bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of objectively assessed physical activity and sedentary time with health‐related quality of life among colon cancer survivors
Authors: Vallance Jeff K. , Boyle Terry , Courneya Kerry S. , Lynch Brigid M.
Published: June 2014

BACKGROUND

The primary purpose of this study was to determine associations of accelerometer‐assessed moderate‐ to vigorous‐intensity physical activity (MVPA) and sedentary time with health‐related quality of life (HRQoL) and physical function and well‐being in colon cancer survivors.

METHODS

Colon cancer survivors (N = 178) from Alberta, Canada (n = 92) and Western Australia (n = 86) completed a mailed survey that assessed HRQoL (Functional Assessment of Cancer Therapy–Colorectal), physical function and well‐being (Trial Outcome Index–Colorectal), and relevant covariates. MVPA and sedentary time were assessed using the Actigraph GT3X+ accelerometer (60‐second epochs) via a 7‐day monitoring protocol. Average daily MVPA and sedentary time was corrected for wear time and then examined as quartiles.

RESULTS

Adjusting for relevant demographic, behavioral, and clinical covariates, a significant difference in HRQoL scores emerged between quartile 1 (Q1) and Q4 (Mdiff = 11.5, P = .038). For physical function and well‐being, a significant difference emerged between Q1 and Q4 (Mdiff = 9.1, P = .009). For fatigue, a significant difference emerged between Q1 and Q4 (Mdiff = 7.1, P = .05). Significant differences were also observed for between Q1 and Q3 (Mdiff = 2.4, P = .041), and Q1 and Q4 (Mdiff = 3.5, P = .002) for colorectal cancer–specific symptoms. There were no statistically significant associations of sedentary time with HRQoL, physical function and well‐being, fatigue, or colorectal cancer–specific symptoms.

CONCLUSIONS

Objectively measured MVPA, but not sedentary time, was associated with better HRQoL, physical function and well‐being, and colorectal cancer–specific symptoms in colon cancer survivors. For MVPA, differences met or exceeded contemporary cutpoints for determining clinically important differences. Cancer 2014;120:2919–2926. © 2014 American Cancer Society.
TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA
Authors: Wang Na , Liu Tiantian , Sofiadis Anastasios , Juhlin C. Christofer , Zedenius Jan , Höög Anders , Larsson Catharina , Xu Dawei
Published: June 2014

BACKGROUND

The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis.

METHODS

The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme‐linked immunosorbent assay kit.

RESULTS

The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T‐negative adenomas lacked TERT expression (C228T versus wild‐type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T‐mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow‐up period (36‐285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival.

CONCLUSIONS

TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup. Cancer 2014;120:2965–2979. © 2014 American Cancer Society.
Seifert Conjecture in the Even Convex Case
Authors: Liu Chungen , Zhang Duanzhi
Published: June 2014

In this paper, we prove that there exist at least n geometrically distinct brake orbits on every C2 compact convex symmetric hypersurface Σ in ℝ2n satisfying the reversible condition NΣ = Σ with N = diag(−In,In). As a consequence, we show that if the Hamiltonian function is convex and even, then Seifert conjecture of 1948 on the multiplicity of brake orbits holds for any positive integern. © 2014 Wiley Periodicals, Inc.
Vorapaxar, an oral PAR‐1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone
Authors: Kosoglou Teddy , Kumar Bharath , Statkevich Paul , Schiller James E. , Kantesaria Bhavna , Hanson Mary E. , Sisk Christine McCrary , Cutler David L.
Published: June 2014

Purpose

To evaluate the potential effects of vorapaxar on the pharmacokinetics and safety of rosiglitazone.

Methods

This was an open‐label, two‐period, two‐treatment, fixed‐sequence study in 18 healthy subjects. On Day 1, Period 1, subjects received a single dose of rosiglitazone 8 mg. In Period 2, subjects received vorapaxar 40 mg on Day 1, vorapaxar 7.5 mg once‐daily on Days 2–7, and a single dose of rosiglitazone 8 mg on Day 7. Rosiglitazone and N‐desmethylrosiglitazone pharmacokinetics were assessed alone (Period 1) and after coadministration with vorapaxar (Period 2). Vorapaxar and its M20 metabolite pharmacokinetics were assessed on Day 7, Period 2. Safety and tolerability were assessed throughout the study.

Results

Coadministration of rosiglitazone with vorapaxar had no effect on rosiglitazone or N‐desmethylrosiglitazone pharmacokinetics. The ratio of geometric means (GMR) and 90% confidence intervals (CI) of the coadministration versus monotherapy for Cmax (GMR 95; 90% CI 88, 103) and AUC0–24 h (GMR 103; 90% CI 98, 108) were within the 80–125% bioequivalence criteria. The metabolite‐to‐parent exposure ratio with and without vorapaxar was unaltered. Coadministration of vorapaxar with rosiglitazone was generally well tolerated.

