bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphological Study: Ultrastructural Aspects of Articular Cartilage and Subchondral Bone in Patients Affected by Post‐Traumatic Shoulder Instability
Authors: Baudi Paolo , Catani Fabio , Rebuzzi Manuela , Ferretti Marzia , Smargiassi Alberto , Campochiaro Gabriele , Serafini Fabio , Palumbo Carla
Published: December 2016

Post‐traumatic shoulder instability is a frequent condition in active population, representing one of most disabling pathologies, due to altered balance involving joints. No data are so far available on early ultrastructural osteo‐chondral damages, associated with the onset of invalidating pathologies, like osteoarthritis‐OA. Biopsies of glenoid articular cartilage and sub‐chondral bone were taken from 10 adult patients underwent arthroscopic stabilization. Observations were performed under Transmission Electron Microscopy‐TEM in tangential, arcuate and radial layers of the articular cartilage and in the sub‐chondral bone. In tangential and arcuate layers chondrocytes display normal and very well preserved ultrastructure, probably due to the synovial liquid supply; otherwise, throughout the radial layer (un‐calcified and calcified) chondrocytes show various degrees of degeneration; occasionally, in the radial layer evidences of apoptosis/autophagy were also observed. Concerning sub‐chondral bone, osteocytes next to the calcified cartilage also show signs of degeneration, while osteocytes farther from the osteo‐chondral border display normal ultrastructure, probably due to the bone vascular supply. The ultrastructural features of the osteo‐chondral complex are not age‐dependent. This study represents the first complete ultrastructural investigation of the articular osteo‐chondral complex in shoulder instability, evaluating the state of preservation/viability of both chondrocytes and osteocytes throughout the successive layers of articular cartilage and sub‐chondral bone. Preliminary observations here collected represent the morphological basis for further deepening of pathogenesis related to shoulder instability, enhancing the relationship between cell shape and microenvironment; in particular, they could be useful in understanding if the early surgical treatment in shoulder instability could avoid the onset of OA. Anat Rec, 300:1208–1218, 2017. © 2016 Wiley Periodicals, Inc.
Reproductive Tract Histology in South American Fur Seal Pups (Arctophoca australis)
Authors: Katz Helena , Johansson Olle
Published: December 2016

In the present study, a detailed histological description of the female reproductive tract of South American fur seal (Arctophoca australis) pups has been conducted. The uterine tube was covered by cuboidal to columnar epithelium; nerve fibers were present in the mesosalpinx and beneath the muscular layer. The uterus was bipartitus; the endometrial surface of the horns was lined by a simple cuboidal or columnar epithelium with deep tubular glands; caudally (“the transition area”), the epithelium changed to pseudostratified columnar, few tubular glands were present and the myometrium increased in width. A bistratified epithelium internally coated the uterine body, whereas it changed to cylindrical stratified epithelium with a highly vascularized lamina propria and a strong muscular layer in the cervix; no endometrial glands were observed in this region. From the transition area of the uterus to the vagina there were several nerve fibers and ganglia belonging to the uterovaginalis plexus. In the vestibule, hymenal folds were poorly developed; adnexa structures included the major vestibular glands and a neurovascular structure similar to the vestibular bulb. Minor vestibular glands were associated with the clitoris. The skin of the perineum was lined by a keratinized stratified epithelium, pigmented, with sebaceous glands, sweat glands and hair follicles. This is the first detailed histological description of the reproductive tract of South American fur seal pups, including the glandular adnexa and nerve structures. These results contribute to the reproductive biology in Pinniped species, and give a better understanding of the utero‐placental perfusion mechanism during diving. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:600–613, 2017. © 2016 Wiley Periodicals, Inc.
Efficient Hydrogenation of Biomass Oxoacids to Lactones by Using NHC–Iridium Coordination Polymers as Solid Molecular Catalysts
Authors: Liu Yaoqi , Sun Zheming , Huang Changyu , Tu Tao
Published: December 2016

A series of NHC–iridium coordination polymers have proven to be robust, efficient and recyclable solid molecular catalysts toward the hydrogenation of biomass levulinic acid (LA) to γ‐valerolactone. Along with quantitative yields attained at 0.01 mol % catalyst loading under 50 atm of H2, the solid molecular catalyst was readily recovered and reused for 12 runs without obvious loss of the selectivity and activity. Remarkably, up to 1.2×105 TON, an unprecedented value could be achieved in this important transformation. In addition, a number of LA homologues, analogues and derivatives were well tolerated to deliver various intriguing and functional lactones in good to excellent yields, which further confirmed the feasibility of the solid molecular catalysts.
Design of an Optimal Fuzzy Sliding Mode Control using Scalar Sign Function
Authors: Chaouech Lotfi , Soltani Moez , Dhahri Slim , Chaari Abdelkader
Published: December 2016

The purpose of this paper is to present a new design for an optimal fuzzy sliding mode control based on a modified parallel distributed compensator and using a scalarsignfunction method. The proposed fuzzy sliding mode control uses a modified parallel distributed compensator scheme to find the optimal gains. To do this, the control gains are not considered constant through the linearized subsystem. Among these, we find state feedback gains, which are determined in offline mode using some prescribed performance criteria. Moreover, the fuzzy sliding surface of the system is designed using a stable eigenvector and the scalarsignfunction. The advantages of the proposed design are minimum energy control effort, faster response, and zero steady‐state error. We analyze and test the performance and stability of the new optimal fuzzy sliding mode control using simulation results that show that the proposed approach is very effective.
Editors' note: Astron. Nachr. 10/2016
Authors: Louis Rohan Eugene , Mann Gottfried , Denker Carsten
Published: December 2016

