bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of a physiologically‐based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate
Authors: Donovan Maria D. , Abduljalil Khaled , Cryan John F. , Boylan Geraldine B. , Griffin Brendan T.
Published: January 2018

Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.
Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes
Authors: Algeelani Sara , Alkhelb Dalal , Greenblatt David J.
Published: January 2018

Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co‐administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non‐steroidal anti‐inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC50 value of 88 μm, compared to chlorpropamide and gliclazide with IC50 values of more than 500 μm. Diclofenac inhibited M5 metabolite formation more than M7, with IC50 values of 32 μm for M5 and 80 μm for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalysed by UGT1A9, with an IC50 value of 1.9 μm and an inhibition constant value of 0.8 μm. A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified.
Detection and Selection Decisions with Conditional Feedback: Interaction of Task Uncertainty and Base Rate
Authors: Holzworth Robert James , Stewart Thomas R. , Mumpower Jeryl L.
Published: January 2018

Effects of task uncertainty on decision thresholds in a multiple cue decision task were examined under two types of feedback and three base rate conditions. In most such decision experiments, participants receive feedback after every trial (full feedback) with a single (usually .5) base rate. Our experiment explored conditional (decision‐contingent) feedback, in a task representing a detection problem (passenger screening) in which the decision maker receives no feedback unless the decision is positive (search the passenger). Increased uncertainty made all dependent measures worse. Task uncertainty had detrimental effects on both judgment and decision making, and interacted with effects of feedback and base rate. Decision performance was better with full feedback than with conditional feedback, but not by much. There may be no single unifying explanation for results of our base rate manipulation. Conditional feedback generally resulted in fewer positive decisions than full feedback, but not in the low (.1) base rate condition. Results provide partial support for constructivist encoding and for accuracy maximization with moderate and high base rates, but not with a low base rate. Our results indicated lower selection rates with conditional feedback compared with full feedback in moderate and high base rate conditions, and a more exploratory strategy with higher selection rates with conditional feedback compared with full feedback when base rate was low. Copyright © 2018 John Wiley & Sons, Ltd.
Glycoengineering in CHO Cells: Advances in Systems Biology
Authors: Tejwani Vijay , Andersen Mikael R. , Nam Jong Hyun , Sharfstein Susan T.
Published: January 2018

For several decades, glycoprotein biologics have been successfully produced from Chinese hamster ovary (CHO) cells. The therapeutic efficacy and potency of glycoprotein biologics are often dictated by their post‐translational modifications, particularly glycosylation, which unlike protein synthesis, is a non‐templated process. Consequently, both native and recombinant glycoprotein production generate heterogeneous mixtures containing variable amounts of different glycoforms. Stability, potency, plasma half‐life, and immunogenicity of the glycoprotein biologic are directly influenced by the glycoforms. Recently, CHO cells have also been explored for production of therapeutic glycosaminoglycans (e.g., heparin), which presents similar challenges as producing glycoproteins biologics. Approaches to controlling heterogeneity in CHO cells and directing the biosynthetic process toward desired glycoforms are not well understood. A systems biology approach combining different technologies is needed for complete understanding of the molecular processes accounting for this variability and to open up new venues in cell line development. In this review, we describe several advances in genetic manipulation, modeling, and glycan and glycoprotein analysis that together will provide new strategies for glycoengineering of CHO cells with desired or enhanced glycosylation capabilities.
Ultra scale‐down approaches to study the centrifugal harvest for viral vaccine production
Authors: Melinek Beatrice J. , Dessoy Sandrine , Wright Bernice , Bracewell Dan G. , Mukhopadhyay Tarit K.
Published: January 2018

Large scale continuous cell‐line cultures promise greater reproducibility and efficacy for the production of influenza vaccines, and adenovirus for gene therapy. This paper seeks to use an existing validated ultra scale‐down tool, which is designed to mimic the commercial scale process environment using only milliliters of material, to provide some initial insight into the performance of the harvest step for these processes. The performance of industrial scale centrifugation and subsequent downstream process units is significantly affected by shear. The properties of these cells, in particular their shear sensitivity, may be changed considerably by production of a viral product, but literature on this is limited to date. In addition, the scale‐down tool used here has not previously been applied to the clarification of virus production processes. The results indicate that virus infected cells do not actually show any increase in sensitivity to shear, and may indeed become less shear sensitive, in a similar manner to that previously observed in old or dead cell cultures. Clarification may be most significantly dependent on the virus release mechanism, with the budding influenza virus producing a much greater decrease in clarification than the lytic, non‐enveloped adenovirus. A good match was also demonstrated to the industrial scale performance in terms of clarification, protein release, and impurity profile.
Isotype dependent on‐column non‐reversible aggregation of monoclonal antibodies
Authors: Farys Monika , Gibson Daniel , Lewis Alan P. , Lewis Will , Kucia‐Tran Richard
Published: January 2018