Conclusion

Coadministration of vorapaxar with rosiglitazone or drugs metabolized via CYP2C8 is unlikely to cause a significant pharmacokinetic interaction.
Probing Protonation Sites of Isolated Flavins Using IR Spectroscopy: From Lumichrome to the Cofactor Flavin Mononucleotide
Authors: Langer Judith , Günther Alan , Seidenbecher Sophie , Berden Giel , Oomens Jos , Dopfer Otto
Published: June 2014

Infrared spectra of the isolated protonated flavin molecules lumichrome, lumiflavin, riboflavin (vitamin B2), and the biologically important cofactor flavin mononucleotide are measured in the fingerprint region (600–1850 cm−1) by means of IR multiple‐photon dissociation (IRMPD) spectroscopy. Using density functional theory calculations, the geometries, relative energies, and linear IR absorption spectra of several low‐energy isomers are calculated. Comparison of the calculated IR spectra with the measured IRMPD spectra reveals that the N10 substituent on the isoalloxazine ring influences the protonation site of the flavin. Lumichrome, with a hydrogen substituent, is only stable as the N1‐protonated tautomer and protonates at N5 of the pyrazine ring. The presence of the ribityl unit in riboflavin leads to protonation at N1 of the pyrimidinedione moiety, and methyl substitution in lumiflavin stabilizes the tautomer that is protonated at O2. In contrast, flavin mononucleotide exists as both the O2‐ and N1‐protonated tautomers. The frequencies and relative intensities of the two CO stretch vibrations in protonated flavins serve as reliable indicators for their protonation site.
Application of liquid‐based transepithelial flexible brush cytology in the detection of high‐grade laryngeal mucosal lesions
Authors: Afrogheh Amir , Pelser Andrew , Hille Jos , Attwood Rory , Loock James , Schubert Pawel Tomasz
Published: June 2014

Background

The aim of this study was to evaluate the effectiveness of liquid‐based transepithelial flexible brush cytology (LBTFBC) in the detection of high‐grade laryngeal mucosal lesions.

Methods

Diagnostic accuracies of LBTFBC and flexible biopsy (FB) were compared with the gold standard of biopsy under general anaesthesia (BUA) in 49 and 46 patients, respectively. Using a flexible laryngoscope, transepithelial cytology and biopsy specimens were obtained with the aid of flexible brushes and biopsy forceps. Cytology specimens were graded and scored using a recently proposed oral cytologic grading and scoring system.

Results

Cytology showed 97, 29% sensitivity, 100% specificity, 97.9% accuracy, and FB disclosed 77.1% sensitivity, 100% specificity, and 82.2% accuracy when compared with BUA. The best cutoff value for discriminating reactive/mildly dysplastic lesions from high‐grade dysplasias/invasive squamous cell carcinomas (SCCs) was determined as a cytologic score of 3, with sensitivity and specificity of 100%.

Conclusion

LBTFBC is a simple office‐based procedure, which in combination with the newly proposed classification scheme appears to be an accurate technique in the detection of high‐grade laryngeal mucosal lesions. LBTFBC is more effective than FB owing to the enhanced range of sampling and ease of application. It effectively eliminates the need for general anaesthesia, and thus reducing theatre costs and the number of hospital admissions. LBTFBC is ideal for patients who require regular clinical examinations, where repeated biopsies may lead to significant vocal morbidity. Diagn. Cytopathol. 2015;43:21–27. © 2014 Wiley Periodicals, Inc.
Ferromagnetic Coupling in an Fe[C(SiMe3)3]2/Ferrihydrite Hetero‐Mixture Molecular Magnet
Authors: Kuzmann Ernő , Zoppellaro Giorgio , Pechousek Jiri , Cuda Jan , Klencsár Zoltán , Homonnay Zoltán , Tucek Jiri , Szalay Roland , Pápai Mátyás , Machala Libor , Zboril Radek
Published: June 2014

Magnetization and low temperature in‐field 57Fe Mössbauer spectroscopy measurements have been performed on a Fe[C(SiMe3)3]2/ferrihydrite hetero‐mixture. The results indicate the presence of ferromagnetic coupling of magnetic moments involving Fe[C(SiMe3)3]2 with a hyperfine magnetic field of about 151 T, attributable mainly to the non‐frozen atomic orbital contribution. The present findings show the sensitivity of single‐ion molecular magnets to local alterations of their lattice‐environment and might explain and reconcile some of the differences found in the literature for the observed bulk magnetic properties of the title Fe[C(SiMe3)3]2 compound.
Mono‐ vs. Dinuclear Gold‐Catalyzed Intermolecular Hydroamidation
Authors: Serrano‐Becerra Juan M. , Maier Alexander F. G. , González‐Gallardo Sandra , Moos Eric , Kaub Christoph , Gaffga Maximilian , Niedner‐Schatteburg Gereon , Roesky Peter W. , Breher Frank , Paradies Jan
Published: June 2014

Mono‐ and dinuclear gold catalysts were investigated in the intermolecular hydroamidation of olefins. Upon activation of [Ph3PAuCl] and [xantphos(AuCl)2] with various silver salts (AgOTf, Ag[BF4], and Ag[SbF6]), diverging reactivity of the resulting cationic gold complexes was observed. It was found that both the binding ability of the counterion and the solvent have a significant impact on the reactivity of the mono‐ and dinuclear complexes.
Alkynylation of Aldehydes and Ketones Using the Bu4NOH/H2O/DMSO Catalytic Composition: A Wide‐Scope Methodology
Authors: Schmidt Elena Yu. , Cherimichkina Natalia A. , Bidusenko Ivan A. , Protzuk Nadezhda I. , Trofimov Boris A.
Published: June 2014

The Favorsky reaction of a wide range of aldehydes and ketones with alkynes has been implemented under mild conditions (5–20 °C). Using a Bu4NOH/H2O/DMSO catalytic system, propargylic alcohols are formed cleanly in 39–93 % (mostly 72–93 %) yields and with ca. 100 % selectivity. The method is suitable for aliphatic, aromatic, and heteroaromatic aldehydes and ketones, and for aliphatic, aromatic, and functionalized acetylenes. Thus, this represents the most general and efficient protocol to achieve the Favorsky reaction.
Protein microarray generation by in situ protein expression from template DNA
Authors: Kilb Normann , Burger Jürgen , Roth Günter
Published: June 2014

