bluuebunny/crossref_metadata_2025 huggingface dataset:
Initial testing (stage 1) of the anti‐microtubule agents cabazitaxel and docetaxel, by the Pediatric Preclinical Testing Program
Authors: Reynolds C. Patrick , Kang Min H. , Maris John M. , Kolb E. Anders , Gorlick Richard , Wu Jianrong , Kurmasheva Raushan T. , Houghton Peter J. , Smith Malcolm A.
Published: July 2015

Background

Although microtubule‐destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule‐stabilizing taxanes are uncommonly used to treat childhood cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug‐resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts.

Procedures

Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01 to 0.1 μM and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5 mg/kg on an every 4 days × 3 I.V. schedule.

Results

In vitro, both cabazitaxel and docetaxel had similar potency (median rIC50 0.47 nM and 0.88 nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel.

Conclusions

Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
Treatment of young children with CNS‐positive acute lymphoblastic leukemia without cranial radiotherapy
Authors: Wilejto Marta , Giuseppe Giancarlo Di , Hitzler Johann , Gupta Sumit , Abla Oussama
Published: July 2015

Background

Due to the long‐term sequelae of cranial radiotherapy (CRT), contemporary treatment protocols for children with acute lymphoblastic leukemia (ALL) aim to limit the use of prophylactic CRT. For patients with central nervous system (CNS) involvement with ALL at diagnosis, the use of CRT remains common. Children <5 years of age are a particularly challenging subgroup in whom the consequences of CRT can be devastating.

Procedure

This study retrospectively describes the overall (OS) and event‐free survival (EFS) of young children (1–5 years) who were treated for CNS‐positive ALL at the Hospital for Sick Children between 2000 and 2013.

Results

Of a total of 19 patients, two were treated with upfront CRT, both as part of the conditioning regimen prior to HSCT. All patients received intensification of CNS‐directed chemotherapy by triple intra‐thecal chemotherapy (84.2%), use of dexamethasone in induction (57.9%) and maintenance (66.7%), and high‐dose methotrexate (77.8%). The OS was 84.2 ± 8.4% and EFS was 79.0 ± 9.4% with a median follow‐up time of 4.3 years (range, 2.6–8.2). The cumulative incidence of CNS relapse was 5.2 ± 5.1%.

Conclusions

We conclude that omission of CRT from the treatment of young children with ALL involving the CNS is associated with acceptable survival and avoids potentially devastating late effects in this group. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
Das Heliumionen‐Mikroskop
Authors: Vieker Henning , Frese Natalie , Gölzhäuser Armin
Published: July 2015

Das Heliumionen‐Mikroskop (HIM) rastert Proben mit einem Strahl aus Heliumionen ab. Gegenüber der etablierten Raster‐Elektronenmikroskopie (REM) bietet es einige Vorteile: höhere Auflösung, höhere Oberflächensensitivität, empfindlichere Kontrastmechanismen, größere Tiefenschärfe und geringere Probenschädigung. Hinzu kommt bei elektrisch isolierenden Proben die Möglichkeit einer Ladungskompensation, die eine elektrostatische Aufladung der Proben verhindert. In konventioneller REM müssen solche Proben mit einer leitfähigen Schicht bedampft werden, die aber feine Oberflächenstrukturen überdeckt. Seine vielen Vorzüge könnten das HIM zu einer Alternative für das REM machen, die in manchen Anwendungen sogar überlegen sein könnte.
Magnetische Speicher: Schalten mit Licht
Authors: Alebrand Sabine , Cinchetti Mirko , Aeschlimann Martin
Published: July 2015

2007 wurde entdeckt, dass die Magnetisierungsrichtung einer ferrimagnetischen GdFeCo‐Legierung allein durch einen zirkular polarisierten ultrakurzen Laserpuls stabil umgekehrt werden kann. Dies funktioniert ohne angelegtes Magnetfeld. Fast acht Jahre nach dieser Entdeckung wissen wir nun, dass der Effekt auch in Ferromagneten auftreten kann. Er ist somit doch weitaus allgemeiner als ursprünglich angenommen. Das erhöht sein Potenzial für mögliche Anwendungen in der Speichertechnologie deutlich. Trotz allem bleibt aber die mikroskopische Ursache des All‐optical Switchings weiter ungeklärt.
Wie ein Band zur Fontäne wird
Authors: Schlichting Hans Joachim
Published: July 2015

Ähnlich wie eine fallende Kugelkette kann man flache Seile in Form von Textil‐ oder Kunststoffbändern dazu bringen, sich fontänenartig aus einem Behälter heraus zu erheben. Anders als bei der Kugelkette müssen die Bänder rosettenartig gefaltet in den Becher gelegt werden.
Quantitative proteomics suggests decrease in the secretogranin‐1 cerebrospinal fluid levels during the disease course of multiple sclerosis
Authors: Kroksveen Ann C. , Jaffe Jacob D. , Aasebø Elise , Barsnes Harald , Bjørlykke Yngvild , Franciotta Diego , Keshishian Hasmik , Myhr Kjell‐Morten , Opsahl Jill A. , van Pesch Vincent , Teunissen Charlotte E. , Torkildsen Øivind , Ulvik Rune J. , Vethe Heidrun , Carr Steven A. , Berven Frode S.
Published: July 2015