Monoclonal antibodies of the IgG2 and IgG4 isotype were found to exhibit an increased propensity for displaying two‐peak elution profiles during cation exchange chromatography. In some cases, this two‐peak elution profile also resulted in the formation of non‐reversible mAb aggregates. Comparison of IgG1, IgG2, and IgG4 molecules with the same variable region reveals that the two‐peak behaviour is predominantly mediated by the constant region and most likely the lower CH1, hinge and upper CH2 regions of the mAb. Furthermore, comparison of the behaviour of two different IgG4 molecules, reveals that the degree of non‐reversible aggregate formation, whilst facilitated by the isotype format, is mediated primarily by the variable region of the molecule. As well as the properties of the mAb molecule itself, the chemistry and structure of the cation exchange resin was also found to have an effect, with the two‐peak elution profile being more pronounced with polymer‐grafted resins such as Capto S Impact and Eshmuno CPX. These results combined support the theory that binding of IgG2 and IgG4 mAbs to cation exchange resins usually occurs through at least two mechanisms mediated by the structural features of the constant region of IgG2s and IgG4s. One of these mechanisms is not only stronger than the other, but also can lead to a conformational change in the molecule. This conformational change can occur in both variable and constant domains of the antibody. This transitory unfolded state can in turn lead to non‐reversible aggregation of some mAb molecules.
An MS excel add‐in for teaching hydraulics of pipe flow in engineering curricula
Authors: Demir Selami , Duman Selin , Manav Demir Neslihan , Karadeniz Aykut , Lubura Edin
Published: January 2018

This paper presents implementation of an MS Excel add‐in incorporating Visual Basic for Applications for teaching pipe flow calculations in undergraduate and graduate level. The add‐in contains a total of 108 functions for several purposes ranging from continuity equation to branching pipes and pipe network problems. Tip texts and a number of userforms were developed for easy use of the tool. A user's guide was also prepared that includes the theory of hydraulic calculations and numerical methods involved. Being an add‐in for MS Excel, the tool is a perfect candidate for implementing as an educational tool in undergraduate and graduate level education.
Competency‐based education: Recent policy trends
Authors: Anderson Lexi
Published: January 2018

Background

The student population on college campuses continues to evolve, including an influx of adult learners. With the specific needs of this student population, states and institutions must assess the current learning environment and explore alternative pathways to earning a credential, including competency‐based education (CBE). This article provides an overview of recent legislation and policy activity regarding CBE. Institution examples are presented as well as policy considerations for policymakers and institutions to keep top of mind when exploring CBE programs.

Materials & Methods

Policies explored were pulled from a databased housed at Education Commission of the States (ECS). ECS began tracking specific higher education policies in 2014, hence this article covers CBE policies beginning that year. The author reviewed introduced and enacted legislation from 2014 to 2017. The author also reviewed institution examples of CBE programs not set in legislation.

Results

2014 and 2015 saw four states introduce CBE legislation with two bills ultimately being enacted. In 2016, three states considered CBE bills, one of which was enacted. At least five states considered CBE bills in 2017, ultimately seeing three of those enacted. In addition to legislative activity, many institutions implement CBE on their campuses without policy. The article highlights three including Western Governors University, the University of Wisconsin Flex option, and Davis Technical College. Policy and practice considerations include:

Institutions should consider moving away from a credentialing approach to an instructional approach;

States need to modernize state financial aid policies to allow students to utilize state funds for CBE programs;

Institutions offering CBE should support students and enhance the educational experience by providing coaches or mentors to navigate both academic rigor and administrative tasks; and

Coordinate efforts between institutions and industry leaders.

Conclusion

As this article highlights, CBE policies in states and at institutions are at various levels of sophistication. Many states are continuing to explore CBE through expert committees, research, and legislative action. With the ever‐increasing number of adult learners coming to campuses, states and institutions need to assess the needs of their student populations and how CBE could benefit all students. A change to the instructional model in postsecondary education can increase completion rates and help states ultimately reach their lofty attainment goals.
Analysis of the Quaternary Structure of Hemoglobin Beckman Variant and Molecular Interpretation of Its Functional Abnormality: A Mass‐Spectrometry‐Based Approach
Authors: Muralidharan Monita , Das Rajdeep , Bhat Vijay , Mandal Amit Kumar
Published: January 2018

Electrostatic attraction between α and β globin chains holds the subunits together in a tetrameric human hemoglobin molecule (α2β2). Compared to normal globin chains, the affinity of a mutant chain to its partner globin might be different in genetic variants of hemoglobin. This leads to an unequal abundance of normal and variant hemoglobin in heterozygous samples, even though the rates of synthesis of both the normal and variant chains are the same. The aforementioned affinities across various globin chains might be assessed by quantification of the different forms of the tetramers present in a variant hemoglobin sample. In the present study, by exploiting mass differences between globin chains, differently populated hemoglobin tetramers present in hemoglobin (Hb) Beckman, a β variant (βA135D), were structurally characterized. The relative populations of dissymmetric tetramers (α2β2, α2ββV, and α2βV2) indicated that both β and βV have different affinities towards the α globin chain. Conformational dynamics analyzed from hydrogen/deuterium exchange kinetics of the three peptide fragments of Hb Beckman in its oxy state displayed molecular insight into its functional abnormality. However, in comparison to normal hemoglobin (α2β2), the point mutation did not show any change in the collision cross‐sections of the functionally active conformers of the variant hemoglobin molecules (α2ββV and α2βV2).
Plant breeding innovation: A global regulatory perspective
Authors: Atanassova Ana , Keiper Felicity
Published: January 2018