Today, whole genomes are analyzed by Next‐Generation Sequencing systems, or displayed by DNA microarray in situ synthesis. However, genomic data are mainly static and do not exactly reveal the complexity of protein interaction networks of any organism or cell. To investigate protein interactions, the generation of protein microarrays, displaying whole proteomes is a prerequisite. But traditional protein microarray generation is time consuming, costly, and is restricted by a wide range of technical difficulties concerning cell culturing, protein purification, and transfer onto microarray. Some of these obstacles can be bypassed by application of cell‐free expression systems, enabling fast in situ synthesis of protein microarrays without need for cell culturing. This review provides a historical timeline of the different methods to generate protein microarrays by cell‐free expression, highlights differences and similarities, and reports the current state of the different approaches.
Estimation of Energy Production of Dye‐Sensitized Solar Cell Modules for Building‐Integrated Photovoltaic Applications
Authors: Reale Andrea , Cinà Lucio , Malatesta Ambra , De Marco Riccardo , Brown Thomas M. , Di Carlo Aldo
Published: June 2014

The standard parameters considered to compare energy‐harvesting efficiency such as the efficiency measured in standard test conditions or the concept of peak Watt power production may lead to an incorrect estimation of the real producible energy. In this work, we aim to confirm that in realistic outdoor building‐integrated photovoltaic (BIPV) installations, the gap between dye‐sensitized solar cells (DSC) and other available technologies is lower than expected in terms of producible energy. We have developed a model for the evaluation of the producible energy on a generic BIPV site with DSC technology. Average daily irradiation and temperature are considered to integrate the instantaneous power to obtain the energy production. To compare the producible energy of DSC technology with other commercial photovoltaic technologies (crystalline and amorphous silicon, CdTe, or copper indium gallium selenide), we use the estimation of energy production available under the Photovoltaic Geographical Information System platform.
The Effect of Nickel and Graphite on the Hydrogen Storage Ability of Magnesium in the First Cycle
Authors: Sohrabi Soheila , Irankhah Abdullah
Published: June 2014

Magnesium can serve as a solid‐state hydrogen‐storage material, and over recent years it has been taken into consideration owing to its high storage capacity. The effect of 10 wt % nickel and graphite (G) on hydrogen sorption of magnesium was compared. The powder mixture was mechanically milled for 35 h under an argon atmosphere. A Sievert apparatus was used for hydrogen sorption analysis. Scanning electron microscopy and X‐ray diffraction were used for morphological characterization. Hydrogen sorption analysis was performed at 3.5 MPa and 473 K. The results showed that graphite had a better effect than nickel on the hydrogen storage properties of magnesium owing to a greater reduction in the particle size of magnesium and the physisorption of hydrogen by graphite. The hydrogen adsorption of Mg+10 wt % G was also investigated at 2.0, 3.5, and 4.0 MPa, and it was found that the compound adsorbed 5.7 wt % hydrogen at 4.0 MPa because hydrogen could penetrate into the inner parts of the magnesium powder at higher pressure.
Identification of interspecific differences in phase II reactions: Determination of metabolites in the urine of 16 mammalian species exposed to environmental pyrene
Authors: Saengtienchai Aksorn , Ikenaka Yoshinori , Nakayama Shouta M.M. , Mizukawa Hazuki , Kakehi Mayu , Bortey-Sam Nesta , Darwish Wageh Sobhy , Tsubota Toshio , Terasaki Masanori , Poapolathep Amnart , Ishizuka Mayumi
Published: June 2014

Interspecific differences in xenobiotic metabolism are a key to determining relative sensitivities of animals to xenobiotics. However, information on domesticated livestock, companion animals, and captive and free-ranging wildlife is incomplete. The present study evaluated interspecific differences in phase II conjugation using pyrene as a nondestructive biomarker of polycyclic aromatic hydrocarbon (PAH) exposure. Polycyclic aromatic hydrocarbons and their metabolites have carcinogenic and endocrine-disrupting effects in humans and wildlife and can have serious consequences. The authors collected urine from 16 mammalian species and analyzed pyrene metabolites. Interspecific differences in urinary pyrene metabolites, especially in the concentration and composition of phase II conjugated metabolites, were apparent. Glucuronide conjugates are dominant metabolites in the urine of many species, including deer, cattle, pigs, horses, and humans. However, they could not be detected in ferret urine even though the gene for ferret Uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) 1A6 is not a pseudogene. Sulfate conjugates were detected mainly in the urine of cats, ferrets, and rabbits. Interestingly, sulfate conjugates were detected in pig urine. Although pigs are known to have limited aryl sulfotransferase activity, the present study demonstrated that pig liver was active in 1-hydroxypyrene sulfation. The findings have some application for biomonitoring environmental pollution. Environ Toxicol Chem 2014; 33:2062–2069. © 2014 SETAC
The direct and indirect effects of a glyphosate-based herbicide and nutrients on Chironomidae (Diptera) emerging from small wetlands
Authors: Baker Leanne F. , Mudge Joseph F. , Houlahan Jeff E. , Thompson Dean G. , Kidd Karen A.
Published: June 2014