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with unknown cause. Proteins with different abundance in the cerebrospinal fluid (CSF) from relapsing‐remitting MS (RRMS) patients and neurological controls could give novel insight to the MS pathogenesis and be used to improve diagnosis, predict prognosis and disease course, and guide in therapy decisions. We combined iTRAQ labeling and Orbitrap mass spectrometry to discover proteins with different CSF abundance between six RRMS patients and 18 neurological disease controls. From 777 quantified proteins seven were selected as biomarker candidates, namely chitinase‐3‐like protein 1, secretogranin‐1 (Sg1), cerebellin‐1, neuroserpin, cell surface glycoprotein MUC18, testican‐2 and glutamate receptor 4. An independent sample set of 13 early‐MS patients, 13 RRMS patients and 13 neurological controls was used in a multiple reaction monitoring verification study. We found the intracellular calcium binding protein Sg1 to be increased in early‐MS patients compared to RRMS and neurological controls. Sg1 should be included in further studies to elucidate its role in the early phases of MS pathogenesis and its potential as a biomarker for this disease.
Identification of proteins involved in desiccation tolerance in the red seaweed Pyropia orbicularis (Rhodophyta, Bangiales)
Authors: López‐Cristoffanini Camilo , Zapata Javier , Gaillard Fanny , Potin Philippe , Correa Juan A. , Contreras‐Porcia Loretto
Published: July 2015

Extreme reduction in cellular water content leads to desiccation, which, if persistent, affects the physiology of organisms, mainly through oxidative stress. Some organisms are highly tolerant to desiccation, including resurrection plants and certain intertidal seaweeds. One such species is Pyropia orbicularis, a rhodophycean that colonizes upper intertidal zones along the Chilean coast. Despite long, daily periods of air exposure due to tides, this alga is highly tolerant to desiccation. The present study examined the proteome of P. orbicularis by 2DE and LC‐MS/MS analyses to determine the proteins associated with desiccation tolerance (DT). The results showed that, under natural conditions, there were significant changes in the protein profile during low tide as compared to naturally hydrated plants at high tide. These changes were mainly in newly appeared proteins spots such as chaperones, monodehydroascorbate reductase, and manganese superoxide dismutase, among others. Previously undescribed proteins under desiccation conditions included phycobiliproteins, glyoxalase I, and phosphomannomutase. These changes evidenced that several physiological responses involved in DT are activated during low tide, including decreased photosynthetic activity, increased antioxidant capacity, and the preservation of cell physiology by regulating water content, cell wall structure, and cell volume. Similar responses have been observed in resurrection plants and bryophytes exposed to desiccation. Therefore, the coordinated activation of different desiccation tolerance pathways in P. orbicularis could explain the successful biological performance of this seaweed in the upper intertidal rocky zones.
Bundling and Unbundling in Public–Private Partnerships: Implications for Risk Sharing in Urban Transport Projects
Authors: Carpintero Samuel , Petersen Ole Helby
Published: July 2015

Public–private partnership (PPP) projects may be organized in a variety of ways, depending on the level of integration of the so-called Special Purpose Vehicle. Based on the analyses of four major PPP light rail projects in Spain, this article outlines two fundamentally different models of organizing the Special Purpose Vehicle in PPP projects; moreover, the article examines the central principles of these two different models of organizing the private sector Special Purpose Vehicle and their implications for risk sharing and project management in large-scale infrastructure PPP projects.
Addressing Risks in Green Retrofit Projects: The Case of Singapore
Authors: Hwang Bon-Gang , Zhao Xianbo , See Yi Lin , Zhong Yun
Published: July 2015

The objectives of this study are to identify the risks in green retrofit projects in Singapore; analyze their risk criticalities; compare the risk criticalities between conventional and green retrofit projects; and provide mitigation measures for the critical risks. Twenty risks and 37 mitigation measures were identified from a literature review. A questionnaire survey was performed with 30 professionals experienced in green retrofits, and five post-survey interviews were conducted. The results indicated “post-retrofit tenants’ cooperation risk” was the top risk, and that 19 risks were more critical in green retrofits than in conventional retrofits. Additionally, 28 mitigation measures obtained significant agreement.
Low‐potential facile electrosynthesis of free‐standing poly(1H‐benzo[g]indole) film as a yellow‐light‐emitter
Authors: Wang Ling , Zhao Dan , Liu Changlong , Nie Guangming
Published: July 2015