Background and objectives

While there has been continued improvement and increasing accessibility of enabling biotechnological tools, their ultimate deployment and range of applications in support of plant breeding will largely depend on how the resulting products are regulated and the extent of premarket assessment required. The features of GMO regulatory systems throughout the world are reviewed, with a focus on recent developments aimed at clarifying their application to biotechnological tools used for targeted mutagenesis and transfer of genetic material between crossable species.

Findings

To date, regulatory clarity for biotechnological innovations in plant breeding is limited to a small number of countries; the few countries with product‐based regulatory systems are generally able to continue using exiting regulatory provisions, and others have provided timely solutions that can result in the exclusion of some types of plant products from the scope of GMO regulations. However, the majority of countries are yet to take decisions on the topic. Their challenge is to achieve proportionate risk regulation for products developed using recent biotechnological tools that can result in a range of products, from transgenic plants to plants that are indistinguishable from conventionally bred plants.

Conclusions

The challenges for providing clarity on the regulation of plant breeding innovations are strongly linked to the features of the existing GMO regulations. Countries that regulate product risks are better equipped to adapt to technological change; conversely, countries that use process‐based regulatory triggers face the challenge of continuously adjusting to technological development and will lag behind unless they can timely develop criteria for regulatory exclusions. As a consequence of these different approaches, adopters of plant breeding innovations are faced with an uncertain and complex global regulatory situation that is unlikely to be resolved in the near future.

Significance and novelty

This review of the global regulatory status of plant breeding innovations demonstrates that to date, few countries have provided regulatory clarity. However, regulatory clarity, including consistent and predictable legislation with clear scope, triggers, and technical criteria, is required to facilitate technology adoption. The current uncertain and complex global regulatory situation is stifling innovation and the realization of the full potential of these technologies.
Effects of xanthan and guar gums on starch digestibility and texture of rice flour blend bread
Authors: Sasaki Tomoko
Published: January 2018

Background and objectives

The effects of adding xanthan and guar gums on starch digestibility and textural properties were examined in rice and wheat flour blend breads.

Findings

The addition of xanthan gum to the bread formula had a high impact on the staling of the crumb compared with guar gum. The addition of gums suppressed the recovery of the crumb after compression. The extent of starch digestion of the bread crumb was determined by an in vitro method using two types of bread crumb samples, milled samples after freeze‐drying and ground samples after moistening. Starch digestibility of the bread crumb reduced after the addition of gums. Xanthan gum resulted in a more pronounced suppressive effect, which was concentration‐dependent. The addition of xanthan gum at concentrations ≥1% to the bread formula caused a significant decrease in the extent of starch digestion in both the samples.

Conclusions

The bread crumb containing xanthan gum had a dense structure and formed an agglomeration after grinding, resulting in delayed enzyme penetration into the crumb structure and thus delayed the enzymatic hydrolysis of starch.

Significance and novelty

Addition of xanthan gum to the formula of rice and wheat flour blend breads significantly retards the starch digestibility of bread crumb.
Evaluation of commercial α‐amylase enzyme‐linked immunosorbent assay (ELISA) test kits for wheat
Authors: Kiszonas Alecia M. , Morris Craig F.
Published: January 2018

Background and objectives

There are few methods in wheat to directly measure α‐amylase, which is the result of preharvest sprouting (PHS) and late maturity α‐amylase (LMA). Both of these conditions are associated with reduced wheat and flour quality. Those methods that do exist for measuring α‐amylase in wheat are based on enzyme activity. The objective of this study was to evaluate commercially available enzyme‐linked immunosorbent assay (ELISA) kits on sound grain, sprouted grain, and grain that had both PHS and LMA.

Findings

Three kits were evaluated; human AMY1 and AMY2, and a “plant α‐amylase” kit. The wheat samples were also assayed for α‐amylase activity using the Megazyme SD α‐amylase method. All three ELISA kits functioned very well based on calibration curves (R2 > .99). Of the three, the AMY1 and plant α‐amylase kits appeared to show no useful detection of wheat α‐amylase. The AMY2 kit, however, detected a 2.7‐fold increase in α‐amylase protein in the PHS and PHS/LMA grain lots, similar to a 2.7‐fold difference in activity.

Conclusions

It appears that the particular human AMY2A ELISA kit, and perhaps others, can detect α‐amylase in wheat and may be a useful alternative technology to enzyme kits. These kits may also be useful in predicting PHS and LMA potential damage.