Laboratory and mesocosm experiments have demonstrated that some glyphosate-based herbicides can have negative effects on benthic invertebrate species. Although these herbicides are among the most widely used in agriculture, there have been few multiple-stressor, natural system–based investigations of the impacts of glyphosate-based herbicides in combination with fertilizers on the emergence patterns of chironomids from wetlands. Using a replicated, split-wetland experiment, the authors examined the effects of 2 nominal concentrations (2.88 mg acid equivalents/L and 0.21 mg acid equivalents/L) of the glyphosate herbicide Roundup WeatherMax, alone or in combination with nutrient additions, on the emergence of Chironomidae (Diptera) before and after herbicide-induced damage to macrophytes. There were no direct effects of treatment on the structure of the Chironomidae community or on the overall emergence rates. However, after macrophyte cover declined as a result of herbicide application, there were statistically significant increases in emergence in all but the highest herbicide treatment, which had also received no nutrients. There was a negative relationship between chironomid abundance and macrophyte cover on the treated sides of wetlands. Fertilizer application did not appear to compound the effects of the herbicide treatments. Although direct toxicity of Roundup WeatherMax was not apparent, the authors observed longer-term impacts, suggesting that the indirect effects of this herbicide deserve more consideration when assessing the ecological risk of using herbicides in proximity to wetlands. Environ Toxicol Chem 2014; 33:2076–2085. © 2014 SETAC
Experimental Validation of Two‐Dimensional H2O and CO2 Co‐Electrolysis Modeling
Authors: Aicart J. , Laurencin J. , Petitjean M. , Dessemond L.
Published: June 2014

This work details an in‐house 2D electrochemical and thermal model of solid oxide electrolysis cell (SOEC) dedicated to the simultaneous electrolysis of steam and carbon dioxide. The apparent exchange current densities for both H2O and CO2 electrochemical reductions have been fitted on single electrolysis polarization curves obtained on a standard cathode supported cell (CSC). By using these values, predictive simulations have been performed in a co‐electrolysis mode. The results have been compared to experimental data obtained in the same conditions. A good agreement is found between the simulated points and the experimental polarization curves, meaning that the model stands to predict accurately the SOEC response in co‐electrolysis mode. Simulations have been performed to investigate co‐electrolysis mechanisms in terms of partial pressures, current densities, and overpotentials distributions along the cell. The relative influence of both water gas shift (WGS) reaction and CO2 electrolysis on the global CO production is also discussed.
The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration‐induced lesions
Authors: Pitter Kenneth L. , Tamagno Ilaria , Feng Xi , Ghosal Kaushik , Amankulor Nduka , Holland Eric C. , Hambardzumyan Dolores
Published: June 2014

In response to neurodegeneration, the adult mammalian brain activates a cellular cascade that results in reactive astrogliosis and microgliosis. The mechanism through which astrocytes become reactive and the physiological consequences of their activation in response to neurodegeneration is complex. While the activation and proliferation of astrocytes has been shown to occur during massive neuronal cell death, the functional relationship between these two events has not been clearly elucidated. Here we show that in response to kainic acid‐ (KA) induced neurodegeneration, the mitogen sonic hedgehog (SHH) is upregulated in reactive astrocytes. SHH activity peaks at 7 days and is accompanied by increased Gli activity and elevated proliferation in several cell types. To determine the functional role of SHH‐Gli signaling following KA lesions, we used a pharmacological approach to show that SHH secreted by astrocytes drives the activation and proliferation of astrocytes and microglia. The consequences of SHH‐Gli signaling in KA‐induced lesions appear to be independent of the severity of neurodegeneration. GLIA 2014;62:1595–1607
Hetaryl Thioketones: Synthesis and Selected Reactions
Authors: Mlostoń Grzegorz , Urbaniak Katarzyna , Gębicki Krzysztof , Grzelak Paulina , Heimgartner Heinz
Published: June 2014

A series of phenyl/hetaryl and bishetaryl thioketones have been prepared via oxygen/sulfur exchange of the corresponding ketones by treatment with Lawesson's reagent. The nonsymmetrical ketones were conveniently accessible via the reactions of lithiated furan, thiophene, and selenophene with N,N‐dimethylbenzamide and hetarylcarboxamides, respectively, whereas the symmetrical ketones were obtained by treatment of ethyl N,N‐dimethylcarbamate with 2 equiv of lithiated heterocycles. Under typical conditions, selected examples of the hetaryl thioketones were oxidized selectively to give thiocarbonyl S‐oxides (sulfines). Reactions with diazomethane at –65°C yielded 1,3‐dithiolanes in a regioselective manner and hetero‐Diels–Alder reactions of 2‐thienyl substituted thioketones with dimethyl acetylenedicarboxylate yielded the corresponding 7H‐thieno[2,3‐c]thiopyran‐4,5‐dicarboxylates.
THE EFFECTS OF TAXING SUGAR‐SWEETENED BEVERAGES ACROSS DIFFERENT INCOME GROUPS
Authors: Sharma Anurag , Hauck Katharina , Hollingsworth Bruce , Siciliani Luigi
Published: June 2014

