bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrodynamical properties of recombinant spider silk proteins: Effects of pH, salts and shear, and implications for the spinning process
Authors: Leclerc Jérémie , Lefèvre Thierry , Gauthier Martin , Gagné Stéphane M. , Auger Michèle
Published: February 2013

We have investigated the effect of pH, salts and shear on the hydrodynamical diameter of recombinant major ampullate (MA) rMaSpI silk proteins in solution as a function of time using 1H solution NMR spectroscopy. The results indicate that the silk proteins in solution are composed of two diffusing populations, a high proportion of “native” solubilized proteins and a small amount of high molecular weight oligomers. Similar results are observed with the MA gland content. Salts help maintaining the proteins in a compact form in solution over time and inhibit aggregation, the absence of salts triggering protein assembly leading to a gel state. Moreover, the aggregation kinetics of rMaSpI at low salt concentration accelerates as the pH is close to the isoelectric point of the proteins, suggesting that the pH decrease tends to slow down aggregation. The data also support the strong impact of shear on the spinning process and suggest that the assembly is driven by a nucleation conformational conversion mechanism. Thus, the adjustment of the physicochemical conditions in the ampulla seems to promote a stable, long term storage. In addition, the optimization of protein conformation as well as their unfolding and aggregation propensity in the duct leads to a specifically organized structure. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 582–593, 2013.
Surgical leadership
Authors: Rothmund M
Published: February 2013

Still important
Development and validation of a highly sensitive LC‐ESI‐MS/MS method for the determination of hyperoside in beagle dog plasma: application to a pharmacokinetic study
Authors: Yin Xingbin , Li Zhaoxia , Zhai Yujing , Zhang Hui , Lin Longfei , Yang Pei , Cao Sali , Zhang Jin , Qi Juanjuan , Tian Jingchen , Fu Jing , Qu Changhai , Ni Jian
Published: February 2013

A highly sensitive, rapid assay method has been developed and validated for the analysis of hyperoside in beagle dog plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive‐ion mode. The assay procedure involves extraction of hyperoside and ginsenoside Re (IS) from beagle dog plasma. Chromatographic separation was carried out on an Agilent Zorbax XDB‐C18 (100 × 2.1 mm, 1.8 µm) column by isocratic elution with acetonitrile and water (50:50, v/v) at a flow rate of 0.25 mL/min with a total run time of 2.0 min. The MS/MS ion transitions monitored were 464.4 → 463.4 for hyperoside and 947.12 → 969.60 for IS. Linear responses were obtained for hyperoside ranging from 10 to 5000 ng/mL. The intra‐and inter‐day precisions (RSDs) were <5.38 and 3.39% and the extraction recovery ranged from 94.39 to 100.78% with an RSD <3.82%. Stability studies showed that hyperoside was stable in preparation and analytical process. The results indicated that the validated method was successfully used to determine the concentration–time profiles of hyperoside. Copyright © 2013 John Wiley & Sons, Ltd.
Surface Segregation of Pd from TiO2‐Supported AuPd Nanoalloys under CO Oxidation Conditions Observed In situ by ETEM and DRIFTS
Authors: Delannoy Laurent , Giorgio Suzanne , Mattei Jean Gabriel , Henry Claude R. , El Kolli Nadia , Méthivier Christophe , Louis Catherine
Published: February 2013

A TiO2‐supported AuPd bimetallic catalyst with an Au/Pd atomic ratio of 8 was prepared by deposition‐precipitation with urea, and its activity in CO oxidation at room temperature was compared to the one of a monometallic Au/TiO2 catalyst. X‐ray photoelectron spectroscopy (XPS) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analyses suggest that Au‐Pd/TiO2 contains bimetallic nanoparticles after reduction under H2 at 500 °C although the presence of monometallic Au particles cannot be totally excluded. The evolution of the AuPd nanoparticles surface composition during exposure to O2 and CO/O2 was studied in situ by environmental high resolution electron microscopy (ETEM) and DRIFTS. Pd segregation at the surface of the bimetallic nanoparticles was evidenced by DRIFTS and directly observed by ETEM under O2 and CO/O2 with the formation of Aucore‐Pdshell structure. The changes in the surface composition of the Au‐Pd nanoparticles under CO/O2 was paralleled with the higher rate of deactivation in the first reaction stages observed for Au‐Pd/TiO2 compared to Au/TiO2, which could be related to the possible replacement of Au in low coordination sites, at the origin of the high activity in CO oxidation, by Pd atoms. These results noticeably underline the modifications induced by the reactant that can undergo a bimetallic AuPd catalyst.
Combination of Black‐Light Photo‐catalysis and Ozonation for Emerging Contaminants Degradation in Secondary Effluents
Authors: Encinas Á. , Rivas F. J. , Beltrán F. J. , Oropesa A.
Published: February 2013

A water solution of emerging contaminants (ECs) was treated by advanced oxidation systems. Ozone‐based processes led to the highest ECs degradation rates. Regardless of the nature of the aqueous matrix, no differences in EC removal were obtained when O3 was added. Mineralization occurred to some extent when activated carbon (AC) or O3 were present. O3, UVA/TiO2/O2, and UVA/TiO2/O3 processes were applied in runs carried out with low ECs concentration. Single ozonation and photocatalytic ozonation led to the complete ECs degradation in less than 5 min. When a secondary effluent was used, the efficiency of the technologies decreased. With the exception of caffeine, a detrimental effect of other organic/inorganic compounds present in secondary effluents was observed.
Polyphenole: Vielseitige Pflanzeninhaltsstoffe
Authors: Kuhnert Nikolai
Published: February 2013