Significance and novelty

Thus far, α‐amylase studies have focused on enzyme kits, whereas this study examined three commercially available ELISA kits to measure α‐amylase content in sound, sprouted, and PHS/LMA grain. Both PHS and LMA are highly detrimental to grain and result in low prices paid to growers.
Effects of Solute Permeability on Permeation and Solute Rejection in Membrane Filtration
Authors: Lopes Gustavo H. , Ibaseta Nelson , Guichardon Pierrette , Haldenwang Pierre
Published: January 2018

Membrane solute permeability plays a role in the buildup of concentration polarization in pressure‐driven crossflow filtration processes, and thus in the determination of the permeate flux, solute rejection, retentate flux, and concentration. Reverse‐osmosis desalination with membranes of fixed solvent permeability but of variable selectivity with respect to the solute is numerically examined. The study highlights an intricate coupling between retentate and filtrate properties. In particular, it reveals that, for given values of solute permeability and feed concentration, there is a maximum operating pressure that optimizes solute rejection regardless of the feed salinity. The conditions leading to this and to other peculiar behaviors for permeation fluxes and concentrations are identified.
Early/Late Heterobimetallic Tantalum/Rhodium Species Assembled Through a Novel Bifunctional NHC‐OH Ligand
Authors: Srivastava Ravi , Moneuse Raphaël , Petit Julien , Pavard Paul‐Alexis , Dardun Vincent , Rivat Madleen , Schiltz Pauline , Solari Marius , Jeanneau Erwann , Veyre Laurent , Thieuleux Chloé , Quadrelli Elsje Alessandra , Camp Clément
Published: January 2018

The straightforward synthesis of a new unsymmetrical hydroxy‐tethered N‐heterocyclic carbene (NHC) ligand, HL, is presented. The free ligand exhibits an unusual OH–carbene hydrogen‐bonding interaction. This OH–carbene motif was used to yield 1) the first tantalum complex displaying both a Fischer‐ and Schrock‐type carbene ligand and 2) a unique NHC‐based early/late heterobimetallic complex. More specifically, the protonolysis chemistry between the ligand's hydroxy group and imido‐alkyl or alkylidene‐alkyl tantalum precursor complexes yielded the rare monometallic tantalum–NHC complexes [Ta(XtBu)(L)(CH2tBu)2] (X=N, CH), in which the alkoxy‐carbene ligand acts as a chelate. In contrast, HL only binds to rhodium through the NHC unit in [Rh(HL)(cod)Cl] (cod=cycloocta‐1,5‐diene), the hydroxy pendant arm remaining unbound. This bifunctional ligand scaffold successfully promoted the assembly of rhodium/tantalum heterobimetallic complexes upon either 1) the insertion of [Rh(cod)Cl]2 into the Ta–NHC bond in [Ta(NtBu)(L)(CH2tBu)2] or 2) protonolysis between the free hydroxy group in [Rh(HL)(cod)Cl] and one alkyl group in [Ta(NtBu)(CH2tBu)3].
Bonding Insights from Structural and Spectroscopic Comparisons of {SnW5} and {TiW5} Alkoxido‐ and Aryloxido‐Substituted Lindqvist Polyoxometalates
Authors: Kandasamy Balamurugan , Bruce Peter G. , Clegg William , Harrington Ross W. , Rodríguez‐Fortea Antonio , Pascual‐Borrás Magda , Errington R. John
Published: January 2018

Incorporation of {MX}n+ groups into polyoxometalates (POMs) provides the means not only to introduce reactivity and functionality but also to tune the electronic properties of the oxide framework by varying M, X and n. In order to elucidate the factors responsible for differences in reactivity between {TiW5} and {SnW5} Lindqvist‐type hexametalates, a series of alkoxido‐ and aryloxido‐tin substituted POMs (nBu4N)3[(RO)SnW5O18] (R=Me, Et, iPr and tBu) and (nBu4N)3[(ArO)SnW5O18] (Ar=C6H5, 4‐MeC6H5, 4‐tBuC6H5, 4‐HOC6H4, 3‐HOC6H4 and 2‐CHOC6H4) has been structurally characterised and studied by multinuclear NMR (1H, 13C, 17O, 119Sn and 183W) and FTIR spectroscopy. Spectroscopic and structural parameters were compared with those of titanium‐substituted homologues and, when coupled with theoretical studies, indicated that Sn−OR and Sn−OAr bonds are ionic with little π‐contribution, whereas Ti−OR and Ti−OAr bonds are more covalent with π‐bonding that is more prevalent for Ti−OR than Ti−OAr. This experimental and theoretical analysis of bonding in a homologous series of reactive POMs is the most extensive and detailed to date, and reveals factors which account for significant differences in reactivity between tin and titanium congeners.
A Well‐Established POM‐based Single‐Crystal Proton‐Conducting Model Incorporating Multiple Weak Interactions
Authors: Cao Xue‐Li , Xie Shuai‐Lei , Li Shun‐Li , Dong Long‐Zhang , Liu Jiang , Liu Xi‐Xi , Wang Wen‐Bin , Su Zhong‐Min , Guan Wei , Lan Ya‐Qian
Published: January 2018

