices may be hedged effectively with the Chicago Mercantile Exchange nonfat dry milk futures at short hedging horizons, whereas the New Zealand (NZ) Stock Exchange whole milk powder futures contract is an effective hedge for the Global Dairy Trade spot pricing benchmark. Four important dimensions of spot market design are identified—timeliness, market‐based measurement, forward‐spot separation, and inclusiveness.
An ERCC4 regulatory variant predicts grade‐3 or ‐4 toxicities in patients with advanced non‐small cell lung cancer treated by platinum‐based therapy
Authors: Zhang Ruoxin , Jia Ming , Xu Yuan , Qian Danwen , Wang Mengyun , Zhu Meiling , Sun Menghong , Chang Jianhua , Wei Qingyi
Published: November 2017

Platinum‐based chemotherapy (PBC) in combination with the 3rd generation drugs is the first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3–4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum‐induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two‐phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR)adj=1.61 and 2.35, 95% confidence interval (CI)=1.11–2.33 and 1.25–4.41, and Padj=0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57–0.65 vs. 0.55–0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment.
Cucurbit[n]urils‐related Multitopic Supramolecular Components: Design, Properties, and Perspectives
Authors: Vícha Robert , Jelínková Kristýna , Rouchal Michal
Published: November 2017

Cucurbit[n]urils (CBns) are an intriguing family of macrocyclic hosts whose chemistry has undergone rapid developments in recent decades. The initial interest in the synthesis, modifications and binding properties has shifted to areas focused on applications in drug storage, delivery, and release, external‐stimuli responsive devices, and molecular nano‐reactors. Since CBns are fruitfully complemented by cyclodextrins (CDs) in such systems, guest molecules that contain several binding sites are needed. These multitopic guests provide not only a scaffold for holding CBns and CDs together in appropriate arrangements but also allow for manipulation with supramolecular aggregates, e. g., reorganization or release of macrocycles. In this review, we summarize recent studies related to the design of multitopic guests. Binding motifs properties, the role of attractive or repulsive lateral interactions, the competition‐compensation effect, and rotaxane versus pseudorotaxane manner are discussed.
A safety and immunogenicity study of a novel subunit plague vaccine in cynomolgus macaques
Authors: Liu Li , Wei Dong , Qu Zhe , Sun Li , Miao Yufa , Yang Yanwei , Lu Jinbiao , Du Weixin , Wang Bingxiang , Li Bo
Published: November 2017

Plague has led to millions of deaths in history and outbreaks continue to the present day. The efficacy limitations and safety concerns of the existing killed whole cell and live‐attenuated vaccines call for the development of new vaccines. In this study, we evaluated the immunogenicity and safety of a novel subunit plague vaccine, comprising native F1 antigen and recombinant V antigen. The cynomolgus macaques in low‐ and high‐dose vaccine groups were vaccinated at weeks 0, 2, 4 and 6, at dose levels of 15 μg F1 + 15 μg rV and 30 μg F1 + 30 μg rV respectively. Specific antibodies and interferon‐γ and interleukin‐2 expression in lymphocytes were measured. For safety, except for the general toxicity and local irritation, we made a systematic immunotoxicity study on the vaccine including immunostimulation, autoimmunity and anaphylactic reaction. The vaccine induced high levels of serum anti‐F1 and anti‐rV antibodies, and caused small increases of interferon‐γ and interleukin‐2 in monkeys. The vaccination led to a reversible increase in the number of peripheral blood eosinophils, the increases in serum IgE level in a few animals and histopathological change of granulomas at injection sites. The vaccine had no impact on general conditions, most clinical pathology parameters, percentages of T‐cell subsets, organ weights and gross pathology of treated monkeys and had passable local tolerance. The F1 + rV subunit plague vaccine can induce very strong humoral immunity and low level of cellular immunity in cynomolgus macaques and has a good safety profile.
Quantum crystallography: A perspective
Authors: Massa Lou , Matta Chérif F.
Published: November 2017