Alle Pflanzen stellen Polyphenole her, die sowohl strukturell als auch in ihren chemischen und biologischen Eigenschaften eine faszinierende Vielfalt zeigen. Während den pflanzlichen Organismen Polyphenole als UV‐Lichtschutz, als chemische Verteidigung gegen Mikroorganismen und Pflanzenfresser dienen und durch ihre Färbung Insekten anlocken, nutzen Menschen ihre Eigenschaften in industriellen Prozessen, dabei vor allem zur Verbesserung unserer Gesundheit. Polyphenole sind sowohl als Bestandteil unserer täglichen Nahrung als auch als Bestandteil traditioneller Arzneipflanzen in der Lage, in vielfältiger Weise mit den biochemischen Strukturen des menschlichen Stoffwechsels zu interagieren und Symptome wie auch Ursachen vieler Erkrankungen zu beeinflussen. Die Wirkung der Polyphenole als Antioxidantien, die viele Jahre lang zur Erklärung der gesundheitsförderlichen Eigenschaften der Polyphenole herangezogen wurde, ist nach neuesten Erkenntnissen in den Hintergrund getreten. Neue Ansätze zur Erklärung der biologischen Eigenschaften der Polyphenole haben sich in den letzten Jahren entwickelt, die die chemischen Veränderungen der Polyphenole durch Lebensmittelprozessierung und Metabolismus berücksichtigen und sich nur auf Verbindungen konzentrieren, die gut bioverfügbar sind. Die Verstoffwechselung und die Wirkweise der Polyphenole im menschlichen Körper hat sich in den letzten Jahren als komplizierter erwiesen als lange angenommen. Eine klare Antwort auf die Frage, welche Verbindungen gesund sind und wie diese wirken, ist erneut Gegenstand aktueller Forschung geworden.
Novel Schiff‐Base‐Derived FabH Inhibitors with Dioxygenated Rings as Antibiotic Agents
Authors: Zhou Yang , Du Qian‐Ru , Sun Jian , Li Jing‐Ran , Fang Fei , Li Dong‐Dong , Qian Yong , Gong Hai‐Bin , Zhao Jing , Zhu Hai‐Liang
Published: February 2013

Fatty acid biosynthesis plays a vital role in bacterial survival and several key enzymes involved in this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Of these promising targets, β‐ketoacyl‐acyl carrier protein (ACP) synthase III (FabH) is the most attractive target that could trigger the initiation of fatty acid biosynthesis and is highly conserved among Gram‐positive and ‐negative bacteria. Designing small molecules with FabH inhibitory activity displays great significance for developing antibiotic agents, which should be highly selective, nontoxic and broad‐spectrum. In this manuscript, a series of novel Schiff base compounds were designed and synthesized, and their biological activities were evaluated as potential inhibitors. Among these 21 new compounds, (E)‐N‐((3,4‐dihydro‐2H‐benzo[b][1,4]dioxepin‐7‐yl)methylene)hexadecan‐1‐amine (10) showed the most potent antibacterial activity with a MIC value of 3.89–7.81 μM−1 against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC50 value of 1.6 μM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.
Localized and metastatic myxoid/round cell liposarcoma
Authors: Hoffman Aviad , Ghadimi Markus P. H. , Demicco Elizabeth G. , Creighton Chad J. , Torres Keila , Colombo Chiara , Peng Tingsheng , Lusby Kristelle , Ingram Davis , Hornick Jason L. , Wang Wei‐Lie , Ravi Vinod , Lazar Alexander J. , Lev Dina , Pollock Raphael E.
Published: February 2013

BACKGROUND.

Myxoid liposarcoma (MLPS), a disease especially of young adults with potential for local recurrence and metastasis, currently lacks solid prognostic factors and therapeutic targets. The authors of this report evaluated the natural history and outcome of patients with MLPS and commonly deregulated protein biomarkers.

METHODS.

Medical records were retrospectively reviewed for patients who presented to the authors' institution with localized (n = 207) or metastatic (n = 61) MLPS (1990 to 2010). A tissue microarray of MLPS patient specimens (n = 169) was constructed for immunohistochemical analysis of molecular markers.

RESULTS.

The 5‐year and 10‐year disease‐specific survival rates among patients with localized disease were 93% and 87%, respectively; male gender, age >45 years, and recurrent tumor predicted poor outcome. The local recurrence rate was 7.4%, and the risk of local recurrence was associated with recurrent tumors and nonextremity disease location. Male gender was the main risk factor for metastatic disease, which occurred in 13% of patients. Forty percent of patients who had localized disease received chemotherapy, mostly in the neoadjuvant setting. Immunohistochemical analysis revealed significantly higher expression of C‐X‐C chemokine receptor type 4 (CXCR4) and platelet‐derived growth factor beta (PDGFR‐β) in metastatic lesions versus localized lesions. Tumors with a round cell phenotype expressed increased levels of CXCR4, p53, adipophilin, PDGFR‐α, PDGFR‐β, and vascular endothelial growth factor relative to myxoid phenotype. Only the receptor tyrosine kinase encoded by the AXL gene (AXL) was identified as a prognosticator of disease‐specific survival in univariate analysis.

CONCLUSIONS.