Three new proton conductors with simple structures based on isolated olyoxometalate anions as well as protonated imidazole and benzimidazole, namely, NNU‐6–8, have been successfully prepared by hydrothermal reaction. We could control the number of proton sources by selecting different types and changing the charges of POM anions. The single crystal sample of NNU‐6 along a‐axis shows a highest proton conductivity of 1.91×10−2 S cm−1, which is two and three orders of magnitude higher than that of 2.42×10−4 and 8.90×10−5 S cm−1 along b‐ and c‐axes, respectively, due to the more unobstructed H‐bonding network and stronger π–π stacking between benzimidazole rings as proton‐transferring pathway along a‐axis than that along b and c axes. It is a straightforward model to understand the metaphysical proton‐conducting process, and this is the first time to put forward the idea that π–π stacking could assist proton transfer and be in favor of proton conduction, which has been demonstrated by calculating potential energy surfaces of proton transfer between benzimidazole molecules.
Synergistic Glycosylation as Key to the Chemical Synthesis of an Outer Core Octasaccharide of Helicobacter pylori
Authors: Zou Xiaopeng , Qin Chunjun , Pereira Claney L. , Tian Guangzong , Hu Jing , Seeberger Peter H. , Yin Jian
Published: January 2018

Helicobacter pylori, a widespread gastric bacterial pathogen that infects 90 % of the population in developing countries, causes chronic gastritis, peptic ulcers and gastric cancer. Battling H. pylori infection is a serious challenge due to the increased resistance to antibiotics and the lack of vaccines. The lipopolysaccharide covering the H. pylori cell‐surface outer membrane is an attractive target for the development of a glycoconjugate vaccine. Here, we report a [3+5] convergent synthesis of an outer core octasaccharide of H. pylori employing just three orthogonally protected building blocks. A synergistic glycosylation strategy enables the creation of five pivotal 1,2‐cis‐α‐glucosidic bonds consist of four types of linkages using just three monomers. This strategy can be expanded to many 1,2‐cis‐α‐gluoside‐containing oligosaccharides both in solution and solid phase.
Chiroptical structure‐property relations in cyclo[18]carbon and its in silico hydrogenation products
Authors: Murphy Veronica L. , Farfan Camille , Kahr Bart
Published: January 2018

The anisotropy of the optical activity of cyclo[18]carbon (C18), fully hydrogenated C18 (C18H36), and 26 hydrogenated compounds of intermediate composition, C18H2n, n = 1,2…17, were computed. These compounds were selected because they resemble loops of wire. The maximum gyration for acetylenic and cumulenic subgroups of compounds was linearly proportional to the product of the geometric area over which the charge can circulate, multiplied by the largest separation between carbon atoms on opposing sides of the loops. These geometric quantities can be likened to transition magnetic dipole moments and transition electric dipole moments, respectively, that can be generated in electronic excitations and which contribute in the main to nonresonant optical activity. The correlation between a computed geometric product of distance and area, and a quantum chemical property, establishes that chiroptical structure‐activity relationships can be well established for judiciously chosen series of comparatively large compounds.
Simultaneous production of phycobiliproteins and carbonic anhydrase by Spirulina platensis LEB‐52
Authors: Sala Luisa , Ores Joana da Costa , Moraes Caroline Costa , Kalil Susana Juliano
Published: January 2018

The simultaneous production of carbonic anhydrase and the phycobiliproteins, C‐phycocyanin and allophycocyanin, was evaluated during the cultivation of Spirulina platensis using Zarrouk's medium in its non‐diluted (100 % ZM) and diluted to 20 % (v/v) (20 % ZM) forms. In both media, Spirulina simultaneously produced carbonic anhydrase and phycobiliproteins. For the phycobiliproteins’ production, higher concentrations (mg/g) of C‐phycocyanin and allophycocyanin were obtained when 100 % ZM was used. For carbonic anhydrase production, higher concentrations (U/g) were obtained on the 6th day of cultivation in both culture media. 100 % ZM promoted greater productions of these bioproducts, and, for simultaneous obtainment, the cells should be harvested after 21 days, obtaining concentrations of 137.4 mg/g C‐phycocyanin, 104.4 mg/g allophycocyanin, and 26.6 U/g carbonic anhydrase.
Farbig fluoreszierende Zinkoxid‐Nanopartikel
Authors: Wilke Timm , Waitz Stefanie , von Hoff Elena , Waitz Thomas
Published: January 2018