Extraction of the complete quantum mechanics from X‐ray scattering data is the ultimate goal of quantum crystallography. This article delivers a perspective for that possibility. It is desirable to have a method for the conversion of X‐ray diffraction data into an electron density that reflects the antisymmetry of anN‐electron wave function. A formalism for this was developed early on for the determination of a constrained idempotent one‐body density matrix. The formalism ensures pure‐stateN‐representability in the single determinant sense. Applications to crystals show that quantum mechanical density matrices of large molecules can be extracted from X‐ray scattering data by implementing a fragmentation method termed the kernel energy method (KEM). It is shown how KEM can be used within the context of quantum crystallography to derive quantum mechanical properties of biological molecules (with low data‐to‐parameters ratio). © 2017 Wiley Periodicals, Inc.
Implementation and performance of the artificial force induced reaction method in the GRRM17 program
Authors: Maeda Satoshi , Harabuchi Yu , Takagi Makito , Saita Kenichiro , Suzuki Kimichi , Ichino Tomoya , Sumiya Yosuke , Sugiyama Kanami , Ono Yuriko
Published: November 2017

This article reports implementation and performance of the artificial force induced reaction (AFIR) method in the upcoming 2017 version of GRRM program (GRRM17). The AFIR method, which is one of automated reaction path search methods, induces geometrical deformations in a system by pushing or pulling fragments defined in the system by an artificial force. In GRRM17, three different algorithms, that is, multicomponent algorithm (MC‐AFIR), single‐component algorithm (SC‐AFIR), and double‐sphere algorithm (DS‐AFIR), are available, where the MC‐AFIR was the only algorithm which has been available in the previous 2014 version. The MC‐AFIR does automated sampling of reaction pathways between two or more reactant molecules. The SC‐AFIR performs automated generation of global or semiglobal reaction path network. The DS‐AFIR finds a single path between given two structures. Exploration of minimum energy structures within the hypersurface in which two different electronic states degenerate, and an interface with the quantum mechanics/molecular mechanics method, are also described. A code termed SAFIRE will also be available, as a visualization software for complicated reaction path networks. © 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
Population PK Analyses of Ubrogepant (MK‐1602), a CGRP Receptor Antagonist: Enriching In‐Clinic Plasma PK Sampling With Outpatient Dried Blood Spot Sampling
Authors: Li Chi‐Chung , Dockendorf Marissa , Kowalski Ken , Yang Bei , Xu Yang , Xie Iris , Kleijn Huub Jan , Bosch Rolien , Jones Christopher , Thornton Bob , Marcantonio Eugene E. , Voss Tiffini , Bateman Kevin P. , Kothare Prajakti A.
Published: November 2017

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late‐stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late‐stage clinical program: ubrogepant (MK‐1602), a novel oral calcitonin gene‐related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure–response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.
Covering 2‐connected 3‐regular graphs with disjoint paths
Authors: Yu Gexin
Published: November 2017

A path cover of a graph is a set of disjoint paths so that every vertex in the graph is contained in one of the paths. The path cover numberof graphGis the cardinality of a path cover with the minimum number of paths. Reed in 1996 conjectured that a 2‐connected 3‐regular graph has path cover number at most. In this article, we confirm this conjecture.
Prostate cancer detection using quantitative T2 and T2‐weighted imaging: The effects of 5‐alpha‐reductase inhibitors in men on active surveillance
Authors: Giganti Francesco , Gambarota Giulio , Moore Caroline M. , Robertson Nicola L. , McCartan Neil , Jameson Charles , Bott Simon R.J. , Winkler Mathias , Whitcher Brandon , Castro‐Santamaria Ramiro , Emberton Mark , Allen Clare , Kirkham Alex
Published: November 2017

Background

T2‐weighted imaging (T2‐WI) information has been used in a qualitative manner in the assessment of prostate cancer. Quantitative derivatives (T2 relaxation time) can be generated from T2‐WI. These outputs may be useful in helping to discriminate clinically significant prostate cancer from background signal.

Purpose/Hypothesis

To investigate changes in quantitative T2 parameters in lesions and noncancerous tissue of men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo daily for 6 months.

Study Type

Retrospective.

Population/Subjects

Forty men randomized to 6 months of daily dutasteride (n = 20) or placebo (n = 20).

Field Strength/Sequence

Multiparametric 3T MRI at baseline and 6 months. This included a multiecho MR sequence for quantification of the T2 relaxation times, in three regions of interest (index lesion, noncancerous peripheral [PZ] and transitional [TZ] zones). A synthetic signal contrast (T2Q contrast) between lesion and noncancerous tissue was assessed using quantitative T2 values. Signal contrast was calculated using the T2‐weighted sequence (T2W contrast).