In this study, the authors identified clinical and molecular outcome prognosticators for patients with MLPS as well as several potential therapeutic targets. Cancer 2013. © 2013 American Cancer Society.
Identification of ROS1 rearrangement in gastric adenocarcinoma
Authors: Lee Jeeyun , Lee Seung Eun , Kang So Young , Do In‐Gu , Lee Sujin , Ha Sang Yun , Cho Jeonghee , Kang Won Ki , Jang Jiryeon , Ou Sai‐Hong Ignatius , Kim Kyoung‐Mee
Published: February 2013

BACKGROUND:

Recently, chromosomal rearrangements involving receptor tyrosine kinases (RTKs) have been described in common epithelial malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer, and breast cancer. One of these RTKs, c‐ros oncogene 1, receptor tyrosine kinase (ROS1), has been identified as a driver mutation in NSCLC, because its inhibition by crizotinib, an anaplastic lymphoma receptor tyrosine kinase (ALK)/met proto‐oncogene hepatocyte growth factor receptor (MET)/ROS1 inhibitor, led to significant tumor shrinkage in ROS1‐rearranged NSCLC. Currently, only human epidermal growth factor 2 (HER2)‐targeted therapy in combination with chemotherapy has been successful in significantly prolonging the survival of patients with advanced gastric cancer (GC). There is a need for the discovery of additional novel targets in GC.

METHODS:

Anti‐ROS1 immunohistochemistry (IHC) was used to screen 495 GC samples and was followed by simultaneous ROS1 break‐apart fluorescence in situ hybridization (FISH) and reverse transcriptase‐polymerase chain reaction (RT‐PCR) analyses in IHC‐positive samples. Fusion partners in ROS1‐rearranged GC were determined by RT‐PCR. In all 495 samples, HER2 amplification was identified with FISH, and MET expression was identified by IHC.

RESULTS:

Twenty‐three tumor samples were ROS1 IHC‐positive. Three of 23 patients were ROS1 FISH positive, HER2 FISH negative, and negative for MET overexpression; and 2 of those 3 patients harbored a solute carrier family 34 (sodium phosphate), member 2 (SLC34A2)‐ROS1 fusion transcripts. No fusion partner was identified in the third patient. Both patients who had SLC34A2‐ROS1 transcripts had poorly differentiated histology with recurrence and death within 2 years of curative surgery. ROS1 IHC‐positive status was not identified as an independent prognostic factor for overall survival.

CONCLUSIONS:

In this study, an SLC34A2‐ROS1 rearrangement was identified in GC, and the results provide a rationale for investigating the clinical efficacy of ROS1 inhibitors in this unique molecular subset of GC. Cancer 2013. © 2013 American Cancer Society.
Patterns of onset and resolution of immune‐related adverse events of special interest with ipilimumab
Authors: Weber Jeffrey S. , Dummer Reinhard , de Pril Veerle , Lebbé Celeste , Hodi F. Stephen ,   for the MDX010‐20 Investigators
Published: February 2013

BACKGROUND:

Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010‐20). Ipilimumab produced a characteristic spectrum of immune‐related adverse events (irAEs) of special interest, consistent with its immune‐based mechanism of action.

METHODS:

In MDX010‐20, 676 previously treated patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with ipilimumab therapy.

RESULTS:

Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0‐12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks.

CONCLUSIONS:

Most ipilimumab‐associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms. Cancer 2013. © 2013 American Cancer Society.
Modulation of Photophysics and pKa Shift of the Anti‐cancer Drug Camptothecin in the Nanocavities of Supramolecular Hosts
Authors: Gavvala Krishna , Sengupta Abhigyan , Hazra Partha
Published: February 2013

This article reports the pKa shift of an anti‐cancer drug, 20(S)‐camptothecin (CPT), upon encapsulation into the nanocavity of a cucurbit[7]uril (CB7) macrocycle. Steady‐state, time‐resolved fluorescence and electrospray ionisation mass spectrometry (ESI‐MS) studies provide evidence for the formation of both 1:1 and 2:1 (CB7⋅CPT) stoichiometries. Astonishingly, we have found that protonation of CPT takes place at a higher concentration of macrocycle (≥50 μM) when the 2:1 stoichiometric complex develops. However, we did not find any proof for protonation of CPT when it is encased by a β‐cyclodextrin cavity, which has a cavity size almost the same as that of CB7. Hence, we conclude that electron‐rich carbonyl portals of CB7 have an important role in protonation of the drug in the 2:1 inclusion complex. Docking and semi‐empirical quantum chemical calculations have been employed to gain an insight into the molecular picture of orientation of CPT in the inclusion complexes. It is clearly seen from the optimised structure of the 2:1 (CB7⋅CPT) inclusion complex that the quinoline nitrogen of CPT does not reside within either of the CB7 cavities, rather it is almost sandwiched between two CB7 rings, and therefore, it experiences huge electron density exerted by both carbonyl portals of the macrocycles. As a result, the pKa of CPT shifts from 1.2 to 6.2. Finally, controlled release of the drug has been achieved through the introduction of NaCl, which is rich in cells, as an external stimulus. We hope this recognition‐mediated binding and release mechanism can be useful for activation of the drug and controlled release of the drug in therapeutic uses.
Diabetic foot disease: impact of ulcer location on ulcer healing
Authors: Pickwell Kristy M. , Siersma Volkert D. , Kars Marleen , Holstein Per E. , Schaper Nicolaas C. ,   on behalf of the Eurodiale consortium
Published: February 2013

Background

Healing of heel ulcers in patients with diabetes is considered to be poor, but there is relatively little information on the influence of ulcer location on ulcer healing.

Methods

The influence of ulcer location on time to healing of diabetic foot ulcers was analysed by multivariate Cox regression analysis for 1000 patients included in the Eurodiale study, a prospective cohort study of patients with diabetic foot disease.