Abstract
Optical detection of different phenolic compounds by means of a novel biosensor based on sol–gel immobilized laccase
Authors: Lepore Maria , Portaccio Marianna
Published: December 2016

A novel sol–gel‐based biosensor exploiting the optical absorption properties of sol–gel immobilized laccase has been constructed to increase enzyme specificity toward different phenolic substrates. Laccase from Trametes versicolor has been immobilized in optically transparent sol–gel matrices. Using Fourier transform infrared spectroscopy and data analysis based on a wavelet algorithm, a successful enzyme immobilization has been determined. The changes in the optical absorption spectra of laccase reaction products at 425, 375, and 400 nm have been used to determine hydroquinone, resorcinol, and catechol concentrations, respectively. Owing to the slow response time of the hydroquinone–laccase reaction, our optical biosensor has been tested with resorcinol and catechol. Linear ranges up to 1.4 and 0.2 mM, limit‐of‐detection (LOD) of 4.5 and 0.6 μΜ, have been evidenced for resorcinol and catechol, respectively. Data for determining the resorcinol concentration have been particularly interesting since no other biosensor device has been reported in the literature. In comparison with other biosensors using laccase from the same native source, our biosensor has been characterized by larger linear ranges, significant sensitivities, and good LODs. To challenge our biosensor with real samples, tap water samples spiked with known amount of catechol and resorcinol have been employed.
Unequivocal evidence supporting the segregated flow intestinal model that discriminates intestine versus liver first‐pass removal with PBPK modeling
Authors: Pang K. Sandy , Yang Qi Joy , Noh Keumhan
Published: December 2016

Merits of the segregated flow model (SFM), highlighting the intestine as inert serosa and active enterocyte regions, with a smaller fractional (fQ < 0.3) intestinal flow (QI) perfusing the enterocyte region, are described. Less drug in the circulation reaches the enterocytes due to the lower flow (fQQI) in comparison with drug administered into the gut lumen, fostering the idea of route‐dependent intestinal removal. The SFM has been found superior to the traditional model (TM), which views the serosa and enterocytes totally as a well‐mixed tissue perfused by 100% of the intestinal flow, QI. The SFM model is able to explain the lower extents of intestinal metabolism of enalapril, morphine and midazolam with i.v. vs. p.o. dosing. For morphine, the urine/bile ratio of the metabolite, morphine glucuronide
for p.o. was 2.6× that of i.v. This was due to the higher proportion of intestinally formed morphine glucuronide, appearing more in urine than in bile due to its low permeability and greater extent of intestinal formation with p.o. administration. By contrast, the TM predicted the same
for p.o. vs. i.v. The TM predicted that the contributions of the intestine:liver to first‐pass removal were 46%:54% for both p.o. and i.v. The SFM predicted same 46%:54% (intestine:liver) for p.o., but 9%:91% for i.v. By contrast, the kinetics of codeine, the precursor of morphine, was described equally well by the SFM‐ and TM‐PBPK models, a trend suggesting that intestinal metabolism of codeine is negligible. Fits to these PBPK models further provide insightful information towards metabolite formation: available fractions and the fractions of hepatic and total clearances that form the metabolite in question. The SFM‐PBPK model is useful to identify not only the presence of intestinal metabolism but the contributions of the intestine and liver for metabolite formation. Copyright © 2016 John Wiley & Sons, Ltd.
Modeling of complex antibody elution behavior under high protein load densities in ion exchange chromatography using an asymmetric activity coefficient
Authors: Huuk Thiemo C. , Hahn Tobias , Doninger Katharina , Griesbach Jan , Hepbildikler Stefan , Hubbuch Jürgen
Published: December 2016

A main requirement for the implementation of model‐based process development in industry is the capability of the model to predict high protein load densities. The frequently used steric mass action isotherm assumes a thermodynamically ideal system and, hence constant activity coefficients. In this manuscript, an industrial antibody purification problem under high load conditions is considered where this assumption does not hold. The high protein load densities, as commonly applied in industrial downstream processing, may lead to complex elution peak shapes. Using Mollerup's generalized ion‐exchange isotherm (GIEX), the observed elution peak shapes could be modeled. To this end, the GIEX isotherm introduced two additional parameters to approximate the asymmetric activity coefficient. The effects of these two parameters on the curvature of the adsorption isotherm and the resulting chromatogram are investigated. It could be shown that they can be determined by inverse peak fitting and conform with the mechanistic demands of model‐based process development.
Microbiome precision editing: Using PEG as a selective fermentation initiator against methicillin‐resistant Staphylococcus aureus
Authors: Kao Ming‐Shan , Huang Stephen , Chang Wei‐Lin , Hsieh Ming‐Fa , Huang Chun‐Jen , Gallo Richard L. , Huang Chun‐Ming
Published: December 2016