Assessment

Two radiologists reviewed the scans in consensus according to Prostate Imaging Reporting and Data System (PI‐RADS v. 2) guidelines.

Statistical Tests

Wilcoxon and Mann–Whitney U‐tests, Spearman's correlation.

Results

When compared to noncancerous tissue, shorter T2 values were observed within lesions at baseline (83.5 and 80.5 msec) and 6 months (81.5 and 81.9 msec) in the placebo and dutasteride arm, respectively. No significant differences for T2W contrast at baseline and after 6 months were observed, both in the placebo (0.40 [0.29–0.49] vs. 0.43 [0.25–0.49]; P = 0.881) and dutasteride arm (0.35 [0.24–0.47] vs. 0.37 [0.22–0.44]; P = 0.668). There was a significant, positive correlation between the T2Q contrast and the T2W contrast values (r = 0.786; P < 0.001).

Data Conclusion

The exposure to antiandrogen therapy did not significantly influence the T2 contrast or the T2 relaxation values in men on active surveillance for prostate cancer.

Level of Evidence: 4

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018;47:1646–1653.
Effect of sample size and resolution on palaeomalacological interpretation: a case study from Holocene calcareous‐fen deposits
Authors: Frodlová Jitka , Hájková Petra , Horsák Michal
Published: November 2017

This study investigates the effects of sample volume, resolution and accumulation time on the interpretation of a mollusc record from terrestrial deposits. We tested (i) if, and to what extent, small sample sizes impoverish the reconstructed mollusc species richness, and (ii) whether fine‐resolution sampling is worth the effort. We analysed three mollusc sequences, covering continuously the entire Holocene, which were collected in a tufa‐forming spring fen and differed in sample size and resolution. More than 36 000 specimens of 76 species were processed. Using a rarefaction method, we observed that different sample volumes had a significant effect on the recorded species richness in this type of environment, and 100‐cm3 samples seemed to be sufficient for a reliable reconstruction in tufa deposits. Although the thickness of the sampled layers had no influence on the palaeoecological interpretation, we observed a shift in the mollusc diversity peak once different resolutions were applied. Furthermore, the layers of finer resolution allowed detailed radiocarbon dating and better understanding of trends in species dynamics. We also observed significant confounding relationships among the number of species, number of specimens and accumulation time that can be disentangled if a precise depth–age model is available.
Rapid determination of ginkgolic acids in Ginkgo biloba kernels and leaves by direct analysis in real time‐mass spectrometry
Authors: Huang Zhongping , Xu Yueting , Huang Yilei , Liu Charles , Jiang Kezhi , Wang Lili
Published: November 2017

A novel method based on direct analysis in real time integrated with mass spectrometry was established and applied into rapid determination of ginkgolic acids in Ginkgo biloba kernels and leaves. Instrument parameter settings were optimized to obtain the sensitive and accurate determination of ginkgolic acids. At the sample introduction speed of 0.2 mm/s, high intensity of [M–H]– ions for ginkgolic acids were observed in the negative ion mode by utilization of high‐purity helium gas at 450°C. Two microliters of methanol extract of G. biloba kernels or leaves dropped on the surface of Quick‐Strip module was analyzed after solvent evaporated to dryness. A series of standard solutions of ginkgolic acid 13:0 in the range of 2–50 mg/L were analyzed with a correlation coefficient r = 0.9981 and relative standard deviation (n = 5) from 12.5 to 13.7%. The limit of detection was 0.5 mg/L. The results of direct analysis in real time‐mass spectrometry were in agreement with those observed by thermochemolysis gas chromatography. The proposed method demonstrated significant potential in the application of the high‐throughput screening and rapid analysis for ginkgolic acids in dietary supplements.
Qualitative analysis of flavors and fragrances added to tea by using GC–MS
Authors: Wang Jianwu , Hang Yuanxin , Yan Tingting , Liang Jiahui , Huang Zhiqiang , Xu Huilan
Published: November 2017