Results

Median time to healing was 147 days for toe ulcers [(95% confidence interval (CI) 135–159 days)], 188 days for midfoot ulcers (95% CI 158–218 days) and 237 days for heel ulcers (95% CI 205–269 days) (p < 0.01). The median time to healing for plantar ulcers was 172 days (95% CI 157–187 days) and 155 days (95% CI 138–172 days) for nonplantar ulcers (p = 0.71). In multivariate Cox regression analysis, the hazard ratio for ulcer healing for midfoot and heel ulcers compared with toe ulcers was 0.77 (95% CI 0.64–0.92) and 0.62 (95% CI 0.47–0.83), respectively; the hazard ratio for ulcer healing for plantar versus nonplantar ulcers was 1 (95% CI 0.84–1.19). Other factors significantly influencing time to healing were the duration of diabetes, ulcer duration, the presence of heart failure and the presence of peripheral arterial disease.

Conclusions

Time to ulcer healing increased progressively from toe to midfoot to heel, but did not differ between plantar and nonplantar ulcers. Our data also indicate that risk factors for longer time to healing differ from factors that affect the ultimate number of ulcers that heal (healing rate). Copyright © 2013 John Wiley & Sons, Ltd.
Preparation of a Heterodimetallic Di‐μ‐chlorido Complex of Palladium and Platinum
Authors: Sethi Navpreet K. , Whitwood Adrian C. , Bruce Duncan W.
Published: February 2013

The dimeric di‐μ‐chlorido anion hexachloridopalladate(II)platinate(II) has been prepared as a mixture with hexachloridodipalladate(II) and hexachloridodiplatinate(II) and has been identified by using a combination of X‐ray crystallography and 195Pt NMR spectroscopy. This is the first report of a heterodinuclear dimer of this type.
Triptycene‐Based, Carboxylate‐Bridged Biomimetic Diiron(II) Complexes
Authors: Li Yang , Soe Chan Myae Myae , Wilson Justin J. , Tuang Suan Lian , Apfel Ulf‐Peter , Lippard Stephen J.
Published: February 2013

A triptycene‐based bis(benzimidazole) ester ligand, L3, was designed to enhance the electron‐donating ability of the heterocyclic nitrogen atoms relative to those of the first‐generation bis(benzoxazole) analogs, L1 and L2. A convergent synthesis of L3 was designed and executed. Three‐component titration experiments using UV/Vis spectroscopy revealed that the desired diiron(II) complex could be obtained with a 1:2:1 ratio of L3/Fe(OTf)2(MeCN)2/external carboxylate reactants. X‐ray crystallographic studies of two diiron complexes derived in this manner from L3 revealed their formulas to be [Fe2L3(μ‐OH)(μ‐O2CR)(OTf)2], where R = 2,6‐bis(p‐tolyl)phenyl (7) or triphenylmethyl (8). The structures are similar to that of a diiron complex derived from L1, [Fe2L1(μ‐OH)(μ‐O2CArTol)(OTf)2] (9), a notable difference being that, in 7 and 8, the geometry at iron more closely resembles square‐pyramidal than trigonal‐bipyramidal. Mössbauer spectroscopic analyses of 7 and 8 indicate the presence of high‐spin diiron(II) cores. These results demonstrate the importance of substituting benzimidazole for benzoxazole for assembling biomimetic diiron complexes with syn disposition of two N‐donor ligands, as found in O2‐activating carboxylate‐bridged diiron centers in biological systems.
Recent effects of tidal and hydro‐meteorological changes on coastal plains near the mouth of the Amazon River
Authors: Guimarães José Tasso Felix , Cohen Marcelo Cancela Lisboa , França Marlon Carlos , Pessenda Luiz Carlos Ruiz , de Jesus Souza Eduardo , Nogueira Afonso César Rodrigues , Alves Ronnie
Published: February 2013

The goal of this work was to understand the main hydrodynamic processes acting on tidal flats of the coast of Amapá near the mouth of the Amazon River, and how they change over the short term (~ 20 years). The analysis of morphological and geobotanical units was carried out by applying processing and interpretation methods to optical and synthetic aperture radar (SAR) images, combined with data on water salinity, maximum flood height, sedimentary facies data, rainfall and river discharge. The temporal analysis of morphological and geobotanical units suggests the relative stabilization of savannah, ‘várzea’ and mangrove areas during the drier period and increasing tidal amplitude between 1987 to 1997. The wetter period and decreasing tidal amplitude between 1997 to 2008 led to an increase in the area of ‘várzea’ and lakes over savannah, and the expansion of mangroves mainly over the inundated field and tidal mud/mixed flats. Therefore, the decrease in rainfall index during the drier period is well‐correlated with the reduction of the Calçoene River discharge and jointly with increasing tidal amplitude favored the increase of migration rate of the mud bank and erosion profile along the littoral. It was followed by the increase of the Calçoene River discharge and jointly with decreasing tidal amplitude during the wetter period, favoring the development of mangroves on muddy substrates near the coastline. Copyright © 2013 John Wiley & Sons, Ltd.
CROSS-SPECIES CONSERVATION OF ENDOCRINE PATHWAYS: A CRITICAL ANALYSIS OF TIER 1 FISH AND RAT SCREENING ASSAYS WITH 12 MODEL CHEMICALS
Authors: Ankley Gerald T. , Gray L. Earl
Published: February 2013