Recent creation of a Unified Microbiome Initiative (UMI) has the aim of understanding how microbes interact with each other and with us. When pathogenic Staphylococcus aureus infects the skin, the interplay between S. aureus and skin commensal bacteria occurs. Our previous data revealed that skin commensal bacteria can mediate fermentation against the growth of USA300, a community‐acquired methicillin‐resistant S. aureus MRSA. By using a fermentation process with solid media on a small scale, we define poly(ethylene glycol) dimethacrylate (PEG‐DMA) as a selective fermentation initiator which can specifically intensify the probiotic ability of skin commensal Staphylococcus epidermidis bacteria. At least five short‐chain fatty acids including acetic, butyric and propionic acids with anti‐USA300 activities are produced by PEG‐DMA fermentation of S. epidermidis. Furthermore, the S. epidermidis‐laden PEG‐DMA hydrogels effectively decolonized USA300 in skin wounds in mice. The PEG‐DMA and its derivatives may become novel biomaterials to specifically tailor the human skin microbiome against invading pathogens.
Translation system engineering in Escherichia coli enhances non‐canonical amino acid incorporation into proteins
Authors: Gan Rui , Perez Jessica G. , Carlson Erik D. , Ntai Ioanna , Isaacs Farren J. , Kelleher Neil L. , Jewett Michael C.
Published: December 2016

The ability to site‐specifically incorporate non‐canonical amino acids (ncAAs) into proteins has made possible the study of protein structure and function in fundamentally new ways, as well as the bio synthesis of unnatural polymers. However, the task of site‐specifically incorporating multiple ncAAs into proteins with high purity and yield continues to present a challenge. At the heart of this challenge lies the lower efficiency of engineered orthogonal translation system components compared to their natural counterparts (e.g., translation elements that specifically use a ncAA and do not interact with the cell's natural translation apparatus). Here, we show that evolving and tuning expression levels of multiple components of an engineered translation system together as a whole enhances ncAA incorporation efficiency. Specifically, we increase protein yield when incorporating multiple p‐azido‐phenylalanine(pAzF) residues into proteins by (i) evolving the Methanocaldococcus jannaschii p‐azido‐phenylalanyl‐tRNA synthetase anti‐codon binding domain, (ii) evolving the elongation factor Tu amino acid‐binding pocket, and (iii) tuning the expression of evolved translation machinery components in a single vector. Use of the evolved translation machinery in a genomically recoded organism lacking release factor one enabled enhanced multi‐site ncAA incorporation into proteins. We anticipate that our approach to orthogonal translation system development will accelerate and expand our ability to site‐specifically incorporate multiple ncAAs into proteins and biopolymers, advancing new horizons for synthetic and chemical biotechnology. Biotechnol. Bioeng. 2017;114: 1074–1086. © 2016 Wiley Periodicals, Inc.
Integrated continuous processing of proteins expressed as inclusion bodies: GCSF as a case study
Authors: Kateja Nikhil , Agarwal Harshit , Hebbi Vishwanath , Rathore Anurag S.
Published: December 2016

Affordability of biopharmaceuticals continues to be a challenge, particularly in developing economies. This has fuelled advancements in manufacturing that can offer higher productivity and better economics without sacrificing product quality in the form of an integrated continuous manufacturing platform. While platform processes for monoclonal antibodies have existed for more than a decade, development of an integrated continuous manufacturing process for bacterial proteins has received relatively scant attention. In this study, we propose an end‐to‐end integrated continuous downstream process (from inclusion bodies to unformulated drug substance) for a therapeutic protein expressed in Escherichia coli as inclusion body. The final process consisted of a continuous refolding in a coiled flow inverter reactor directly coupled to a three‐column periodic counter‐current chromatography for capture of the product followed by a three‐column con‐current chromatography for polishing. The continuous bioprocessing train was run uninterrupted for 26 h to demonstrate its capability and the resulting output was analyzed for the various critical quality attributes, namely product purity (>99%), high molecular weight impurities (<0.5%), host cell proteins (<100 ppm), and host cell DNA (<10 ppb). All attributes were found to be consistent over the period of operation. The developed assembly offers smaller facility footprint, higher productivity, fewer hold steps, and significantly higher equipment and resin utilization. The complexities of process integration in the context of continuous processing have been highlighted. We hope that the study presented here will promote development of highly efficient, universal, end‐to‐end, fully continuous platforms for manufacturing of biotherapeutics. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:998–1009, 2017
Transient and stable CHO expression, purification and characterization of novel hetero‐dimeric bispecific IgG antibodies
Authors: Rajendra Yashas , Peery Robert B. , Hougland Maria D. , Barnard Gavin C. , Wu Xiufeng , Fitchett Jonathan R. , Bacica Michael , Demarest Stephen J.
Published: December 2016

IgG bispecific antibodies (BsAbs) represent one of the preferred formats for bispecific antibody therapeutics due to their native‐like IgG properties and their monovalent binding to each target. Most reported studies utilized transient expression in HEK293 cells to produce BsAbs. However, the expression of biotherapeutic molecules using stable CHO cell lines is commonly used for biopharmaceutical manufacturing. Unfortunately, limited information is available in the scientific literature on the expression of BsAbs in CHO cell lines. In this study we describe an alternative approach to express the multiple components of IgG BsAbs using a single plasmid vector (quad vector). This single plasmid vector contains both heavy chain genes and both light chain genes required for the expression and assembly of the IgG BsAb, along with a selectable marker. We expressed, purified, and characterized four different IgG BsAbs or “hetero‐mAbs” using transient CHO expression and stable CHO minipools. Transient CHO titers ranged from 90 to 160 mg/L. Stable CHO titers ranged from 0.4 to 2.3 g/L. Following a simple Protein A purification step, the percentage of correctly paired BsAbs ranged from 74% to 98% as determined by mass spectrometry. We also found that information generated from transient CHO expression was similar to information generated using stable CHO minipools. In conclusion, the quad vector approach represents a simple, but effective, alternative approach for the generation of IgG BsAbs in both transient CHO and stable CHO expression systems. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:469–477, 2017
Spore‐displayed enzyme cascade with tunable stoichiometry
Authors: Chen Long , Mulchandani Ashok , Ge Xin
Published: December 2016