High‐quality free‐standing poly(1H‐benzo[g]indole) (PBIn) films were synthesized electrochemically by direct anodic oxidation of 1H‐benzo[g]indole (BIn) in boron trifluoride diethyl etherate. PBIn films obtained from this medium showed good electrochemical behavior and better thermal stability with a conductivity of 0.29 S cm−1. PBIn films with low band gap value (1.59 eV) were insoluble in acetone and tetrahydrofuran. The structure and morphology of the polymer were studied by UV–vis, FTIR, and scanning electron microscopy, respectively. The results of quantum chemistry calculations and the spectroscopies of dedoped PBIn indicate that the polymerization of BIn mainly occurs via C(2) and C(5) position. The polymer film was compact with regular nanoparticles on the surface. Fluorescent spectral studies indicate that solid‐state PBIn film is a good yellow‐light‐emitter. Thermal stability of PBIn film is higher than poly(indole‐6‐carboxylic acid), poly(5‐formylindole), and polyindole. To the best of our knowledge, this is the first report on the electrosynthesis of free‐standing polyindole derivatives as yellow‐light‐emitter. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2730–2738
Breaking E6 via trinification in F‐theory
Authors: Drissi El Bouzaidi M. , Nassiri S.
Published: July 2015

We consider E6 GUT model in F‐theory approach where E6 is broken via trinification to the Standard Model (SM) gauge group using non‐abelian fluxes. Including the gauge singlet wave function we found hierarchically small values for both the μ term as well as Dirac neutrino masses.
The putative P‐gp inhibitor telmisartan does not affect the transcellular permeability and cellular uptake of the calcium channel antagonist verapamil in the P‐glycoprotein expressing cell line MDCK II MDR1
Authors: Saaby Lasse , Tfelt‐Hansen Peer , Brodin Birger
Published: July 2015

Verapamil is used in high doses for the treatment of cluster headache. Verapamil has been described as a P‐glycoprotein (P‐gp, ABCB1) substrate. We wished to evaluate in vitro whether co administration of a P‐gp inhibitor with verapamil could be a feasible strategy for increasing CNS uptake of verapamil. Fluxes of radiolabelled verapamil across MDCK II MDR1 monolayers were measured in the absence and presence of the putative P‐gp inhibitor telmisartan (a clinically approved drug compound). Verapamil displayed a vectorial basolateral‐to‐apical transepithelial efflux across the MDCK II MDR1 monolayers with a permeability of 5.7 × 10−5 cm sec−1 compared to an apical to basolateral permeability of 1.3 × 10−5 cm sec‐1. The efflux could be inhibited with the P‐gp inhibitor zosuquidar. Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB‐A/PA‐B) for verapamil 4.6–1.6. The presence of telmisartan, however, only caused a slight reduction in P‐gp‐mediated verapamil transport to an efflux ratio of 3.4. Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P‐gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co‐administration with telmisartan.
Increased efficacy of VX‐809 in different cellular systems results from an early stabilization effect of F508del‐CFTR
Authors: Farinha Carlos M. , Sousa Marisa , Canato Sara , Schmidt André , Uliyakina Inna , Amaral Margarida D.
Published: July 2015

Cystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX‐809, a corrector of F508del‐CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX‐809 is additive to two other correctors (VRT‐325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell‐specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro‐Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse‐chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX‐809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX‐809 significantly stabilizes F508del‐CFTR immature form, an effect that is not observed for C3 nor C4. VX‐809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX‐809 increases the stability of F508del‐CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue.
Propofol restores TRPV1 sensitivity via a TRPA1‐, nitric oxide synthase‐dependent activation of PKCε
Authors: Sinharoy Pritam , Zhang Hongyu , Sinha Sayantani , Prudner Bethany C. , Bratz Ian N. , Damron Derek S.
Published: July 2015

We previously demonstrated that the intravenous anesthetic, propofol, restores the sensitivity of transient receptor potential vanilloid channel subtype‐1 (TRPV1) receptors via a protein kinase C epsilon (PKCε)‐dependent and transient receptor potential ankyrin channel subtype‐1 (TRPA1)‐dependent pathway in sensory neurons. The extent to which the two pathways are directly linked or operating in parallel has not been determined. Using a molecular approach, our objectives of the current study were to confirm that TRPA1 activation directly results in PKCε activation and to elucidate the cellular mechanism by which this occurs. F‐11 cells were transfected with complimentary DNA (cDNA) for TRPV1 only or both TRPV1 and TRPA1. Intracellular Ca2+ concentration was measured in individual cells via fluorescence microscopy. An immunoblot analysis of the total and phosphorylated forms of PKCε, nitric oxide synthase (nNOS), and TRPV1 was also performed. In F‐11 cells containing both channels, PKCε inhibition prevented the propofol‐ and allyl isothiocyanate (AITC)‐induced restoration of TRPV1 sensitivity to agonist stimulation as well as increased phosphorylation of PKCε and TRPV1. In cells containing TRPV1 only, neither agonist induced PKCε or TRPV1 phosphorylation. Moreover, NOS inhibition blocked propofol‐and AITC‐induced restoration of TRPV1 sensitivity and PKCε phosphorylation, and PKCε inhibition prevented the nitric oxide donor, SNAP, from restoring TRPV1 sensitivity. Also, propofol‐and AITC‐induced phosphorylation of nNOS and nitric oxide (NO) production were blocked with the TRPA1‐antagonist, HC‐030031. These data indicate that the AITC‐ and propofol‐induced restoration of TRPV1 sensitivity is mediated by a TRPA1‐dependent, nitric oxide synthase‐dependent activation of PKCε.
Efficacy of tomato concentrates in mouse models of dyslipidemia and cancer
Authors: Chattopadhyay Arnab , Grijalva Victor , Hough Greg , Su Feng , Mukherjee Pallavi , Farias‐Eisner Robin , Anantharamaiah G. M. , Faull Kym F. , Hwang Lin H. , Navab Mohamad , Fogelman Alan M. , Reddy Srinivasa T.
Published: July 2015