Many structural and functional aspects of the vertebrate hypothalamic−pituitary−gonadal (HPG) axis are known to be highly conserved, but the significance of this from a toxicological perspective has received comparatively little attention. High-quality data generated through development and validation of Tier 1 tests for the U.S. Environmenal Protection Agency Endocrine Disruptor Screening Program (EDSP) offer a unique opportunity to compare responses of mammals versus fish to chemicals that may affect shared pathways within the HPG axis. The present study focuses on data generated with model chemicals that act (primarily) as estrogen receptor agonists (17α-ethynylestradiol, methoxychlor, bisphenol A), androgen receptor agonists (methyltestosterone, 17β-trenbolone), androgen receptor antagonists (flutamide, vincolozolin, p,p′-DDE), or inhibitors of different steroidogenic enzymes (ketoconazole, fadrozole, fenarimol, prochloraz). All 12 chemicals had been tested in the EDSP fish short-term (21 d) reproduction assay and in one or more of the four in vivo Tier 1 screens with rats (uterotrophic, Hershberger, male and female pubertal assays). There was a high concordance between the fish and rat assays with respect to identifying chemicals that impacted specific endocrine pathways of concern. Although most chemicals were detected as positive in both rat and fish assays, eliminating data from one class of vertebrate or the other would weaken the battery. For example, the effects of competitive inhibitors of steroid hormone synthesis were far more obvious in the fish assay, whereas the activity of androgen receptor antagonists was clearer in mammalian assays. The observations are significant both to the cross-species extrapolation of toxicity of HPG-active substances and the optimization of screening and testing frameworks for endocrine-disrupting chemicals. Environ. Toxicol. Chem. 2013;32:1084–1087. © 2013 SETAC
An inverse relationship between production and export efficiency in the Southern Ocean
Authors: Maiti Kanchan , Charette Matthew A. , Buesseler Ken O. , Kahru Mati
Published: February 2013

In the past two decades, a number of studies have been carried out in the Southern Ocean to look at export production using drifting sediment traps and thorium‐234 based measurements, which allows us to reexamine the validity of using the existing relationships between production, export efficiency, and temperature to derive satellite‐based carbon export estimates in this region. Comparisons of in situ export rates with modeled rates indicate a two to fourfold overestimation of export production by existing models. Comprehensive analysis of in situ data indicates two major reasons for this difference: (i) in situ data indicate a trend of decreasing export efficiency with increasing production which is contrary to existing export models and (ii) the export efficiencies appear to be less sensitive to temperature in this region compared to the global estimates used in the existing models. The most important implication of these observations is that the simplest models of export, which predict increase in carbon flux with increasing surface productivity, may require additional parameters, different weighing of existing parameters, or separate algorithms for different oceanic regimes.
Tremors along the Queen Charlotte Margin triggered by large teleseismic earthquakes
Authors: Aiken Chastity , Peng Zhigang , Chao Kevin
Published: February 2013

We conduct a systematic search of tectonic tremors along the Queen Charlotte Margin (QCM) in western Canada triggered by distant earthquakes. We identify triggered tremor as non‐impulsive, high‐frequency signals coherent among several stations and coincident with passing surface waves. So far, the 2002 Mw7.9 Denali Fault, the 2004 Mw9.2 Sumatra, and the 2011 Mw9.1 Tohoku‐Oki earthquakes have triggered clear tremor in this region. The 2010 Mw8.8 Maule, Chile and the 2012 Mw8.6 Sumatra earthquakes may have triggered, but tremors in these two cases did not meet all of our criteria. The triggered tremors are mostly located east of the Queen Charlotte Fault in the southern portion of Haida Gwaii, near the epicenter of the 28 October 2012 Mw7.7 earthquake. Similar to the observations in other regions, the triggered tremors were initiated by the Love waves and continued during the subsequent Rayleigh waves. Tremor bursts correlate with both the particle velocity and displacement of the Love waves, indicating they are triggered at either low‐angle thrust or vertical strike‐slip faults. In addition, we find that the triggering potential for the QCM is controlled by a combination of amplitude, period, and incident angles.
Up-Regulation of Circulating Mir-20A Is Correlated With Hepatitis C Virus-Mediated Liver Disease Progression
Authors: Shrivastava Shubham , Petrone Jessica , Steele Robert , Lauer Georg M. , Di Bisceglie Adrian M. , Ray Ratna B.
Published: February 2013

Chronic hepatitis C virus (HCV) infection is one of the major causes of liver fibrosis and liver transplantation in the United States. Circulating microRNAs (miRNAs) in the blood are emerging as biomarkers for pathological conditions. In the present study we performed a systematic screening approach to identify up-regulated miRNAs in the plasma/serum of HCV-infected patients with different stages of hepatic histological disease severity. We initially screened serum samples of HCV-infected patients with fibrosis and compared them with sera of healthy volunteers using serum miRNA array profiling and identified a group of modulated miRNAs. Subsequent study demonstrated that miR-20a and miR-92a in HCV-infected fibrosis patients sera were significantly up-regulated when compared with that of healthy volunteers or non-HCV-associated liver disease. We have also observed an increase of plasma miR-20a and miR-92a in acute and chronic HCV-infected patients as compared to that of healthy volunteers. However, there was no correlation between the plasma/serum levels of any of these miRNAs with HCV viral loads. We next investigated longitudinal plasma samples from HCV-infected patients. Our results suggested that miR-20a and miR-92a remained unaltered in HCV-infected patients who progressed from acute to chronic infection. On the other hand, miR-92a expression was reduced in acute to resolved individuals. These data provide evidence that plasma/serum levels of miR-20a and miR-92a have potential as sensitive and cost-effective biomarkers for early detection of HCV infection. Conclusion: Circulating miR-20a may serve as a potential for predictive biomarker in HCV-mediated fibrosis. (Hepatology 2013;53:863–871)
Implication of the proprotein convertases in iron homeostasis: Proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin
Authors: Guillemot Johann , Canuel Maryssa , Essalmani Rachid , Prat Annik , Seidah Nabil G.
Published: February 2013