Taking the advantages of inert and stable nature of endospores, we developed a biocatalysis platform for multiple enzyme immobilization on Bacillus subtilis spore surface. Among B. subtilis outer coat proteins, CotG mediated a high expression level of Clostridium thermocellum cohesin (CtCoh) with a functional display capability of ∼104 molecules per spore of xylose reductase‐C. thermocellum dockerin fusion protein (XR‐CtDoc). By co‐immobilization of phosphite dehydrogenase (PTDH) on spore surface via Ruminococcus flavefaciens cohesin‐dockerin modules, regeneration of NADPH was achieved. Both xylose reductase (XR) and PTDH exhibited enhanced stability upon spore surface display. More importantly, by altering the copy numbers of CtCoh and RfCoh fused with CotG, the molar ratio between immobilized enzymes was adjusted in a controllable manner. Optimization of spore‐displayed XR/PTDH stoichiometry resulted in increased yields of xylitol. In conclusion, endospore surface display presents a novel approach for enzyme cascade immobilization with improved stability and tunable stoichiometry. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:383–389, 2017
Analysis of Tubespins as a suitable scale‐down model of bioreactors for high cell density CHO cell culture
Authors: Gomez Natalia , Ambhaikar Malhar , Zhang Li , Huang Chung‐Jr , Barkhordarian Hedieh , Lull Jonathan , Gutierrez Chris
Published: December 2016

High cell density (HCD) culture increases recombinant protein productivity via higher biomass. Compared to traditional fed‐batch cultures, HCD is achieved by increased nutrient availability and removal of undesired metabolic components via regular medium replenishment. HCD process development is usually performed in instrumented lab‐scale bioreactors (BR) that require time and labor for setup and operation. To potentially minimize resources and cost during HCD experiments, we evaluated a 2‐week 50‐mL Tubespin (TS) simulated HCD process where daily medium exchanges mimic the medium replacement rate in BR. To best assess performance differences, we cultured 13 different CHO cell lines in simulated HCD as satellites from simultaneous BR, and compared growth, metabolism, productivity and product quality. Overall, viability, cell‐specific productivity and metabolism in TS were comparable to BR, but TS cell growth and final titer were lower by 25 and 15% in average, respectively. Peak viable cell densities were lower in TS than BR as a potential consequence of lower pH, different medium exchange strategy and dissolved oxygen limitations. Product quality attributes highly dependent on intrinsic molecule or cell line characteristics (e.g., galactosylation, afucosylation, aggregation) were comparable in both scales. However, product quality attributes that can change extracellularly as a function of incubation time (e.g., deamidation, C‐terminal lysine, fragmentation) were in general lower in TS because of shorter residence time than HCD BR. Our characterization results and two case studies show that TS‐simulated HCD cultures can be effectively used as a simple scale‐down model for relative comparisons among cell lines for growth or productivity (e.g., clone screening), and for investigating effects on protein galactosylation. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:490–499, 2017
Limit campus liability by staying aware of popular apps
Authors: Porter Michael , Van Rysselberghe Alex
Published: December 2016

Today, there is an app for almost everything. And some apps can raise liability concerns for college and university campuses. But staying informed about popular apps can help colleges and universities to limit legal and other liabilities associated with the use of these apps on campus.
Responses to romidepsin by line of therapy in patients with relapsed or refractory peripheral T‐cell lymphoma
Authors: Foss Francine , Pro Barbara , Miles Prince H. , Sokol Lubomir , Caballero Dolores , Horwitz Steven , Coiffier Bertrand
Published: December 2016

Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of aggressive non‐Hodgkin lymphomas typically associated with poor prognosis. Most patients with PTCL receive chemotherapy as first‐line treatment, but many experience rapid relapse. For patients with relapsed/refractory PTCL, responses to treatment and long‐term outcomes tend to worsen with increasing lines of therapy. Romidepsin is a potent class I histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of PTCL in patients who have received ≥1 prior therapy. A pivotal phase 2 trial of romidepsin in patients with relapsed/refractory PTCL demonstrated an objective response rate of 25% (33/130), including 15% with confirmed/unconfirmed complete response, and a median duration of response of 28 months. In the analysis presented herein, romidepsin was shown to have similar responses and long‐term outcomes in patients with 1, 2, and ≥3 prior lines of treatment, including in patients with disease refractory to the last prior therapy. Although adverse events increased with increasing lines of treatment, the rate of dose modifications and discontinuations due to adverse events was not significantly different. These data support the use of romidepsin as salvage treatment for PTCL irrespective of the number of prior therapies.
Survival prognostic factors for metachronous second primary head and neck squamous cell carcinoma
Authors: Chen Jin‐Hua , Yen Yu‐Chun , Chen Tsung‐Ming , Yuan Kevin Sheng‐Po , Lee Fei‐Peng , Lin Kuan‐Chou , Lai Ming‐Tang , Wu Chia‐Che , Chang Chia‐Lun , Wu Szu‐Yuan
Published: December 2016