We previously reported that adding freeze‐dried tomato powder from transgenic plants expressing the apolipoprotein A‐I mimetic peptide 6F at 2.2% by weight to a Western diet (WD) ameliorated dyslipidemia and atherosclerosis in mice. The same dose in a human would require three cups of tomato powder three times daily. To reduce the volume, we sought a method to concentrate 6F. Remarkably, extracting the transgenic freeze‐dried tomato overnight in ethyl acetate with 5% acetic acid resulted in a 37‐fold reduction in the amount of transgenic tomato needed for biologic activity. In a mouse model of dyslipidemia, adding 0.06% by weight of the tomato concentrate expressing the 6F peptide (Tg6F) to a WD significantly reduced plasma total cholesterol and triglycerides (P < 0.0065). In a mouse model of colon cancer metastatic to the lungs, adding 0.06% of Tg6F, but not a control tomato concentrate (EV), to standard mouse chow reduced tumor‐associated neutrophils by 94 ± 1.1% (P = 0.0052), and reduced tumor burden by two‐thirds (P = 0.0371). Adding 0.06% of either EV or Tg6F by weight to standard mouse chow significantly reduced tumor burden in a mouse model of ovarian cancer; however, Tg6F was significantly more effective (35% reduction for EV vs. 53% reduction for Tg6F; P = 0.0069). Providing the same dose of tomato concentrate to humans would require only two tablespoons three times daily making this a practical approach for testing oral apoA‐I mimetic therapy in the treatment of dyslipidemia and cancer.
Pharmacology and physiology of gastrointestinal enteroendocrine cells
Authors: Mace O. J. , Tehan B. , Marshall F.
Published: July 2015

Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein‐coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux‐en‐Y gastric surgery. Typically obese patients exhibit ~30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self‐limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.
Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants
Authors: de Jong Jan , Skee Donna , Murphy Joe , Sukbuntherng Juthamas , Hellemans Peter , Smit Johan , de Vries Ronald , Jiao Juhui James , Snoeys Jan , Mannaert Erik
Published: July 2015

Ibrutinib (PCI‐32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B‐cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose‐normalized (DN) exposure [DN‐AUClast: 24‐fold; DN‐Cmax: 29‐fold], rifampin decreased ibrutinib exposure [Cmax: 13‐fold; AUClast: 10‐fold]. Under nonfasted condition, GFJ caused a moderate increase [DN‐Cmax: 3.5‐fold; DN‐AUC: 2.2‐fold], most likely through inhibition of intestinal CYP3A. Half‐life was not affected by CYP perpetrators indicating the interaction was mainly on first‐pass extraction. All treatments were well‐tolerated.
Pharmacodynamic assays to facilitate preclinical and clinical development of pre‐mRNA splicing modulatory drug candidates
Authors: Shi Yihui , Joyner Amanda S. , Shadrick William , Palacios Gustavo , Lagisetti Chandraiah , Potter Philip M. , Sambucetti Lidia C. , Stamm Stefan , Webb Thomas R.
Published: July 2015

The spliceosome has recently emerged as a new target for cancer chemotherapy and novel antitumor spliceosome targeted agents are under development. Here, we describe two types of novel pharmacodynamic assays that facilitate drug discovery and development of this intriguing class of innovative therapeutics; the first assay is useful for preclinical optimization of small‐molecule agents that target the SF3B1 spliceosomal protein in animals, the second assay is an ex vivo validated, gel‐based assay for the measurement of drug exposure in human leukocytes. The first assay utilizes a highly specific bioluminescent splicing reporter, based on the skipping of exons 4–11 of a Luc‐MDM2 construct, which specifically yields active luciferase when treated with small‐molecule spliceosome modulators. We demonstrate that this reporter can be used to monitor alternative splicing in whole cells in vitro. We describe here that cell lines carrying the reporter can be used in vivo for the efficient pharmacodynamic analysis of agents during drug optimization and development. We also demonstrate dose‐ and time‐dependent on‐target activity of sudemycin D6 (SD6), which leads to dramatic tumor regression. The second assay relies on the treatment of freshly drawn human blood with SD6 ex vivo treatment. Changes in alternative splicing are determined by RT‐PCR using genes previously identified in in vitro experiments. The Luc‐MDM2 alternative splicing bioluminescent reporter and the splicing changes observed in human leukocytes should allow for the more facile translation of novel splicing modulators into clinical application.
Preclinical evaluation of SMM‐189, a cannabinoid receptor 2‐specific inverse agonist
Authors: Presley Chaela , Abidi Ammaar , Suryawanshi Satyendra , Mustafa Suni , Meibohm Bernd , Moore Bob M.
Published: July 2015

Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune‐related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3′,5′‐dichloro‐2,6‐dihydroxy‐biphenyl‐4‐yl)‐phenyl‐methanone (SMM‐189) and the characterization of the beneficial effects of SMM‐189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM‐189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM‐189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM‐189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.
Power diamond vertical Schottky barrier diode with 10 A forward current
Authors: Tarelkin Sergey , Bormashov Vitaly , Buga Sergei , Volkov Alexander , Teteruk Dmitry , Kornilov Nikolay , Kuznetsov Mikhail , Terentiev Sergey , Golovanov Anton , Blank Vladimir
Published: July 2015

We developed and investigated the vertical diamond Schottky barrier diodes on large area IIb HPHT high quality substrates. The drift CVD layers with boron content of 1016 and 2 × 1017 cm−3 were made. The diodes possess an integral forward current higher than 10 A in the temperature range of 25–200 °C. The self‐heating effect further improves the diode forward characteristics. We tested different crystal‐to‐case thermal interfaces. Diodes have less than 3.5 V forward voltage drop for 10 A at 25 °C and less than 1 V at 200 °C with the on‐resistance as low as 0.05 Ω (10 mΩ cm2). We calculated the real Baliga figures of merit (BFOM) of diodes taking into account an incomplete acceptors ionization and a finite substrate resistivity. The low doped diamond conductivity model was used to calculate and optimize the BFOM for various diode designs. The diodes with BFOM up to 200 MW/cm2 can be made for diamond drift layer with the blocking field of 2 MV/cm and as high as 18000 MW/cm2 in the case of EMAX ∼8 MV/cm.
Retraction: Poly(3‐hexylthiophene) films by electrospray deposition for crystalline silicon/organic hybrid junction solar cells
Authors: Hiate Taiga , Miyauchi Naoto , Tang Zeguo , Ishikawa Ryo , Ueno Keiji , Shirai Hajime
Published: July 2015

The above article, published online on 25 July 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor‐in‐Chief, Stefan Hildebrandt, and Wiley‐VCH GmbH & Co. KGaA. The retraction has been agreed since the contents of the article have already been published by the corresponding author in Jpn. J. Appl. Phys. 51, 061602 (2015) on 4 June 2015.

The manuscript submitted to physica status solidi (c) was part of the E‐MRS 2015 Spring Meeting, Symposium A, Proceedings. The authors regret the dual publication and express their sincere apologies to readers. (© 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Phloroglucinol Protects INS‐1 Pancreatic β‐cells Against Glucotoxicity‐Induced Apoptosis
Authors: Park Mi Hwa , Han Ji Sook
Published: July 2015

Decreasing numbers, and impaired function, of pancreatic β‐cells are key factors in the development of type 2 diabetes. This study was designed to investigate whether phloroglucinol protected pancreatic β‐cells against glucotoxicity‐induced apoptosis using a rat insulinoma cell line (INS‐1). High glucose treatment (30 mM) induced INS‐1 cell death; however, the level of glucose‐induced apoptosis was significantly reduced in cells treated with 100‐μM phloroglucinol. Treatment with 10–100‐μM phloroglucinol increased cell viability and decreased intracellular levels of reactive oxygen species, nitric oxide, and lipid peroxidation dose‐dependently in INS‐1 cells pretreated with high glucose. Furthermore, phloroglucinol treatment markedly reduced the protein expression of Bax, cytochrome c, and caspase 9, while increasing anti‐apoptotic Bcl‐2 protein expression. Cell death type was examined using annexin V/propidium iodide staining, revealing that phloroglucinol markedly reduced high glucose‐induced apoptosis. These results demonstrated that phloroglucinol could be useful as a potential therapeutic agent for the protection of pancreatic β‐cells against glucose‐induced apoptosis. Copyright © 2015 John Wiley & Sons, Ltd.
Attribute‐based credentials with cryptographic collusion prevention
Authors: Hajny Jan , Dzurenda Petr , Malina Lukas
Published: July 2015