In diesem Beitrag wird ein im Chemieunterricht umsetzbarer Versuch zur Herstellung verschiedenfarbig fluoreszierender Zinkoxid‐Nanopartikeldispersionen vorgestellt. Es wird gezeigt, dass sich sowohl das Phänomen der Fluoreszenz als auch die verschiedenen Fluoreszenzfarben mit Hilfe chemischer Basiskonzepte deuten lassen. Neben der grundsätzlichen Erkenntnis, dass sich Nanomaterialien in ihren Eigenschaften von denen ihrer makroskopisch großen Analoga unterscheiden, kann mit Hilfe des vorgestellten Versuchs anschaulich erarbeitet werden, dass sich innerhalb eines Größenbereichs auf der Nanomaterskala Stoffeigenschaften in Abhängigkeit von der Teilchengröße steuern lassen, was heute in diversen technischen Anwendungen genutzt wird. Darüber hinaus werden im Beitrag auch Versuche zur Verwendung von Zinkoxid‐Nanopartikeln als „low cost“ UV‐Lichtdetektor, zum Nachweis der photokatalytischen Aktivität sowie zur Wirkung auf pflanzliche Zellen präsentiert.
A Novel Prodrug of a γ‐Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer
Authors: Ii Hiromi , Yoshiya Taku , Nakata Susumu , Taniguchi Keiko , Hidaka Koushi , Tsuda Shugo , Mochizuki Masayoshi , Nishiuchi Yuji , Tsuda Yuko , Ito Kosei , Kageyama Susumu , Yoshiki Tatsuhiro
Published: January 2018

γ‐Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester‐type cell‐permeable prodrug, pro‐GA, was developed based on the structure of N‐glutaryl‐l‐alanine (GA), by structure optimization using temporary fluorophore‐tagged prodrug candidates. The antiproliferative activity of pro‐GA was demonstrated using GGCT‐overexpressing NIH‐3T3 cells and human cancer cells including MCF7, HL‐60, and PC3 cells. By contrast, normal cells were not significantly affected by pro‐GA treatment. Moreover, pro‐GA administration exhibited anticancer effects in a xenograft model using immunocompromised mice inoculated with PC3 cells. These results indicate that the enzymatic activity of GGCT accelerates tumor growth and that GGCT inhibition is a promising therapeutic strategy for the treatment of GGCT‐overexpressing tumors.
Increased pathologic upstaging with rising time to treatment initiation for head and neck cancer: A mechanism for increased mortality
Authors: Xiao Roy , Ward Matthew C. , Yang Kailin , Adelstein David J. , Koyfman Shlomo A. , Prendes Brandon L. , Burkey Brian B.
Published: January 2018

BACKGROUND

Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical‐to‐pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC).

METHODS

Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively.

RESULTS

Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P < .001) were found to predict T upstaging, a finding that is consistent for N and stage group upstaging. Using restricted cubic splines, relative odds of T and stage group upstaging escalated to 2.25 and 1.93, respectively, at a TTI of 365 days. In survival analyses, T (hazard ratio [HR], 1.53), N (HR, 1.88), and stage group (HR, 1.69) upstaging all predicted mortality (P < .001), whereas TTI only predicted mortality after 70 days (HR, 1.11; P = .023).

CONCLUSIONS

Tumor progression, measured by clinical‐to‐pathologic upstaging, increases mortality for patients with HNSCC experiencing treatment delays. Cancer 2018;124:1400‐14. © 2018 American Cancer Society.
Copper Nanospheres Self‐Propelled into Continuums of Iron Nanoclusters to Fabricate and Engineer Two‐Dimensional Heterometallic Arrays under an External Magnetic Field
Authors: Abadi P. Ghaderi‐Shekhi , Rafiee E. , Joshaghani M.
Published: January 2018

Controlled dislocation/arrangement metals in a metallic network with nonmagnetic species presents a challenge to fabricate/engineer structured heterometallic compounds. Heterometallic structures have dangling bonds at the shell of neighboring metallic particles, and therefore present a strong strain field in the vicinity of these particles. These structures can be used as a suitable bed with high surface energy to catalyze organic reactions. Here, we show a method for the production of two‐dimensional (2‐D) arrays of Cu nanospheres self‐propelled into continuums of Fe nanoclusters. The synthesis was carried out under magnetic‐field induction (MFI) with adjusting intensity. Electromagnetic (EM) results show that Cu species trapping themselves at the Fe species interface under the influence of magnetic momentum of Fe particles and MFI to rearrange periodic particle arrays of Cu and Fe. The metallic regions in 2‐D composites appear to be efficient catalytic centers in Csp−S cross‐coupling reactions. The synergistic effect of metallic species is a key support for the high activity of 2‐D Cu/Fe nanocompounds in coupling reactions. Nanocompounds are very stable after multiple reaction cycles.
Pharmacokinetics, Safety, and Tolerability of Tedizolid Phosphate in Elderly Subjects
Authors: Flanagan Shawn D. , Minassian Sonia L. , Prokocimer Philippe
Published: January 2018