We examined the overall survival rates of a national cohort to determine optimal treatments and prognostic factors for patients with metachronous second primary head and neck squamous cell carcinomas (mspHNSCCs) at different stages and sites. We analyzed data of mspHNSCC patients collected from the Taiwan Cancer Registry database. The patients were categorized into four groups based on the treatment modality: Group 1 (control arm; chemotherapy [CT] alone), Group 2 (reirradiation [re‐RT] alone with intensity‐modulated radiotherapy [IMRT]), Group 3 (concurrent chemoradiotherapy alone [irradiation with IMRT]), and Group 4 (salvage surgery with or without RT or CT). We enrolled 1741 mspHNSCC patients without distant metastasis. Multivariate Cox regression analyses revealed that Charlson comorbidity index (CCI) ≥6, stage of second HNSCC, stage of first HNSCC, and duration from first primary HNSCC of <3 years were significant poor independent prognostic risk factors for overall survival. After adjustment, adjusted hazard ratios and 95% confidence intervals for the overall all‐cause mortality risk at mspHNSCC clinical stages III and IV were 0.72 (0.40–1.82), 0.52 (0.35–0.75), and 0.32 (0.22–0.45) in Groups 2, 3, and 4, respectively. A Cox regression analysis indicated that a re‐RT dose of ≥6000 cGy was an independent protective prognostic factor for treatment modalities. CCI ≥ 6, stage of second HNSCC, stage of first HNSCC, and duration from first primary HNSCC of <3 years were significant poor independent prognostic risk factors for overall survival. A re‐RT dose of ≥6000 cGy may be necessary for mspHNSCCs.
Natural Products among Brown Algae: The Case of Cystoseira schiffneri Hamel (Sargassaceae, Phaeophyceae)
Authors: Salem Abdelkader Ben , Di Giuseppe Graziano , Anesi Andrea , Hammami Saoussen , Mighri Zine , Guella Graziano
Published: December 2016

A chemotaxonomic study on the marine brown alga Cystoseira schiffneri collected from the Tunisian marine coast allowed us to identify kjellmanianone (1) and a new isololiolide derivative named schiffnerilolide (2). The structure elucidation and the assignment of relative configurations of the isolated natural products were based on advanced mass spectrometric and nuclear magnetic resonance techniques. This outcome suggested a close phylogenetic relationship of C. schiffneri with brown algae belonging to genus Sargassum C. Agardh. Molecular characterization using the nuclear small subunit rRNA (SSU rRNA) gene (18S) sequence as genetic marker was made. Pigment analysis showed a significant seasonal change of carotenoids, in particular of fucoxanthin and fucoxanthinol. Also galactolipids, the main constituents of the thylakoid membranes, showed remarkable seasonal changes.
Coupled Immobilized Amine Dehydrogenase and Glucose Dehydrogenase for Asymmetric Synthesis of Amines by Reductive Amination with Cofactor Recycling
Authors: Liu Ji , Pang Bryan Q. W. , Adams Joseph P. , Snajdrova Radka , Li Zhi
Published: December 2016

The amine dehydrogenase (AmDH) engineered from the phenylalanine dehydrogenase of Rhodococcus sp. M4 was directly immobilized on magnetic nanoparticles (MNP) from the cell‐free extract containing his‐tagged AmDH through affinity attachment to give AmDH‐MNPs with high yield, enzyme loading efficiency, and specific enzyme loading. AmDH‐MNPs showed higher activity and productivity than the free enzyme for the asymmetric reductive amination of 4‐phenyl‐2‐butanone 1 a and phenylacetone 1 b, producing the corresponding amines (R)‐2 a,b in 99 % ee and 99 % yield, and with recycling of NADH for up to 3956 times. AmDH‐MNPs were easily recycled, retaining 91 % of the original productivity in the third cycle of the reductive amination of 1 a. Coupling of immobilized AmDH and immobilized glucose dehydrogenase (GDH) for the asymmetric reductive amination of 1 a gave (R)‐2 a in 99 % ee and 74 % yield, with a total turnover number (TTN) of 2940 for NADH recycling. Both immobilized enzymes showed good recyclability, retaining 81 % productivity in the third reaction cycle. The developed method with coupled immobilized AmDH and immobilized GDH for the asymmetric reductive amination of ketones is useful for the synthesis of enantiopure amines, superior to the use of coupled isolated enzymes with enhanced catalytic performance and reduced enzyme cost through catalyst recycling.
Visible‐Light‐Driven Aerobic Photooxidation of Aldehydes to Methyl Esters Catalyzed by Riboflavin Tetraacetate
Authors: Mühldorf Bernd , Wolf Robert
Published: December 2016

Riboflavin tetraacetate (RFT) catalyzes the aerobic esterification of para‐substituted benzaldehydes to their corresponding methyl esters. The reaction proceeds under visible‐light irradiation in MeOH/MeCN in the presence of a Brønsted acid such as HCl. Electron transfer from the in situ formed dimethyl acetal to the photoexcited triplet flavin appears to be a key mechanistic step. The acid catalyzes the formation of the acetal and increases the reduction potential of RFT by protonation. The photocatalyst is regenerated by reaction with atmospheric oxygen, which serves as the terminal oxidant.
Heavy Grignard Reagents: Synthesis, Physical and Structural Properties, Chemical Behavior, and Reactivity
Authors: Westerhausen Matthias , Koch Alexander , Görls Helmar , Krieck Sven
Published: December 2016