A precise identification method was developed to identify the flavors and fragrances added to tea matrix artificially using gas chromatography with mass spectrometry and gas chromatography with quadrupole time‐of‐flight mass spectrometry. The proposed method was based on the corresponding “three‐column retention indices, two exact mass numbers, one mass spectrum matching degree” database of 40 kinds of common flavors and fragrances. The intraday and the interday relative standard deviation of the retention indices were less than 0.048 and 0.093%, respectively. The accuracy of exact mass was between 0.15 and 6.22 ppm. And the validation of the created database was performed by analyzing the tea samples. Thus, the proposed method is suitable for the precise identification of the flavors and fragrances added to tea matrix artificially without standard substances as a reference.
Nonconventional Fluorescent Polynorbornenes Bearing Aminosuccinimide Side Groups
Authors: Xu Jing , Luo Dan , Yin Xianze , Zhang Hongwei , Wang Luoxin , Wang Hua
Published: November 2017

In this contribution, a new class of fluorescent polynorbornenes containing side chains that homogeneously decorated with aminosuccinimide side groups as nonconventional chromophores is introduced. First of all, monomers M1–M3 are synthesized in an efficient and straightforward fashion by means of Michael addition between three kinds of alkyl amines and monomer precursor 1, a compound containing norbornene (polymerizable group) and maleimide (Michael acceptor) groups. Subsequently, ring‐opening metathesis polymerization of M1–M3 is conducted to generate polymers P1–P3 with high molecular weights (Mn values exceeding 9800) and narrow molecular weight distributions (Ð values no more than 1.20), respectively. Quantitative conversion of monomers and microstructural integrity of polymers are verified in all cases. Finally, thermal stability, glass transition behavior, wettability, and optical properties of polymers P1–P3 are investigated. In particular, this new class of fluorescent polymeric materials exhibits blue emission (470–478 nm) under UV irradiation with large Stokes shifts (over 110 nm).
Elements of Effective Employee Relations
Authors: DeMaria Alfred T.
Published: November 2017

The corporate culture is the way an organization conducts its business. That culture is reflected in its policies and procedures, compensation arrangements, business values and ethics, customer service, reputation, traditions, history, and style of management.
Experimental validation of two dual‐energy CT methods for proton therapy using heterogeneous tissue samples
Authors: Bär Esther , Lalonde Arthur , Zhang Rongxiao , Jee Kyung‐Wook , Yang Kai , Sharp Gregory , Liu Bob , Royle Gary , Bouchard Hugo , Lu Hsiao‐Ming
Published: November 2017

Purpose

The purpose of this work is to evaluate the performance of dual‐energy CT (DECT) for determining proton stopping power ratios (SPRs) in an experimental environment and to demonstrate its potential advantages over conventional single‐energy CT (SECT) in clinical conditions.

Methods

Water equivalent range (WER) measurements of 12 tissue‐equivalent plastic materials and 12 fresh animal tissue samples are performed in a 195 MeV broad proton beam using the dose extinction method. SECT and DECT scans of the samples are performed with a dual‐source CT scanner (Siemens SOMATOM Definition Flash). The methods of Schneider et al. (1996), Bourque et al. (2014), and Lalonde et al. (2017) are used to predict proton SPR on SECT and DECT images. From predicted SPR values, the WER of the proton beam through the sample is predicted for SECT and DECT using Monte Carlo simulations and compared to the measured WER.

Results

For homogeneous tissue‐equivalent plastic materials, results with DECT are consistent with experimental measurements and show a systematic reduction of SPR uncertainty compared to SECT, with root‐mean‐square errors of 1.59% versus 0.61% for SECT and DECT, respectively. Measurements with heterogeneous animal samples show a clear reduction of the bias on range predictions in the presence of bones, with −0.88% for SECT versus −0.58% and −0.14% for both DECT methods. An uncertainty budget allows isolating the effect of CT number conversion to SPR and predicts improvements by DECT over SECT consistently with theoretical predictions, with 0.34% and 0.31% for soft tissues and bones in the experimental setup compared to 0.34% and 1.14% with the theoretical method.