Cryptographic attribute‐based credentials (ABCs) allow users to prove their personal attributes remotely and in a privacy‐friendly way. While staying anonymous and untraceable, the users are able to prove their attributes, such as age, membership, or nationality, before using a network service. Unfortunately, there are very few practical cryptographic ABC schemes available today. Furthermore, some existing schemes rely on the hardware tamper‐resistance of smart cards to avoid collusion attacks. The trust in hardware limits the usage of such schemes on poorly protected cards and on smart phones. In this paper, we present the full cryptographic specification of an ABC scheme, which makes the collusion attacks impossible even on insecure hardware like mobile phones. Furthermore, the scheme provides features, which are difficult to achieve using existing schemes, namely the practical revocation of users, the de‐anonymization of malicious users, and the unlinkability of verification sessions. Besides the cryptographic architecture, we also present our practical implementation on a smart phone and embedded platforms. Copyright © 2015 John Wiley & Sons, Ltd.
High‐Performance Flexible Organic Nano‐Floating Gate Memory Devices Functionalized with Cobalt Ferrite Nanoparticles
Authors: Jung Ji Hyung , Kim Sunghwan , Kim Hyeonjung , Park Jongnam , Oh Joon Hak
Published: July 2015

Nano‐floating gate memory (NFGM) devices are transistor‐type memory devices that use nanostructured materials as charge trap sites. They have recently attracted a great deal of attention due to their excellent performance, capability for multilevel programming, and suitability as platforms for integrated circuits. Herein, novel NFGM devices have been fabricated using semiconducting cobalt ferrite (CoFe2O4) nanoparticles (NPs) as charge trap sites and pentacene as a p‐type semiconductor. Monodisperse CoFe2O4 NPs with different diameters have been synthesized by thermal decomposition and embedded in NFGM devices. The particle size effects on the memory performance have been investigated in terms of energy levels and particle–particle interactions. CoFe2O4 NP‐based memory devices exhibit a large memory window (≈73.84 V), a high read current on/off ratio (read Ion/Ioff) of ≈2.98 × 103, and excellent data retention. Fast switching behaviors are observed due to the exceptional charge trapping/release capability of CoFe2O4 NPs surrounded by the oleate layer, which acts as an alternative tunneling dielectric layer and simplifies the device fabrication process. Furthermore, the NFGM devices show excellent thermal stability, and flexible memory devices fabricated on plastic substrates exhibit remarkable mechanical and electrical stability. This study demonstrates a viable means of fabricating highly flexible, high‐performance organic memory devices.
Food Provision and Environmental Goals in the Swiss Agri‐Food System: System Dynamics and the Social‐ecological Systems Framework
Authors: Kopainsky Birgit , Huber Robert , Pedercini Matteo
Published: July 2015

An important challenge for the Swiss agri‐food system is how to align food provision with environmental goals in the context of increasingly complex conditions. This paper describes a system dynamics model that analyses the trade‐offs and synergies between these goals arising from different fields of action. The model is grounded in the social‐ecological systems framework and was developed in a participatory process with stakeholders across the Swiss agri‐food system. Model analysis indicates that yield improvements and the implementation of more sustainable production systems have important leverage for increasing food provision and simultaneously improving environmental performance. However, these fields of action need to be complemented by fields of action outside agriculture such as reductions in food waste and losses or changes in consumption patterns. Model analysis also shows that the feedback perspective, inherent to the system dynamics methodology, promises to yield valuable synergies with the social‐ecological systems approach. Copyright © 2015 John Wiley & Sons, Ltd.
Dynamic Consequences of Performance‐Based Payment Systems in Public Hospitals
Authors: Meker Tuğrul , Barlas Yaman
Published: July 2015

The goal of performance‐based payment system (PBPS) is to increase the efficiency of healthcare resources by paying physicians and hospitals for increased performance. PBPS in Turkey has been implemented since 2004. After 10 years, assessments about the effectiveness of this system have been mixed. The purpose of this study is to model and analyze the dynamic impacts of PBPS on the behaviors of public hospitals and their physicians. The model includes physicians' interactions with patients, revenue pressures on physicians and the resulting impacts on health outputs. In order to increase productivity, PBPS encourages physicians to perform more medical activity. Thus, a physician who experiences revenue pressure may increase his or her medical activity and attach less importance to quality. Resulting inadequate treatments and wrongly diagnosed patients would have negative effects on health quality. On the other hand, physicians who have no revenue concerns may attach the quality of healthcare absolute priority, undermining higher productivity. This attitude may result in hospital crowding, hence crowding pressures on physicians. Such conflicting feedback forces are included in the model to investigate the impacts of PBPS on health outputs. Simulation results obtained agree with some of the dynamic behaviors recently observed and discussed in Turkish healthcare. Copyright © 2015 John Wiley & Sons, Ltd.
Thermal Analysis Study on the Carbothermic Reduction of Chromite Ore with the Addition of Mill Scale
Authors: Hu Xianfeng , Yang Qixing , Sundqvist Ökvist Lena , Björkman Bo
Published: July 2015