The first seven members of the proprotein convertase (PC) family activate protein precursors by cleavage after basic residues. While PC7 has no known specific substrates, it shows redundancy with other PCs. A genome-wide association study suggested that circulating levels of shed human transferrin receptor 1 (hTfR1) are regulated by PC7. We thus examined whether hTfR1 constitutes a specific substrate for PC7. Coexpression of hTfR1 with PCs in several cell lines indicated that PC7 is the only convertase that sheds this receptor into the medium. Site-directed mutagenesis showed that cleavage occurs at the unusual site KTECER100↓LA, in which the P1 Arg100 and P6 Lys95 are critical. Pharmacological treatments revealed that shedding of hTfR1 by PC7 requires endocytosis into acidic clathrin-coated vesicles. A PC7 chimera, in which the transmembrane domain and the cytosolic tail of PC7 were replaced by that of the convertase furin, lost its ability to cleave the receptor, demonstrating the importance of these domains in the regulation of PC7 function. Analysis of primary hepatocytes from mice lacking furin, PC5, PACE4, or PC7 revealed that hepcidin, which limits iron availability in the circulation, is specifically generated by furin and not by PC7. Finally, depletion of iron in the medium of hepatoma cell lines incubated with the iron chelator desferrioxamine resulted in PC7 down-regulation.

Conclusion:

Among the PC family members, only furin activates hepcidin in hepatocytes, and uniquely the full-length membrane-bound PC7 can directly shed hTfR1 by cleavage at Arg100↓. Our results support the notion that, when iron is limiting, hTfR1 levels increase at least in part by way of the down-regulation of PC7 expression.
Dietary fructose in nonalcoholic fatty liver disease
Authors: Vos Miriam B. , Lavine Joel E.
Published: February 2013

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in adults and children. A number of genetic and environmental factors are known to predispose individuals to NAFLD. Certain dietary sugars, particularly fructose, are suspected to contribute to the development of NAFLD and its progression. The increasing quantity of fructose in the diet comes from sugar additives (most commonly sucrose and high fructose corn syrup) in beverages and processed foods. Substantial links have been demonstrated between increased fructose consumption and obesity, dyslipidemia, and insulin resistance. Growing evidence suggests that fructose contributes to the development and severity of NAFLD. In human studies, fructose is associated with increasing hepatic fat, inflammation, and possibly fibrosis. Whether fructose alone can cause NAFLD or if it serves only as a contributor when consumed excessively in the setting of insulin resistance, positive energy balance, and sedentary lifestyle is unknown. Sufficient evidence exists to support clinical recommendations that fructose intake be limited through decreasing foods and drinks high in added (fructose-containing) sugars.
Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma
Authors: Hsu Yao-Chun , Ho Hsiu J. , Wu Ming-Shiang , Lin Jaw-Town , Wu Chun-Ying
Published: February 2013

Hepatocellular carcinoma (HCC) frequently recurs after surgical resection. This population-based research aimed to investigate the association between postoperative antiviral treatment and risk of recurrent HCC in patients with hepatitis C virus (HCV) infection. By analyzing the Taiwan National Health Insurance Research Database, we initially screened a total of 100,938 patients diagnosed with HCC for the first time between October 2003 and December 2010. Among 2,237 antiviral-naïve HCV-infected patients with curatively resected HCC, there were 213 patients receiving antiviral treatment with pegylated interferon plus ribavirin for 16 weeks or more after surgery (treated cohort). These treated patients were matched 1:4 with 852 controls who were never treated for HCV infection (untreated cohort) by age, gender, cirrhosis, and the elapsed time between surgery and antiviral therapy. Cumulative incidences of and hazard ratios for recurrent HCC were calculated after adjusting for competing mortality. The recurrence rate of HCC was significantly lower in the treated than untreated cohort, with 52.1% (95% confidence interval [CI], 42.0-62.2%) and 63.9% (95% CI, 58.9-68.8%) after 5 years of follow-up, respectively (P = 0.001). The number needed to treat for one fewer recurrent HCC at 5 years was 8. The association between postoperative antiviral treatment and risk of recurrent HCC was independent of adjustment for multiple covariates, with an adjusted hazard ratio of 0.64 (95% CI, 0.50-0.83). Stratified analyses revealed that the attenuation in recurrence risk was greater in patients younger than 60 years and those without cirrhosis or diabetes. Conclusion: Postoperative pegylated interferon plus ribavirin is associated with reduced recurrence of HCC in patients with HCV infection. Age, liver cirrhosis, and diabetes mellitus appear to modify this association. (HEPATOLOGY 2013)
A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis
Authors: Han Han , Sun Dan , Li Wenjuan , Shen Hongxing , Zhu Yahui , Li Chen , Chen Yuxing , Lu Longfeng , Li Wenhua , Zhang Jinxiang , Tian Yuan , Li Youjun
Published: February 2013

c-Myc (Myc) plays an important role in normal liver development and tumorigenesis. We show here that Myc is pathologically activated in and essential for promoting human hepatocellular carcinoma (HCC). Myc induces HCC through a novel, microRNA (miRNA)-mediated feedback loop comprised of miR-148a-5p, miR-363-3p, and ubiquitin-specific protease 28 (USP28). Myc directly binds to conserved regions in the promoters of the two miRNAs and represses their expression. miR-148a-5p directly targets and inhibits Myc, whereas miR-363-3p destabilizes Myc by directly targeting and inhibiting USP28. Inhibition of miR-148a-5p or miR-363-3p induces hepatocellular tumorigenesis by promoting G1 to S phase progression, whereas activation of them has the opposite effects. The Myc-miRNA feedback loop is dysregulated in human HCC.