The Grignard reaction offers a straight forward atom‐economic synthesis of organomagnesium halides, which undergo redistribution reactions (Schlenk equilibrium) yielding diorganylmagnesium and magnesium dihalides. The homologous organocalcium complexes (heavy Grignard reagents) gained interest only quite recently owing to several reasons. The discrepancy between the inertness of this heavy alkaline earth metal and the enormous reactivity of its organometallics hampered a vast and timely development after the first investigation more than 100 years ago. In this overview the synthesis of organocalcium reagents is described as is the durability in ethereal solvents. Aryl‐, alkenyl‐, and alkylcalcium halides are prepared by direct synthesis. Characteristic structural features and NMR parameters are discussed. Ligand redistribution reactions can be performed by addition of potassium tert‐butanolate to ethereal solutions of arylcalcium iodides yielding soluble diarylcalcium, whereas sparingly soluble potassium iodide and calcium bis(tert‐butanolate) precipitate. Furthermore, reactivity studies with respect to metalation and addition to unsaturated organic compounds and metal‐based Lewis acids, leading to the formation of heterobimetallic complexes, are presented.
Unravelling the Pathway Complexity in Conformationally Flexible N‐Centered Triarylamine Trisamides
Authors: Adelizzi Beatrice , Filot Ivo A. W. , Palmans Anja R. A. , Meijer E. W.
Published: December 2016

Two families of C3‐symmetrical triarylamine‐trisamides comprising a triphenylamine‐ or a tri(pyrid‐2‐yl)amine core are presented. Both families self‐assemble in apolar solvents via cooperative hydrogen‐bonding interactions into helical supramolecular polymers as evidenced by a combination of spectroscopic measurements, and corroborated by DFT calculations. The introduction of a stereocenter in the side chains biases the helical sense of the supramolecular polymers formed. Compared to other C3‐symmetrical compounds, a much richer self‐assembly landscape is observed. Temperature‐dependent spectroscopy measurements highlight the presence of two self‐assembled states of opposite handedness. One state is formed at high temperature from a molecularly dissolved solution via a nucleation–elongation mechanism. The second state is formed below room temperature through a sharp transition from the first assembled state. The change in helicity is proposed to be related to a conformational switch of the triarylamine core due to an equilibrium between a 3:0 and a 2:1 conformation. Thus, within a limited temperature window, a small conformational twist results in an assembled state of opposite helicity.
Structural Transformation from Dimerization to Tetramerization of Serine‐Decorated Rare‐Earth‐Incorporated Arsenotungstates Induced by the Usage of Rare‐Earth Salts
Authors: Li Hai‐Lou , Liu Ya‐Jie , Liu Jing‐Lin , Chen Li‐Juan , Zhao Jun‐Wei , Yang Guo‐Yu
Published: December 2016

Three types of serine‐decorated rare‐ earth‐containing arsenotungstate [H2N(CH3)2]6NaH[RE2 W4O10(H2O)8(Ser)2(B‐α‐AsW9O33)2]⋅30 H2O (RE3+=Eu3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+, and Y3+; 1), [H2N(CH3)2]6Na6−xRExH4−2 x[RE4W8O19(H2O)10+y(OH)2(Ser)2(B‐α‐AsW9O33)4]⋅n H2O (RE3+=Tb3+, x=1, y=2, n=36; RE3+=Dy3+, Ho3+, Er3+, Yb3+, Y3+, x=0, y=0, n=38; RE3+= Tm3+, x=1, y=0, n=38; Ser=serine; 2), and [H2N(CH3)2]6−2 xNa2+3 xRExH10−6 x+y[RE4W8O19(H2O)8(OH)2(Ser)4(B‐α‐AsW9O33)4]⋅Cly⋅n H2O (RE3+=Ce3+, Pr3+, x=1, y=0, n=65; RE3+=Nd3+, Sm3+, x=0, y=0, n=65; RE3+=Eu3+, Gd3+, x=1, y=2, n=45; 3) were synthesized with the participation of the organic solubilizers dimethylamine hydrochloride and l‐serine and were structurally characterized. The use of different amounts of rare‐earth salts results in the structural transformation from dimerization to tetramerization of types 1–3. Type 1 is a dimeric sandwich‐type assembly of a dual‐Ser‐participating [RE2W4O10(H2O)8(Ser)2]10+ entity sandwiched by two [B‐α‐AsW9O33]9− moieties, whereas types 2 and 3 have a tetrameric square structure formed by four [B‐α‐AsW9O33]9− moieties that anchor a dual/tetra‐ Ser‐participating [RE4W8O19(H2O)10+y(OH)2(Ser)2]20+ or [RE4W8O19(H2O)8(OH)2(Ser)4]20+ core. The solid‐state luminescence properties and lifetime–decay behaviors of these compounds were investigated. The chromaticity coordinates, dominant wavelengths, color purities, and correlated color temperatures were also calculated.
Oxidized Ores as Future Resource for Platinum Group Metals: Current State of Research
Authors: Kraemer Dennis , Junge Malte , Bau Michael
Published: December 2016