This paper presents a fundamental study on the carbothermic reduction of chromite ore with the addition of mill scale, which forms the basis for designing an alloying precursor, “chromite ore + mill scale + carbon,” for direct chromium alloying. The reduction of chromite ore by petroleum coke with or without the addition of mill scale is investigated by Thermogravimetric Analysis (TGA) under non‐isothermal conditions (from room temperature to 1823 K) in the argon atmosphere; the fractional reduced samples were characterized by SEM/EDS and XRD analyses. The experimental results show that the mill scale in the alloying mixture is reduced to high active iron first and disseminated around the chromite ore particles; the reduction of chromite ore is enhanced with the addition of mill scale especially at temperatures higher than 1623 K, and the enhancing effect increased with increasing mill scale addition. The enhancing effect is attributed to the presence of molten Fe–C alloy in the vicinity of chromite ore, which can decrease the thermodynamic activity of chromium by having chromium in situ dissolve into the melt.
HC-HA/PTX3 Purified From Amniotic Membrane Promotes BMP Signaling in Limbal Niche Cells to Maintain Quiescence of Limbal Epithelial Progenitor/Stem Cells
Authors: Chen Szu-Yu , Han Bo , Zhu Ying-Ting , Mahabole Megha , Huang Jie , Beebe David C. , Tseng Scheffer C. G.
Published: July 2015

To explore how limbal niche cells (LNCs) may control quiescence, self-renewal, and corneal epithelial lineage commitment/differentiation of limbal epithelial progenitor/stem cells (LEPCs), we have established an in vitro sphere assay by reunion between the two cell types in three-dimensional Matrigel. The resultant sphere exhibits inhibition of corneal epithelial lineage commitment/differentiation and marked clonal growth of LEPCs, of which the latter is correlated with activation of canonical Wnt signaling. Herein, we have created a similar reunion assay in immobilized heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3), which is purified from amniotic membrane (AM) and consists of a complex formed by hyaluronic covalently linked to heavy chain 1 of inter-α-inhibitor and noncovalently linked to pentraxin 3. The resultant spheres exhibited similar suppression of corneal epithelial lineage commitment/differentiation but upregulation of quiescence markers including nuclear translocation of Bmi-1, and negligible clonal growth of LEPCs. This outcome was correlated with the suppression of canonical Wnt but activation of noncanonical (Planar cell polarity) Wnt signaling as well as BMP signaling in both LEPCs and LNCs. The activation of BMP signaling in LNCs was pivotal because nuclear translocation of pSmad1/5/8 was prohibited in hLEPCs when reunioned with mLNCs of conditionally deleted Bmpr1a;Acvr1DCKO mice. Furthermore, ablation of BMP signaling in LEPCs led to upregulation of cell cycle genes, downregulation of Bmi-1, nuclear exclusion of phosphorylated Bmi-1, and marked promotion of the clonal growth of LEPCs. Hence, HC-HA/PTX3 uniquely upregulates BMP signaling in LNCs which leads to BMP signaling in LEPCs to achieve quiescence, helping explain how AM transplantation is clinically useful to be used as a matrix for ex vivo expansion of LEPCs and to treat corneal blindness caused by limbal stem cells deficiency. Stem Cells  2015;33:3341–3355
Intranodal Mapping Using Carbon Dye Results in More Accurate Lymph Node Staging in Colon Cancer Patients
Authors: Weixler Benjamin , Warschkow Rene , Zettl Andreas , Riehle Hans‐Martin , Guller Ulrich , Viehl Carsten T. , Zuber Markus
Published: July 2015

Introduction

Small nodal tumor infiltrates (SNTI)—defined as isolated tumor cells and micrometastases—are associated with worse disease‐free and overall survival in stage I and II colon cancer patients. Their detection, however, remains challenging. The objective of the present study was to evaluate whether there is a correlation between the location of SNTI and phagocytosed carbon dye particles in sentinel lymph nodes (SLN) of colon cancer patients.

Materials and Methods

Isosulfan blue and carbon dye were injected intraoperatively near the tumor to mark the SLN. Serial sections of SLN were stained with hematoxylin–eosin and immunohistochemistry. Intranodal distribution of phagocytosed carbon particles was compared to the presence of SNTI.

Results

Of a cohort of 159 patients, 24 patients had SNTI in their lymph nodes (LN). SNTI were found in a total of 116 LN of which 66 were SLN and 50 were non‐SLN. In 59, these 116 LN with SNTI phagocytosed carbon dye were found (50.9 %). Phagocytosed carbon dye was identified significantly more often in SLN (49 of 66 SNTI positive SLN) compared to 10 of 50 SNTI positive non‐SLN (p < 0.001). In 52 out of 59 LN (88.1 %), phagocytosed carbon dye was in close proximity to SNTI.