Conclusion:

These results define miR-148a-5p and miR-363-3p as negative regulators of Myc, thus revealing their heretofore unappreciated roles in hepatocarcinogenesis.
The impact of timing and prioritization on the cost-effectiveness of birth cohort testing and treatment for hepatitis C virus in the United States
Authors: McEwan Phil , Ward Thomas , Yuan Yong , Kim Ray , L'Italien Gilbert
Published: February 2013

Recent United States guidelines recommend one-time birth cohort testing for hepatitis C infection in persons born between 1945 and 1965; this represents a major public health policy undertaking. The purpose of this study was to assess the role of treatment timing and prioritization on predicted cost-effectiveness. The MONARCH hepatitis C lifetime simulation model was used in conjunction with a testing and treatment decision tree to estimate the cost-effectiveness of birth cohort versus risk-based testing incorporating information on age, fibrosis stage and treatment timing. The study used a 1945-1965 birth cohort and included disease progression, testing and treatment-related parameters. Scenario analysis was used to evaluate the impact of hepatitis C virus (HCV) prevalence, treatment eligibility, age, fibrosis stage and timing of treatment initiation on total costs, quality-adjusted life years (QALYs), HCV-related complications and cost-effectiveness. The cost-effectiveness of birth cohort versus risk-based testing was $28,602. Assuming 91% of the population is tested, at least 278,000 people need to be treated for birth cohort testing to maintain cost-effectiveness. Prioritizing treatment toward those with more advanced fibrosis is associated with a decrease in total cost of $7.5 billion and 59,035 fewer HCV-related complications. Total QALYs and complications avoided are maximized when treatment initiation occurs as soon as possible after testing. Conclusion: This study confirms that birth cohort testing is, on average, cost-effective. However, this remains true only when enough tested and HCV-positive subjects are treated to generate sufficient cost offsets and QALY gains. Given the practical and financial challenges associated with implementing birth cohort testing, the greatest return on investment is obtained when eligible patients are treated immediately and those with more advanced disease are prioritized. (HEPATOLOGY 2013)
Good long-term outcome of Budd-Chiari syndrome with a step-wise management
Authors: Seijo Susana , Plessier Aurelie , Hoekstra Jildou , Dell'Era Alessandra , Mandair Dalvinder , Rifai Kinan , Trebicka Jonel , Morard Isabelle , Lasser Luc , Abraldes Juan G. , Darwish Murad Sarwa , Heller Jörg , Hadengue Antoine , Primignani Massimo , Elias Elwyn , Janssen Harry L.A. , Valla Dominique C. , Garcia-Pagan Juan-Carlos
Published: February 2013

Budd-Chiari syndrome (BCS) is a rare, life-threatening disease caused by obstruction of hepatic venous outflow. The aim of the study was to assess long-term outcome and identify prognostic factors in BCS patients managed by a step-wise approach using anticoagulation, angioplasty/thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), and orthotopic liver transplantation (OLT). We reviewed long-term data on 157 patients previously included by the European Network for Vascular Disorders of the Liver, a multicenter prospective study of newly diagnosed BCS patients in nine European countries. Patients were followed for a median of 50 months (range, 0.1-74.0). During the study, 88 patients (56%) received at least one invasive intervention (22 patients angioplasty/thrombolysis, 62 TIPS, and 20 OLT) and 36 (22.9%) died. Most interventions and/or deaths occurred in the first 2 years after diagnosis. The Rotterdam score was excellent in predicting intervention-free survival, and no other variable could significantly improve its prognostic ability. Moreover, BCS-TIPS prognostic index (PI) score (based on international normalized ratio, bilirubin, and age) was strongly associated with survival and had a discriminative capacity, which was superior to the Rotterdam score.

Conclusions:

The current study confirms, in a large cohort of patients with BCS recruited over a short period, that a step-wise treatment approach provides good long-term survival. In addition, the study validates the Rotterdam score for predicting intervention-free survival and the BCS-TIPS PI score for predicting survival. (Hepatology 2013;)
GABA induces the differentiation of small into large cholangiocytes by activation of Ca2+/CaMK I-dependent adenylyl cyclase 8
Authors: Mancinelli Romina , Franchitto Antonio , Glaser Shannon , Meng Fanyin , Onori Paolo , DeMorrow Sharon , Francis Heather , Venter Julie , Carpino Guido , Baker Kimberley , Han Yuyan , Ueno Yoshiyuki , Gaudio Eugenio , Alpini Gianfranco
Published: February 2013