The platinum group elements (PGE), which are used in many high technology applications, are classified as critical metals by the EU. Therefore, research has to focus on potential alternative resources. Oxidized ores are found in the weathered zones of common sulfidic deposits, such as the Bushveld and the Great Dyke, and could be considered as potential future resources. The grades and reserves are high. However, due to geochemical and mineralogical changes induced by weathering, extraction of PGE is still limited and uneconomic. The current state of research on oxidized PGE ores in geosciences and processing is summarized.
Neoadjuvant long‐course chemoradiation remains strongly favored over short‐course radiotherapy by radiation oncologists in the United States
Authors: Mowery Yvonne M. , Salama Joseph K. , Zafar S. Yousuf , Moore Harvey G. , Willett Christopher G. , Czito Brian G. , Hopkins M. Benjamin , Palta Manisha
Published: December 2016

BACKGROUND

Short‐course radiotherapy (SC‐RT) and long‐course chemoradiotherapy (LC‐CRT) are accepted neoadjuvant treatments of rectal cancer. In the current study, the authors surveyed US radiation oncologists to assess practice patterns and attitudes regarding SC‐RT and LC‐CRT for patients with rectal cancer.

METHODS

The authors distributed a survey to 1701 radiation oncologists regarding treatment of neoadjuvant rectal cancer. Respondents were asked questions regarding the number of patients with rectal cancer treated, preference for SC‐RT versus LC‐CRT, and factors influencing regimen choice.

RESULTS

Of 1659 contactable physicians, 182 responses (11%) were received. Approximately 83% treated at least 5 patients with rectal cancer annually. The majority of responding radiation oncologists (96%) preferred neoadjuvant LC‐CRT for the treatment of patients with locally advanced rectal cancer and 44% never used SC‐RT. Among radiation oncologists using SC‐RT, respondents indicated they would not recommend this regimen for patients with low (74%) or bulky tumors (70%) and/or concern for a positive circumferential surgical resection margin (69%). The most frequent reasons for not offering SC‐RT were insufficient downstaging for sphincter preservation (53%) and a desire for longer follow‐up (45%). Many radiation oncologists indicated they would prescribe SC‐RT for patients not receiving chemotherapy (62%) or patients with a geographic barrier to receiving LC‐CRT (82%). Patient comorbidities appeared to influence regimen preferences for 79% of respondents. Approximately 20% of respondents indicated that altered oncology care reimbursement using capitated payment by diagnosis would impact their consideration of SC‐RT.

CONCLUSIONS

US radiation oncologists rarely use neoadjuvant SC‐RT despite 3 randomized controlled trials demonstrating no significant differences in outcome compared with LC‐CRT. Further research is necessary to determine whether longer follow‐up coupled with the benefits of lower cost, increased patient convenience, and lower acute toxicity will increase the adoption of SC‐RT by radiation oncologists in the United States. Cancer 2017;123:1434–1441. © 2016 American Cancer Society.
Local therapy reduces the risk of liver failure and improves survival in patients with intrahepatic cholangiocarcinoma: A comprehensive analysis of 362 consecutive patients
Authors: Yamashita Suguru , Koay Eugene Jon , Passot Guillaume , Shroff Rachna , Raghav Kanwal P. , Conrad Claudius , Chun Yun Shin , Aloia Thomas A. , Tao Randa , Kaseb Ahmed , Javle Milind , Crane Christopher H. , Vauthey Jean‐Nicolas
Published: December 2016

BACKGROUND

Treatment methods for intrahepatic cholangiocarcinoma (ICC) have improved, but their impact on outcome remains unclear. We evaluated the outcomes of patients definitively treated with resection, radiation, and chemotherapy for ICC, stratified by era.

METHODS

Clinico‐pathologic characteristics, cause of death, disease‐specific survival (DSS), and intrahepatic progression‐free survival (IPFS) were compared among patients who underwent resection, radiation, or chemotherapy as definitive treatment strategies for ICC (without distant organ metastasis) between 1997 and 2015. Variables were also analyzed by era (1997‐2006 [early] or 2007‐2015 [late]) within each group.

RESULTS

Among 362 patients in our cohort, 122 underwent resection (early, 38; late, 84), 85 underwent radiation (early, 17; late, 68), and 148 underwent systemic chemotherapy alone (early, 51; late, 97) as definitive treatment strategies, and 7 patients received best supportive care. In the resection group, the 3‐year DSS rate was 58% for the early era and 67% for the late era (P = .036), and the 1‐year IPFS was 50% for the early era and 75% for the late era (P = .048). In the radiation group, the 3‐year DSS was 12% for the early era and 37% for the late era (P = .048), and the 1‐year IPFS was 48% for the early era and 64% for the late era (P = .030). In the chemotherapy group, DSS and IPFS did not differ by era. Patients treated with chemotherapy developed liver failure at the time of death significantly more frequently than patients treated with resection (P < .001) or radiation (P < .001). Multivariable analysis identified local therapy (resection or radiation) as a sole predictor of death without liver failure.