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We evaluated the pharmacokinetics of tedizolid in elderly subjects to guide dosing recommendations. In an open‐label phase 1 study (ClinicalTrials.gov identifier NCT01496677), 14 elderly (≥65 years) and 14 younger control (18–45 years) subjects each received a single oral dose of tedizolid phosphate 200 mg. Blood samples were collected before dose and more than 72 hours after dose. The pharmacokinetic parameters of tedizolid after a single dose were similar in both age groups. Geometric mean ratios (elderly/younger controls) and corresponding 90% confidence intervals were maximum observed plasma concentration (Cmax), 1.091 (0.917–1.297); AUC from time 0 extrapolated to infinity (AUC0–∞), 1.132 (0.954–1.343). Tedizolid plasma exposure was similar in elderly and younger control subjects. The findings indicated that after intravenous or oral administration of tedizolid phosphate 200 mg once daily, no dose adjustment was warranted in elderly subjects to achieve therapeutic levels.
Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II–Inhibitor Complexes
Authors: Pecina Adam , Brynda Jiří , Vrzal Lukáš , Gnanasekaran Ramachandran , Hořejší Magdalena , Eyrilmez Saltuk M. , Řezáč Jan , Lepšík Martin , Řezáčová Pavlína , Hobza Pavel , Majer Pavel , Veverka Václav , Fanfrlík Jindřich
Published: January 2018

Accurate prediction of protein–ligand binding affinities is essential for hit‐to‐lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn2+ in the active site. This new dataset consists of the high‐resolution (1.1–1.4 Å) crystal structures and experimentally determined inhibitory constant (Ki) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of R2 of 0.56–0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof‐of‐concept study of SQM/COSMO ranking for metalloprotein–ligand systems demonstrates its potential for hit‐to‐lead applications.
Drug‐Induced Micelle‐to‐Vesicle Transition of a Cationic Gemini Surfactant: Potential Applications in Drug Delivery
Authors: Rajput Sargam M. , Kumar Sugam , Aswal Vinod K. , El Seoud Omar A. , Malek Naved I. , Kailasa Suresh Kumar
Published: January 2018

An impetus for the sustained interest in the formation of vesicles is their potential application as efficient drug‐delivery systems. A simple approach for ionic surfactants is to add a vesicle‐inducing drug of opposite charge. In ionic gemini surfactants (GSs) two molecules are covalently linked by a spacer. Regarding drug delivery, GSs are more attractive candidates than their single‐chain counterparts because of their high surface activity and the effect on the physicochemical properties of their solutions caused by changing the length of the spacer and inclusion of heteroatoms therein. Herein, the effect of the (anionic) anti‐inflammatory drug diclofenac sodium (DS) on the morphology of aqueous micellar aggregates of gemini surfactant hexamethylene‐1,6‐bis (dodecyldimethylammonium) dibromide (12‐6‐12) at 25 °C is reported. Several independent techniques are used to demonstrate drug‐induced micelle‐to‐vesicle transition. These include UV/Vis spectrophotometry, dynamic light scattering, TEM, and small‐angle neutron scattering. The micelles are transformed into vesicles with increasing [DS]/[12‐6‐12] molar ratio; precipitation of the catanionic (DS‐GS) complex then occurred, followed by partial resuspension of the weakly anionic precipitate. The stability of some of the prepared vesicles at human body temperature shows their potential use in drug delivery.
Integrated Multifunctional Micelles Co‐Self‐Assembled from Polypeptides Conjugated with Natural Ferulic Acid and Lipoic Acid for Doxorubicin Delivery
Authors: Chen Tao , Qiu Min , Zhang Jian , Sun Huanli , Deng Chao , Zhong Zhiyuan
Published: January 2018

The development of safe, easily accessible, and multifunctional nanocarriers is a big topic in nanomedicine research. Here, integrated multifunctional micelles (IMM) were developed by co‐self‐assembly of poly(ethylene glycol)‐b‐poly(l‐lysine) derivatives with natural ferulic acid (FA) or lipoic acid (LA). FA confers IMM with intrinsic antitumor activity, improved loading of doxorubicin (DOX) through π–π stacking, and reduced DOX cardiotoxicity. LA provides IMM with reversible crosslinking property, which leads to a high colloidal stability with inhibited drug leakage and triggered intracellular DOX release. Notably, our results showed that cRGD‐decorated IMM (cRGD‐IMM) had a small size (≈56 nm) and superior loading of DOX (27.1 wt. %). Blank cRGD‐IMM, though nontoxic to normal cells, exhibited obvious antiproliferative activity against cancer cells including B16F10 and HCT‐116 cells at 150 μg FA equiv. mL−1. DOX‐loaded cRGD‐IMM displayed enhanced growth inhibition of αvβ3‐positive B16F10 and HCT‐116 cells, a long elimination half‐life of 3.85 h, and a high maximum‐tolerated dose of over 100 mg DOX equiv. kg−1. Histological analysis revealed that DOX‐loaded cRGD‐IMM at 100 mg DOX equiv. kg−1 caused negligible cardiotoxicity, which is a major issue for the clinical use of DOX. These integrated multifunctional micelles with excellent safety and accessibility have emerged as a new platform for targeted cancer chemotherapy.
Ambivalence resolution in brief psychotherapy for depression
Authors: Braga Cátia , Ribeiro António P. , Gonçalves Miguel M. , Oliveira João Tiago , Botelho Alexandra , Ferreira Helena , Sousa Inês
Published: January 2018