This paper investigates the impact of sugar‐sweetened beverages (SSB) taxes on consumption, bodyweight and tax burden for low‐income, middle‐income and high‐income groups using an Almost Ideal Demand System and 2011 Household level scanner data. A significant contribution of our paper is that we compare two types of SSB taxes recently advocated by policy makers: A 20% flat rate sales (valoric) tax and a 20 cent/L volumetric tax. Censored demand is accounted for using a two‐step procedure. We find that the volumetric tax would result in a greater per capita weight loss than the valoric tax (0.41 kg vs. 0.29 kg). The difference between the change in weight is substantial for the target group of heavy purchasers of SSBs in low‐income households, with a weight reduction of up to 3.20 kg for the volumetric and 2.06 kg for the valoric tax. The average yearly per capita tax burden on low‐income households is $17.87 (0.21% of income) compared with $15.17 for high‐income households (0.07% of income) for the valoric tax, and $13.80 (0.15%) and $10.10 (0.04%) for the volumetric tax. Thus, the tax burden is lower, and weight reduction is higher under a volumetric tax. Copyright © 2014 John Wiley & Sons, Ltd.
WHAT EXPLAINS THE QUALITY AND PRICE OF GP SERVICES? AN INVESTIGATION USING LINKED SURVEY AND ADMINISTRATIVE DATA
Authors: Johar Meliyanni , Jones Glenn , Savage Elizabeth
Published: June 2014

We examine patient socioeconomic status, the strength of the patient–doctor relationship and local area competition as determinants of the quality and price of GP services. We exploit a large‐sample patient data set in Australia and its linkage to administrative databases. The sample contains over 260 000 patients and over 12 600 GPs, observed between 2005 and 2010. Controlling for GP fixed effects and patient health, we find no strong evidence that quality differs by patient age, gender, country of origin, health concession card status and income, but quality is increased by stronger patient–doctor relationship. Using a competition measure that is defined at the individual GP level and not restricted to a local market, we find that competition lowers quality. Price is increasing in patient income, whereas competition has a small impact on price. Copyright © 2014 John Wiley & Sons, Ltd.
Targeting CDK9 by wogonin and related natural flavones potentiates the anti‐cancer efficacy of the Bcl‐2 family inhibitor ABT‐263
Authors: Polier Gernot , Giaisi Marco , Köhler Rebecca , Müller Wolfgang W. , Lutz Christoph , Buss Eike C. , Krammer Peter H. , Li‐Weber Min
Published: June 2014

Tumor initiation, progression and resistance to therapies are tightly associated with over‐expression of anti‐apoptotic proteins Bcl‐2, Bcl‐xL, Bcl‐w and Mcl‐1. ABT‐263 (Navitoclax), an orally bio‐available small‐molecule mimetic of the Bcl‐2 homology domain 3, inhibits Bcl‐2, Bcl‐xL, and Bcl‐w and has shown anti‐cancer effects mainly on lymphomas and lymphocytic leukemia. Despite promising results obtained from the clinical trials, the use of ABT‐263 in patients is dose‐limited due to causing thrombocytopenia via inhibition of Bcl‐xL in platelets. ABT‐199 specifically inhibits Bcl‐2; however, its use is limited to tumors over‐expressing only Bcl‐2. Besides, many tumors resist treatment due to high levels of Mcl‐1 expression or develop resistance via up‐regulation of Mcl‐1 during long‐term exposure. These obstacles highlight the demand to improve the ABT‐263‐based therapy. In this study, we show that anti‐cancer flavones, e.g., wogonin, baicalein, apigenin, chrysin and luteolin enhance ABT‐263‐induced apoptosis in different cancer cell lines and in primary AML and ALL cells by down‐regulation of Mcl‐1 expression. Importantly, wogonin does not enhance the toxicity of ABT‐263 to proliferating normal T cells and thrombocytes. Wogonin also potentiates the lethality of ABT‐263 in cancer cells which have acquired resistance to ABT‐263. Furthermore, we show that combination of wogonin with ABT‐263 promotes in vivo tumor regression in a human T‐cell leukemia xenograft mouse model. Our study demonstrates that wogonin (and related flavones) reduce the effective dose of ABT‐263 thereby possibly decreasing the risk of adverse side effects.
HIPEC ROC I: A phase i study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum‐based chemotherapy in patients with platinum‐sensitive recurrent epithelial ovarian cancer
Authors: Zivanovic Oliver , Abramian Alina , Kullmann Maximilian , Fuhrmann Christine , Coch Christoph , Hoeller Tobias , Ruehs Hauke , Keyver‐Paik Mignon Denise , Rudlowski Christian , Weber Stefan , Kiefer Nicholas , Poelcher Martin L. , Thiesler Thore , Rostamzadeh Babak , Mallmann Michael , Schaefer Nico , Permantier Maryse , Latten Sandra , Kalff Joerg , Thomale Juergen , Jaehde Ulrich , Kuhn Walther C.
Published: June 2014

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum‐sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum‐based intravenous chemotherapy. Twelve patients with operable, recurrent platinum‐sensitive EOC (recurrence ≥6 months after first‐line therapy) were included according to the classical 3+3 dose‐escalation design at three dose levels—60, 80 and 100 mg/m2. After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41–43°C. Postoperatively, all patients were treated with standard intravenous platinum‐based combination chemotherapy. One of six patients experienced a dose‐limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m2. The remaining five patients treated with 100 mg/m2 tolerated their treatment well. The recommended phase II dose was established at 100 mg/m2. The mean peritoneal‐to‐plasma AUC ratio was 19·5 at the highest dose level. Cisplatin‐induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1–3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum‐based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m2 has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum‐sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m2. The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.
Molecular mechanisms and anti‐cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines)
Authors: Li‐Weber Min
Published: June 2014