Conclusions

In the majority of patients, SNTI are located in the same SLN compartment as phagocytosed carbon dye particles. Our investigation provides evidence that the use of carbon dye facilitates SNTI detection and improves LN staging in colon cancer. Therefore, the concept of intranodal mapping—which has been previously described for melanoma—can be extended to colon cancer patients.
Comparison of Survival Outcomes Between Right Posterior Sectionectomy and Right Hepatectomy for Hepatocellular Carcinoma in Cirrhotic Liver: A Single‐Centre Experience
Authors: Yip Vincent S. K. , Poon Ronnie T. P. , Chok Kenneth S. H. , Chan Albert C. Y. , Dai Wing Chiu , Tsang Simon H. Y. , Chan See Ching , Lo Chung Mau , Cheung Tan To
Published: July 2015

Background

Right hepatectomy (RH) instead of right posterior sectionectomy (RPS) is commonly performed for hepatocellular carcinoma (HCC) in cirrhotic livers located lateral to the right hepatic vein in order to ensure adequate resection margin. This potentially increased the risk of postoperative liver failure. This study aims to compare survival outcomes and surgical morbidities between RH and RPS.

Methods

All patients between 2003 and 2013 with resection for solitary HCC in cirrhotic livers at segment 6/7 were reviewed. Baseline demographics, liver function, perioperative outcomes, and overall (OS) and disease‐free survival (DFS) were compared between RH and RPS.

Results

Eighty‐one patients were included in this study. Thirty‐two patients had RH and forty‐nine with RPS were selected as controls. Majority of the HCC patients (91.4 %) suffered from chronic hepatitis B. There was no significant difference in age, gender and Child‐Pugh grade between the two groups. The median tumour size of RH group was 6 vs. 4 cm in the RPS group (p < 0.0001). Both groups had no statistical difference in resection margin and their associated morbidities. The 5‐year OS for RH and RPS was 76 and 83.8 %, respectively (p = 0.766), whereas their corresponding DFS was 52.6 and 52.2 % (p = 0.859). Despite the discrepancy of tumour size among the two groups, there was no statistical difference in subgroup analysis based on their corresponding stage of disease.

Conclusion

RPS can achieve similar OS and DFS as RH for HCC, and should be considered as the treatment of choice in order to optimise the postoperative remnant parenchymal liver functions.
Influence of glucose fermentation on CO2 assimilation to acetate in homoacetogen Blautia coccoides GA-1
Authors: Liu Chong , Li Jianzheng , Zhang Yupeng , Philip Antwi , Shi En , Chi Xue , Meng Jia
Published: July 2015

Fermentation of glucose influences CO2 assimilation to acetate in homoacetogens. Blautia coccoides was investigated for a better understanding of the metabolic characteristics of homoacetogens in mixotrophic cultures. Batch cultures of the strain with H2/CO2 as a sole carbon source reached an acetate yield of 5.32 g/g dry cell weight after 240 h of incubation. Autotrophic metabolism was inhibited as glucose was added into the culture: the higher the glucose concentration the lower the autotrophic ability of the bacterium. Autotrophy was inhibited by high glucose concentration, probably due to the competition for coenzyme A between the Embden-Meyerhof-Parnas pathway and the Wood-Ljungdahl carbon fixation pathway, the energy (adenosine triphosphate) allocation for synthesis of cell carbon and reduction of CO2, in combination with the low pH caused by the accumulation of acetate.
Exploring medium-chain-length polyhydroxyalkanoates production in the engineered yeast Yarrowia lipolytica
Authors: Gao Cuijuan , Qi Qingsheng , Madzak Catherine , Lin Carol Sze Ki
Published: July 2015

Medium-chain-length polyhydroxyalkanoates (mcl-PHAs) are a large class of biopolymers that have attracted extensive attention as renewable and biodegradable bio-plastics. They are naturally synthesized via fatty acid de novo biosynthesis pathway or β-oxidation pathway from Pseudomonads. The unconventional yeast Yarrowia lipolytica has excellent lipid/fatty acid catabolism and anabolism capacity depending of the mode of culture. Nevertheless, it cannot naturally synthesize PHA, as it does not express an intrinsic PHA synthase. Here, we constructed a genetically modified strain of Y. lipolytica by heterologously expressing PhaC1 gene from P. aeruginosa PAO1 with a PTS1 peroxisomal signal. When in single copy, the codon optimized PhaC1 allowed the synthesis of 0.205 % DCW of PHA after 72 h cultivation in YNBD medium containing 0.1 % oleic acid. By using a multi-copy integration strategy, PHA content increased to 2.84 % DCW when the concentration of oleic acid in YNBD was 1.0 %. Furthermore, when the recombinant yeast was grown in the medium containing triolein, PHA accumulated up to 5.0 % DCW with as high as 21.9 g/L DCW, which represented 1.11 g/L in the culture. Our results demonstrated the potential use of Y. lipolytica as a promising microbial cell factory for PHA production using food waste, which contains lipids and other essential nutrients.