Large, but not small, cholangiocytes (1) secrete bicarbonate by interaction with secretin receptors (SRs) through activation of cystic fibrosis transmembrane regulator (CFTR), Cl−/HCO3
− (apex) anion exchanger 2 (Cl−/HCO3
− AE2), and adenylyl cyclase (AC)8 (proteins regulating large biliary functions) and (2) proliferate in response to bile duct ligation (BDL) by activation of cyclic adenosine monophosphate (cAMP) signaling. Small, mitotically dormant cholangiocytes are activated during damage of large cholangiocytes by activation of D-myo-inositol 1,4,5-trisphosphate/Ca2+/calmodulin-dependent protein kinase (CaMK) I. gamma-Aminobutyric acid (GABA) affects cell functions by modulation of Ca2+-dependent signaling and AC. We hypothesized that GABA induces the differentiation of small into large cholangiocytes by the activation of Ca2+/CaMK I-dependent AC8. In vivo, BDL mice were treated with GABA in the absence or presence of 1,2-bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid, tetraacetoxymethyl ester (BAPTA/AM) or N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W7) before evaluating apoptosis and intrahepatic bile ductal mass (IBDM) of small and large cholangiocytes. In vitro, control- or CaMK I-silenced small cholangiocytes were treated with GABA for 3 days before evaluating apoptosis, proliferation, ultrastructural features, and the expression of CFTR, Cl−/HCO3
− AE2, AC8, and secretin-stimulated cAMP levels. In vivo administration of GABA induces the apoptosis of large, but not small, cholangiocytes and decreases large IBDM, but increased de novo small IBDM. GABA stimulation of small IBDM was blocked by BAPTA/AM and W7. Subsequent to GABA in vitro treatment, small cholangiocytes de novo proliferate and acquire ultrastructural and functional phenotypes of large cholangiocytes and respond to secretin. GABA-induced changes were prevented by BAPTA/AM, W7, and stable knockdown of the CaMK I gene. Conclusion: GABA damages large, but not small, cholangiocytes that differentiate into large cholangiocytes. The differentiation of small into large cholangiocytes may be important in the replenishment of the biliary epithelium during damage of large, senescent cholangiocytes. (HEPATOLOGY 2013;)
Financing incidence analysis of household out‐of‐pocket spending for healthcare: getting more health for money in Nigeria?
Authors: Onwujekwe Obinna , Hanson Kara , Ichoku Hyacinth , Uzochukwu Benjamin
Published: February 2013

The study examined the burden of out‐of‐pocket spending (OOPS) to households, because available data showed that OOPS dominates household expenditure on health in Nigeria. The study took place in rural and urban districts in Nigeria. A household questionnaire was used to collect data from 4873 households on their healthcare expenditures and payment mechanisms by using a 1‐month expenditure recall period. Financing incidence analysis was assessed at the household level on the basis of socio‐economic status (SES) groups and rural–urban location of the households. Concentration curves of OOPS were plotted with the Lorenz curve of total household expenditures to show the distribution of the burden of OOPS by SES compared with total household expenditure. The Kakwani index was computed to examine the overall progressivity or regressivity of OOPS. There was lack of financial risk protection for healthcare in the study area. The results showed that 3150 (98.8%) of payments were made using OOPS, nine (0.3%) using reimbursement by employers, one (0.03%) through private voluntary health insurance (PVHI), nine (0.3%) using instalment and 14 (0.44%) through ‘others’. The average monthly household OOPS was 2219.1 Naira. The Kakwani index for financing incidence of OOPS was −0.18, showing that OOPS was regressive. The most‐poor SES groups and rural dwellers experienced the highest burden of health expenditure. Urgent steps should be taken by the government to increase or enhance universal coverage in the country with financial protection mechanisms such as the National Health Insurance Scheme in addition to possibly abolishing some of the user fees that cause high incidence and burden of OOPS. Copyright © 2013 John Wiley & Sons, Ltd.
Prognostic factors in gemcitabine–cisplatin polychemotherapy regimens in pancreatic cancer: XPD‐Lys751Gln polymorphism strikes back
Authors: Avan Amir , Pacetti Paola , Reni Michele , Milella Michele , Vasile Enrico , Mambrini Andrea , Vaccaro Vanja , Caponi Sara , Cereda Stefano , Peters Godefridus J. , Cantore Maurizio , Giovannetti Elisa
Published: February 2013

The use of platinated agents in combination chemotherapy regimens for advanced pancreatic cancer is controversial owing to the lack of an outstanding impact on the outcome and a substantial increase in hematologic and extra‐hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. The Xeroderma‐Pigmentosum group‐D polymorphism at codon‐751 (XPD‐Lys751Gln) emerged as the most significant independent predictor for death‐ and progression‐risk in our previous study on functional polymorphisms in 122 advanced pancreatic cancer patients treated with cisplatin–docetaxel–capecitabine–gemcitabine and cisplatin–epirubicin–capecitabine–gemcitabine (or EC‐GemCap). To confirm the prognostic role of this variable, we further evaluated the correlation of XPD‐Lys751Gln with outcome in another 125 patients treated with the same regimens, and 90 treated with gemcitabine monotherapy. Genotyping was successfully carried out in the vast majority of DNA samples. Genotype frequencies followed Hardy–Weinberg equilibrium, and XPD‐Lys751Gln was associated with differential progression‐free and overall‐survival. Multivariate analysis confirmed its prognostic significance in platinum‐based regimens. In particular, XPD‐Gln751Gln was significantly associated with risk of death (hazard ratio, HR = 1.7, 95% confidence interval [CI], 1.1–2.6, p = 0.011) and risk of progression (HR = 1.7, 95% CI, 1.1–2.5, p = 0.013). No correlation was observed in gemcitabine monotherapy‐treated patients. The analysis of DNA damage using extra‐long‐PCR in lymphocytes supported the association of XPD‐Gln751Gln with greater resistance to cisplatin‐induced damage. The increasing evidence of XPD‐Lys751Gln impact on the outcome of gemcitabine–cisplatin‐based polychemotherapy leads to plan prospective studies to validate the role of this polymorphism as a new tool for optimization of the currently available treatments in pancreatic cancer.