Rocaglamides (= flavaglines) are potent natural anti‐cancer phytochemicals that inhibit cancer growth at nanomolar concentrations by the following mechanisms: (1) inhibition of translation initiation via inhibition of phosphorylation of the mRNA cap‐binding eukaryotic translation initiation factor eIF4E and stabilization of RNA‐binding of the translation initiation factor eIF4A in the eIF4F complex; (2) blocking cell cycle progression by activation of the ATM/ATR‐Chk1/Chk2 checkpoint pathway; (3) inactivation of the heat shock factor 1 (HSF1) leading to up‐regulation of thioredoxin‐interacting protein (TXNIP) and consequent reduction of glucose uptake and (4) induction of apoptosis through activation of the MAPK p38 and JNK and inhibition of the Ras‐CRaf‐MEK‐ERK signaling pathway. Besides the anti‐cancer activities, rocaglamides are also shown to protect primary cells from chemotherapy‐induced cell death and alleviate inflammation‐ and drug‐induced injury in neuronal tissues. This review will focus on the recently discovered molecular mechanisms of the actions of rocaglamides and highlights the benefits of using rocaglamides in cancer treatment.
Advances and Challenges in the Synthesis of Poly(p‐phenylene vinylene)‐Based Polymers
Authors: Blayney Alan J. , Perepichka Igor F. , Wudl Fred , Perepichka Dmitrii F.
Published: June 2014

We provide an overview of the current progress in the synthesis of poly(p‐phenylene vinylene) (PPV) polymers. The described synthetic approaches can be divided into four main categories: polymerization of quinodimethane intermediates, metathesis polymerization, nucleophilic polycondensation, and palladium‐catalyzed cross‐coupling. While such variety is remarkable and very high‐molecular‐weight PPV can be prepared by some methods, the synthetic chemistry of PPV still limits the structural variety and purity of arylene vinylene polymers. In particular, palladium‐catalyzed cross‐coupling reactions, the method of choice in the contemporary conjugated polymer chemistry, often shows limited success in PPV series. On the other hand, the possibility of using metathesis polymerization creates new opportunities not available for other classes of conjugated polymers.
Odanacatib Treatment Affects Trabecular and Cortical Bone in the Femur of Postmenopausal Women: Results of a Two-Year Placebo-Controlled Trial
Authors: Engelke Klaus , Fuerst Thomas , Dardzinski Bernard , Kornak John , Ather Shabana , Genant Harry K , de Papp Anne
Published: June 2014

Odanacatib, a selective cathepsin K inhibitor, increases areal bone mineral density (aBMD) at the spine and hip of postmenopausal women. To gain additional insight into the effects on trabecular and cortical bone, we analyzed quantitative computed tomography (QCT) data of postmenopausal women treated with odanacatib using Medical Image Analysis Framework (MIAF; Institute of Medical Physics, University of Erlangen, Erlangen, Germany). This international, randomized, double-blind, placebo-controlled, 2-year, phase 3 trial enrolled 214 postmenopausal women (mean age 64 years) with low aBMD. Subjects were randomized to odanacatib 50 mg weekly (ODN) or placebo (PBO); all participants received calcium and vitamin D. Hip QCT scans at 24 months were available for 158 women (ODN: n = 78 women; PBO: n = 80 women). There were consistent and significant differential treatment effects (ODN-PBO) for total hip integral (5.4%), trabecular volumetric BMD (vBMD) (12.2%), and cortical vBMD (2.5%) at 24 months. There was no significant differential treatment effect on integral bone volume. Results for bone mineral content (BMC) closely matched those for vBMD for integral and trabecular compartments. However, with small but mostly significant differential increases in cortical volume (1.0% to 1.3%) and thickness (1.4% to 1.9%), the percentage cortical BMC increases were numerically larger than those of vBMD. With a total hip BMC differential treatment effect (ODN-PBO) of nearly 1000 mg, the proportions of BMC attributed to cortical gain were 45%, 44%, 52%, and 40% for the total, neck, trochanter, and intertrochanter subregions, respectively. In postmenopausal women treated for 2 years, odanacatib improved integral, trabecular, and cortical vBMD and BMC at all femur regions relative to placebo when assessed by MIAF. Cortical volume and thickness increased significantly in all regions except the femoral neck. The increase in cortical volume and BMC paralleled the increase in cortical vBMD, demonstrating a consistent effect of ODN on cortical bone. Approximately one-half of the absolute BMC gain occurred in cortical bone. © 2014 American Society for Bone and Mineral Research.
Prednisone has no effect on the pharmacokinetics of CYP3A4 metabolized drugs – midazolam and odanacatib
Authors: Marcantonio Eugene E. , Ballard Jeanine , Gibson Christopher R. , Kassahun Kelem , Palamanda Jairam , Tang Cuyue , Evers Raymond , Liu Chengcheng , Zajic Stefan , Mahon Chantal , Mostoller Kate , Hreniuk David , Mehta Anish , Morris Denise , Wagner John A. , Stoch S. Aubrey
Published: June 2014