CONCLUSION

Survival outcomes have improved for local therapy‐based definitive treatment strategies for ICC, which may be attributable to maintaining control of intrahepatic disease, thereby reducing the occurrence of death due to liver failure. Cancer 2017;123:1354–1362. © 2016 American Cancer Society.
The toxicity and efficacy of concomitant chemoradiotherapy in patients aged 70 years and older with oropharyngeal carcinoma in the intensity‐modulated radiotherapy era
Authors: Zumsteg Zachary S. , Lok Benjamin H. , Ho Allen S. , Drill Esther , Zhang Zhigang , Riaz Nadeem , Shiao Stephen L. , Ma Jennifer , McBride Sean M. , Tsai C. Jillian , Baxi Shrujal S. , Sherman Eric J. , Lee Nancy Y.
Published: December 2016

BACKGROUND

Despite controversy surrounding its benefit, the use of concomitant chemoradiotherapy (CCRT) in patients with oropharyngeal squamous cell carcinoma (OPSCC) who are aged > 70 years is increasing. However, to the authors' knowledge, few studies to date have compared the outcomes of different systemic treatments in this population.

METHODS

Records from 74 patients aged ≥ 70 years with stage III to stage IVB OPSCC who were undergoing CCRT from 2002 to 2013 at a single institution were reviewed. Patients were stratified according to the systemic therapy received, including cisplatin, carboplatin with either 5‐fluorouracil or paclitaxel (CARB), or cetuximab to compare oncologic outcome and toxicity.

RESULTS

The median follow‐up was 36 months. The median age of the patients was 75.3 years (range, 70‐91 years), with significantly older patients receiving cetuximab (P = .03). A total of 28, 20, and 26 patients, respectively, received CCRT with cisplatin, CARB, and cetuximab. RT interruptions of > 1 day were needed in 4% of patients receiving cisplatin, 20% of patients receiving CARB, and 15% of patients receiving cetuximab (P = .19). Unplanned hospitalizations during CCRT occurred in 25%, 55%, and 58%, respectively, of patients receiving cisplatin, CARB, and cetuximab (P = .03). There were 2 treatment‐related deaths, both of which occurred among the patients who were treated with cetuximab. At 5 years, locoregional control was achieved in 100%, 88%, and 60% (P<.001), respectively, and the overall survival rate was 87%, 61%, and 47% (P = .03), respectively, among patients treated with cisplatin, CARB, and cetuximab.

CONCLUSIONS

Toxicity from CCRT remains a challenge for older adults with OPSCC. Herein, the authors found no evidence that this toxicity was mitigated by treatment with cetuximab. Nevertheless, a subset of patients aged ≥70 years appear to tolerate cisplatin‐based treatment with acceptable toxicity and excellent outcomes. Further identification of this patient subgroup is crucial to optimize therapy for older patients with OPSCC. Cancer 2017;123:1345–1353. © 2016 American Cancer Society.
Elucidation of the Physicochemical Properties Ruling the Colloidal Stability of Iron Oxide Nanoparticles under Physiological Conditions
Authors: Aires Antonio , Cabrera David , Alonso‐Pardo Laura C. , Cortajarena Aitziber L. , Teran Francisco J.
Published: December 2016

Nanotechnology has brought countless novel applications regarding therapeutic, diagnostic, and sensing innovations. In particular, nanoparticle engineering enables the synthesis of nanocrystals with customized physical, chemical, and biological activities, which are generally well validated in vitro. However, when nanoparticles are tested in vivo they often show a disappointing loss of efficacy or increase of toxicity. These phenomena are related to the interaction of the nanoparticle surface with proteins, lipids, and ions present in the blood stream. Herein, we assess the physicochemical properties of an array of iron oxide nanoparticles coated with 15 different biocompatible materials dispersed in physiological aqueous media and human blood plasma. Our findings establish valid criteria for the prediction of the colloidal stability of nanoparticles dispersed in physiological aqueous media and human blood plasma. The criteria are based on the hydrophilicity and the net surface charge of the pristine nanoparticle coating in water dispersion. Hence, the methodology to select the most adequate nanoparticle coating for in vivo studies will be improved.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy
Authors: Moriyama B , Obeng A Owusu , Barbarino J , Penzak SR , Henning SA , Scott SA , Agúndez JAG , Wingard JR , McLeod HL , Klein TE , Cross SJ , Caudle KE , Walsh TJ
Published: December 2016

Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel
Authors: Zhong W‐P , Wu H , Chen J‐Y , Li X‐X , Lin H‐M , Zhang B , Zhang Z‐W , Ma D‐L , Sun S , Li H‐P , Mai L‐P , He G‐D , Wang X‐P , Lei H‐P , Zhou H‐K , Tang L , Liu S‐W , Zhong S‐L
Published: December 2016

Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP‐binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.
How Dimerization Through a Spiro Junction Modifies the Nonlinear Optical Properties of a Push–Pull Organic Dye: Insights from Theory and Hyper‐Rayleigh Scattering
Authors: Castet Frédéric , Lerychard Timothée , Pielak Kornelia , Szalóki György , Dalinot Clément , Leriche Philippe , Sanguinet Lionel , Champagne Benoît , Rodriguez Vincent
Published: December 2016

The second‐order nonlinear optical (NLO) properties of a push–pull monomer, as well as of its dimer composed of two monomeric units connected through a non‐conjugated spiro junction, are investigated by means of hyper‐Rayleigh scattering (HRS) and quantum chemical calculations. It is shown that dimerization to form a molecule with an orthogonal geometry enhances the first hyperpolarizability by circa 20 % and induces a decrease of the dipolar character of the HRS response. Theoretical calculations correlate well with experimental measurements and allow an in‐depth rationalization of the impact of the spiro linkage on the NLO properties through a detailed analysis of the relevant electronic excited states.