Conclusions

The present work uses experimental measurements in a realistic clinical environment to show potential benefits of DECT for proton therapy treatment planning. Our results show clear improvements over SECT in tissue‐equivalent plastic materials and animal tissues. Further work towards using Monte Carlo simulations for treatment planning with DECT data and a more detailed investigation of the uncertainties on I‐value and limitations on the Bragg additivity rule could potentially further enhance the benefits of this imaging technology for proton therapy.
Selective proton‐observed, carbon‐edited (selPOCE) MRS method for measurement of glutamate and glutamine 13C‐labeling in the human frontal cortex
Authors: De Feyter Henk M. , Herzog Raimund I. , Steensma Bart R. , Klomp Dennis W.J. , Brown Peter B. , Mason Graeme F. , Rothman Douglas L. , de Graaf Robin A.
Published: November 2017

Purpose

13C magnetic resonance spectroscopy (MRS) in combination with infusion of 13C‐labeled substrates has led to unique insights into human brain metabolism and neurotransmitter cycling. However, the low sensitivity of direct 13C MRS and high radiofrequency power requirements has limited 13C MRS studies to predominantly data acquisition in large volumes of the occipital cortex. The purpose of this study is to develop an MRS technique for localized detection of 13C‐labeling of glutamate and glutamine in the human frontal lobe.

Methods

We used an indirect (1H‐[13C]), proton‐observed, carbon‐edited MRS sequence (selPOCE) for detection of 13C‐labeled metabolites in relatively small volumes located in the frontal lobe at 4 T. The SelPOCE method allows for selective and separate detection of glutamate and glutamine resonances, which significantly overlap at magnetic field strengths used for clinical MRI.

Results

Phantom data illustrate how selPOCE can be tuned to selectively detect 13C labeling in different metabolites. Three‐dimensional specific absorption rate simulations of radiofrequency power deposition show that the selPOCE method operates comfortably within the global and local Food and Drug Administration specific absorption rate guidelines. In vivo selPOCE data are presented, which were acquired from a 45‐mL volume in the frontal lobe of healthy subjects. The in vivo data show the time‐dependent 13C‐labeling of glutamate and glutamine during intravenous infusion of [1‐13C]‐glucose. Metrics describing spectral fitting quality of the glutamate and glutamine resonances are reported.

Conclusions

The SelPOCE sequence allows the detection of 13C‐labeling in glutamate and glutamine from a relatively small volume in the human frontal lobe at low radiofrequency power requirements. Magn Reson Med 80:11–20, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Advances in computational and statistical diffusion MRI
Authors: O'Donnell Lauren J. , Daducci Alessandro , Wassermann Demian , Lenglet Christophe
Published: November 2017

Computational methods are crucial for the analysis of diffusion magnetic resonance imaging (MRI) of the brain. Computational diffusion MRI can provide rich information at many size scales, including local microstructure measures such as diffusion anisotropies or apparent axon diameters, whole‐brain connectivity information that describes the brain's wiring diagram and population‐based studies in health and disease. Many of the diffusion MRI analyses performed today were not possible five, ten or twenty years ago, due to the requirements for large amounts of computer memory or processor time. In addition, mathematical frameworks had to be developed or adapted from other fields to create new ways to analyze diffusion MRI data. The purpose of this review is to highlight recent computational and statistical advances in diffusion MRI and to put these advances into context by comparison with the more traditional computational methods that are in popular clinical and scientific use. We aim to provide a high‐level overview of interest to diffusion MRI researchers, with a more in‐depth treatment to illustrate selected computational advances.
Efficient time stepping for the multiplicative Maxwell fluid including the Mooney‐Rivlin hyperelasticity
Authors: Shutov A. V.
Published: November 2017

A popular version of the finite‐strain Maxwell fluid is considered, which is based on the multiplicative decomposition of the deformation gradient tensor. The model combines Newtonian viscosity with hyperelasticity of the Mooney‐Rivlin type; it is a special case of the viscoplasticity model proposed by Simo and Miehe in 1992. A simple, efficient, and robust implicit time‐stepping procedure is suggested. Lagrangian and Eulerian versions of the algorithm are available, with equivalent properties. The numerical scheme is iteration free, unconditionally stable, and first order accurate. It exactly preserves the inelastic incompressibility, symmetry, and positive definiteness of the internal variables and w‐invariance. The accuracy of the stress computations is tested using a series of numerical simulations involving a nonproportional loading and large strain increments. In terms of accuracy, the proposed algorithm is equivalent to the modified Euler backward method with exact inelastic incompressibility; the proposed method is also equivalent to the classical integration method based on exponential mapping. Since the new method is iteration free, it is more robust and computationally efficient. The algorithm is implemented into MSC.MARC, and a series of initial boundary value problems is solved to demonstrate the usability of the numerical procedures.