We evaluated the effect of prednisone on midazolam and odanacatib pharmacokinetics. In this open‐label, 2‐period crossover study in healthy male subjects, midazolam 2 mg was administered (Day −1) followed by odanacatib 50 mg (Day 1) during Part 1. In Period 2, prednisone 10 mg once daily (qd) was administered on Days 1–28; odanacatib was co‐administered on Day 14 and midazolam 2 mg was co‐administered on Days 1 and 28. Subjects were administered midazolam 2 mg on Days 42 and 56. Safety and tolerability were assessed throughout the study. A physiologically‐based pharmacokinetic (PBPK) model was also built. There were 15 subjects enrolled; mean age was 31 years. The odanacatib AUC0−∞ GMR (90% CI) [odanacatib + prednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC0−∞ GMR (90%CI) [midazolam + prednisone (Day 28, Period 2)/midazolam alone (Day −1, Period 1] was 1.08 (0.93,1.26). There were no serious AEs or AEs leading to discontinuation. PBPK modeling showed that prednisone does not cause significant effects on the exposure of sensitive CYP3A4 substrates in vivo at therapeutic doses. Co‐administration of prednisone 10 mg qd had no effect on pharmacokinetics of either odanacatib 10 mg or midazolam 2 mg.
Free‐floating thrombus in stroke patients with nonstenotic internal carotid artery—An ultrasonographic study
Authors: Vassileva Evguenia , Daskalov Marin , Stamenova Paraskeva
Published: June 2014

Background

There are multiple causes of free‐floating thrombus (FFT) formation in carotid arteries. The purpose of this study was to evaluate the incidence and natural history of FFT in nonstenotic internal carotid arteries of patients with acute ischemic stroke.

Methods

During a 50‐month period, 3,200 consecutive patients with acute ischemic stroke were evaluated for internal carotid artery stenosis and the presence of FFT by color‐coded duplex ultrasonography. Diagnostic workup included brain CT, transthoracic echocardiography, Holter electrocardiogram, and hypercoagulability state evaluation.

Results

We found an FFT in 5 (0.18%) of 2,757 patients with acute stroke and nonstenotic internal carotid artery (mean age 44 years). The underlying pathology was hypercoagulable state in active pulmonary tuberculosis (n = 1), essential thrombocythemia (n = 1), thrombotic complications of nonstenotic plaques (n = 1), unknown (n = 2). All patients clinically improved under antiplatelet therapy. Follow‐up color‐coded duplex ultrasonography showed complete dissolution of FFT in all cases. There was no stroke recurrence.

Conclusions

Internal carotid artery FFT could be found in young stroke patients without identifiable arterial disease and could be resolved with antithrombotic treatment © 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:34–38, 2015
Pyridinium Ylide Assisted Highly StereoselectiveOne‐Pot Synthesis of trans‐2‐(4‐Chlorobenzoyl)‐3‐aryl‐spiro[cyclopropane‐1,2′‐inden]‐1′,3′‐diones and Their Antimicrobial and Nematicidal Activities
Authors: Banothu Janardhan , Basavoju Srinivas , Bavantula Rajitha
Published: June 2014

A series of highly stereoselective polysubstituted cyclopropane derivatives were synthesized via one‐pot two‐step tandem reaction starting from pyridine, 4‐chloro phenacyl bromide, 1,3‐indandione and aromatic aldehydes in acetonitrile using triethylamine as catalyst. Pyridinium ylide generated from 4‐chloro phenacyl bromide undergo cyclopropanation with 2‐arylidene‐2H‐indene‐1,3‐dione in situ afford the title compounds. Structures of all the compounds were confirmed by their analytical and spectral studies. Single crystal X‐ray analysis was also performed on compound 4c in order to determine the crystal structure. All the compounds were screened for antimicrobial and nematicidal activities. Significant antimicrobial activity was shown by the compounds derived from 2‐hydroxybenzaldehyde (4i) and 4‐(dimethylamino)benzaldehyde (4m) against all the tested bacterial and fungal strains. Compound 4i has shown good activity (48% mortality) against Meloidogyne incognita after 48 h of exposure at 250 µg/mL concentration.
Polymer‐Supported Sulfonic Acid‐Catalyzed Candid Synthesis and Photophysical Properties of 2H‐indazolo[2,1‐b]phthalazinetriones
Authors: Mulik Abhijeet , Chandam Dattatraya , Patil Prasad , Patil Dayanand , Jagdale Suryabala , Sankpal Sandip , Deshmukh Madhukar
Published: June 2014

Polystyrene‐supported sulfonic acid has been found to be an efficient catalyst for the one‐pot, three‐component synthesis of 2H‐indazolo[2,1‐b]phthalazinetriones in greener solvent glycerol. Use of greener solvent glycerol along with a polymer‐supported, low toxic, and inexpensive catalyst renders the method eco‐friendly. High yields, simple product isolation procedure, and fluorescent and electroluminescent natures of the products are the noteworthy aspects of this protocol.
Micro‐Raman spectra of extremely rare and endemic Tl‐sulfosalts from Allchar deposit
Authors: Makreski Petre , Jovanovski Gligor , Boev Blazo
Published: June 2014

The micro‐Raman spectra of the extremely rare Tl‐sulfosalts from Allchar (fangite, vrbaite, raguinite and rebulite) are presented and the bands are assigned for the first time although the minerals are known at least for 30 years. For the ease of the interpretation, the spectra–structure correlations were derived with the assistance of other natural Tl‐containing minerals also collected from Allchar (lorandite and parapierrotite) and other synthetic Tl‐analogues (ellisite, stibioellisite, and weissbergite), whose spectral characteristics have already been described. The similarities occurring in the Raman spectra arise from the presence of XS3 trigonal pyramids (X = As and/or Sb) and/or XS4 tetrahedral units (X = As and Fe) in the structure of all discussed Tl‐sulfosalts. In addition, particular attention is stressed on the used laser intensity, establishing proper individualized protocol for each laser‐sensitive Tl‐sulfosalt. Copyright © 2014 John Wiley & Sons, Ltd.
A Straightforward Synthesis of Chlorine‐Bearing Donor–Acceptor Alternating Copolymers with Deep Frontier Orbital Levels
Authors: Gao Xiang , Shen Jiulin , Hu Bin , Tu Guoli
Published: June 2014