Ambivalence in the process of psychotherapeutic change should be addressed and resolved if we are to avoid psychotherapeutic failure and promote sustained change. In this context, ambivalence can be defined as the cyclical conflictual relation between two opposed positions of the self: one expressed as an innovation, and a subsequent one expressed in a trivialization or rejection of the innovation (problematic position). This conflict may be resolved in two different ways: (a) the dominance of the innovative position and the consequent inhibition of the problematic one and (b) the negotiation between the innovative and the problematic positions. In this study, we sought to study the evolution of the dominance and the negotiation processes in recovered and unchanged cases; to analyse if different therapeutic models produce different results on the evolution of the dominance and negotiation processes, and finally, to study if these processes are predictive of ambivalence resolution. The complete sessions of 22 clinical cases of depression (6 cognitive‐behavioural therapy, 10 narrative therapy, and 6 emotion‐focused therapy cases) were independently coded for innovative moments, ambivalence, and ambivalence resolution. Results revealed that recovered cases had a progressively higher proportion of negotiation along treatment, whereas in unchanged cases, negotiation was virtually absent throughout treatment. Both dominance and negotiation were significant predictors of ambivalence reduction, however, negotiation had a higher impact than dominance. Overall, these results did not significantly differ for the 3 therapeutic models. The theoretical implications of these findings are discussed, and theoretical derived suggestions for clinicians are presented.
Do health‐related factors predict major depression? A longitudinal epidemiologic study
Authors: Zhang Xiao Chi , Woud Marcella L. , Becker Eni S. , Margraf Jürgen
Published: January 2018

Major depressive disorder (MDD) is a leading cause of global disease burden. Hence, examining the role of risk and protective factors for MDD is an important target in psychological research. Various studies showed that obesity, smoking, and alcohol consumption are related to depressive symptoms. In contrast, physical activity has been found to be a protective factor. The present population‐based study tested whether these health‐related factors are prospectively associated with incidence of MDD. Data were taken from the Dresden Predictor Study, which was designed to investigate risk and protective factors of mental health in young women. It included two assessments approximately 17 months apart. Results of single logistic regression analyses showed that being overweight, being a smoker, and being in a high‐risk drinking group at baseline were predictive of developing MDD at follow‐up. Engaging in regular physical activity and having good physical health were found to be protective factors of MDD. However, being in a medium‐risk drinking group was not predictive of incidence of MDD, and irregular physical activity was not a protective factor. This is the first prospective, longitudinal study to show that obesity, smoking, and high‐risk drinking are predictive of new onsets of MDD and that physical health is a protective factor. These data provide promising avenues for future research.
Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults
Authors: Mangal Naveen , Hamadeh Issam S. , Arwood Meghan J. , Cavallari Larisa H. , Samant Tanay S. , Klinker Kenneth P. , Bulitta Jurgen , Schmidt Stephan
Published: January 2018

Therapeutic concentrations of voriconazole in invasive fungal infections (IFIs) are ensured using a drug monitoring approach, which relies on attainment of steady‐state pharmacokinetics. For voriconazole, time to reach steady state can vary from 5–7 days, not optimal for critically ill patients. We developed a population pharmacokinetic/pharmacodynamic model‐based approach to predict doses that can maximize the net benefit (probability of efficacy‐probability of adverse events) and ensure therapeutic concentrations, early on during treatment. The label‐recommended 200 mg voriconazole dose resulted in attainment of targeted concentrations in ≥80% patients in the case of Candida spp. infections, as compared to only 40–50% patients, with net benefit ranging from 5.8–61.8%, in the case of Aspergillus spp. infections. Voriconazole doses of 300–600 mg were found to maximize the net benefit up to 51–66.7%, depending on the clinical phenotype (due to CYP2C19 status and pantoprazole use) of the patient and type of Aspergillus infection.
Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective
Authors: Shebley Mohamad , Sandhu Punam , Emami Riedmaier Arian , Jamei Masoud , Narayanan Rangaraj , Patel Aarti , Peters Sheila Annie , Reddy Venkatesh Pilla , Zheng Ming , de Zwart Loeckie , Beneton Maud , Bouzom Francois , Chen Jun , Chen Yuan , Cleary Yumi , Collins Christiane , Dickinson Gemma L. , Djebli Nassim , Einolf Heidi J. , Gardner Iain , Huth Felix , Kazmi Faraz , Khalil Feras , Lin Jing , Odinecs Aleksandrs , Patel Chirag , Rong Haojing , Schuck Edgar , Sharma Pradeep , Wu Shu‐Pei , Xu Yang , Yamazaki Shinji , Yoshida Kenta , Rowland Malcolm
Published: January 2018

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.