Donor–acceptor alternating copolymers with chlorine atoms on the backbone are synthesized via a straightforward Stille polycondensation. Thiophene and chlorine‐substituted 2,3‐diphenylquinoxaline are chosen as the donor and acceptor moieties, respectively. Compared with the corresponding non‐substituted and fluorine‐substituted analogues, which are also synthesized for systematical studies, the chlorine‐bearing copolymer exhibits the deepest lowest unoccupied molecular orbital (LUMO). The highest occupied molecular orbital (HOMO) level of the chlorine‐bearing copolymer can be modified by applying different donor moieties. Additionally, these chlorine‐bearing copolymers show low self‐absorption and large Stokes Shift.

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Multiple solutions for a modified Kirchhoff‐type equation in RN
Authors: Feng Zong‐Hong , Wu Xian , Li Hong‐Xu
Published: June 2014

In this paper, we study the following modified Kirchhoff‐type equations of the form:
urn:x-wiley:1704214:media:mma3102:mma3102-math-0001

where a > 0, b ≥ 0, and . Under appropriate assumptions on V (x) and h(x,u), some existence results for positive solutions, negative solutions, and sequence of high energy solutions are obtained via a perturbation method. Copyright © 2014 John Wiley & Sons, Ltd.
Well‐conditioned boundary integral formulations for high‐frequency elastic scattering problems in three dimensions
Authors: Darbas M. , Le Louër F.
Published: June 2014

We construct and analyze a family of well‐conditioned boundary integral equations for the Krylov iterative solution of three‐dimensional elastic scattering problems by a bounded rigid obstacle. We develop a new potential theory using a rewriting of the Somigliana integral representation formula. From these results, we generalize to linear elasticity the well‐known Brakhage–Werner and combined field integral equation formulations. We use a suitable approximation of the Dirichlet‐to‐Neumann map as a regularizing operator in the proposed boundary integral equations. The construction of the approximate Dirichlet‐to‐Neumann map is inspired by the on‐surface radiation conditions method. We prove that the associated integral equations are uniquely solvable and possess very interesting spectral properties. Promising analytical and numerical investigations, in terms of spherical harmonics, with the elastic sphere are provided. Copyright © 2014 John Wiley & Sons, Ltd.
Stability and bifurcations analysis of a competition model with piecewise constant arguments
Authors: Kartal S. , Gurcan F.
Published: June 2014

In this paper, we investigate local and global asymptotic stability of a positive equilibrium point of system of differential equations
urn:x-wiley:1704214:media:mma3196:mma3196-math-0001

where t ≥ 0, the parameters r1, k1, α1, α2, r2, k2, and d1 are positive, and [t] denotes the integer part of t ∈ [0, ∞ ). x(t) and y(t) represent population density for related species. Sufficient conditions are obtained for the local and global stability of the positive equilibrium point of the corresponding difference system. We show through numerical simulations that periodic solutions arise through Neimark–Sacker bifurcation. Copyright © 2014 John Wiley & Sons, Ltd.
Formulation and numerical exploitation of mixed variational principles for coupled problems of Cahn–Hilliard‐type and standard diffusion in elastic solids
Authors: Miehe C. , Mauthe S. , Ulmer H.
Published: June 2014

This work develops variational principles for the coupled problem of standard and extended Cahn–Hilliard‐type species diffusion in solids undergoing finite elastic deformations. It shows that the coupled problem of diffusion in deforming solids, accounting for phenomena like swelling, diffusion‐induced stress generation and possible phase segregation caused by the diffusing species, is related to an intrinsic mixed variational principle. It determines the rates of deformation and concentration along with the chemical potential, where the latter plays the role of a mixed variable. The principle characterizes a canonically compact model structure, where the three governing equations involved, that is, the mechanical equilibrium condition, the mass balance for the species content and a microforce balance that determines the chemical potential, appear as the Euler equation of a variational statement. The existence of the variational principle underlines an inherent symmetry of the coupled deformation–diffusion problem. This can be exploited in the numerical implementation by the construction of time‐discrete and space‐discrete incremental potentials, which fully determine the update problems of typical time stepping procedures. The mixed variational principles provide the most fundamental approach to the monolithic finite element solution of the coupled deformation–diffusion problem based on low‐order basis functions. They induce in a natural format the choice of symmetric solvers for Newton‐type iterative updates, providing a speedup and reduction of data storage when compared with non‐symmetric implementations. This is a strong argument for the use of the developed variational principles in the computational design of deformation–diffusion problems. Copyright © 2014 John Wiley & Sons, Ltd.
Bridging multiple structural scales with a generalized finite element method
Authors: Plews J.A. , Duarte C.A.
Published: June 2014

This paper presents a generalized FEM based on the solution of interdependent coarse‐scale (global) and fine‐scale (local) problems in order to resolve multiscale effects due to fine‐scale heterogeneities. Overall structural behavior is captured by the global problem, while local problems focus on the resolution of fine‐scale solution features in regions where material heterogeneities may govern the structural response. Fine‐scale problems are accurately solved in parallel, and, to address the intrinsic coupling of scales, these solutions are embedded into the global solution space using a partition of unity approach. This method is demonstrated on representative heat transfer examples in order to examine its accuracy, efficiency, and flexibility. Copyright © 2014 John Wiley & Sons, Ltd.