bluuebunny/crossref_metadata_2025 huggingface dataset:
Poly (ADP‐ribose) polymerase‐1 deficiency does not affect ethylnitrosourea mutagenicity in liver and testis of lacZ transgenic mice
Authors: Louro Henriqueta , Faustino Inês , Dias Anabela , Boavida Maria G. , Silva Maria J.
Published: March 2010

Poly (ADP‐ribose) polymerase‐1 (Parp1) has been implicated in DNA base excision repair, single‐ and double‐strand break repair pathways, as well as in cell death by apoptosis or necrosis. We used Parp1−/− lacZ plasmid‐based transgenic mice to investigate whether Parp1 deficiency influences the in vivo mutagenic and clastogenic response to the alkylating agent N‐ethyl‐N‐Nitrosourea (ENU) in somatic and germ‐cell tissues. The comparison of the lacZ mutant frequencies (MFs) between Parp1+/+ and Parp1−/− mice showed that the ablation of Parp1 does not affect the spontaneous or ENU‐induced MFs in liver and testis. In addition, the spectrum of the ENU‐induced mutations was not dependent on the Parp1 status, given that similar spectra, consisting mostly of point mutations and a small fraction of deletions/insertions, wereobserved in organs of both Parp1−/− and Parp1+/+ mice. Sequencing of point mutations revealed a consistent significant increase in A:T → T:A base substitutions, typically induced by ENU. Overall, we observed that neither the frequency nor the spectrum of ENU‐induced mutations demonstrated a specificity that could be attributed to the Parp1 impairment in mice organs. The analysis of micronucleus frequency in peripheral blood reticulocytes showed that ENU was clastogenic in both Parp1−/− and Parp1+/+ mice and had a strong cytotoxic effect in Parp1−/− mice only. The present data suggest that, at a whole‐organism level, Parp1‐independent repair mechanisms may be operative in the removal of ENU‐induced DNA lesions or that highly damaged cells may be preferentially committed to death when Parp1 is inactivated. Environ. Mol. Mutagen. 2010. © 2010 Wiley‐Liss, Inc.
Dimensionality of three versions of the eating disorder inventory in adolescent girls
Authors: García‐Grau Eugeni , Fusté Adela , Mas Natàlia , Gómez Juana , Bados Arturo , Saldaña Carmina
Published: March 2010

Objectives

To analyze the dimensionality of three versions of the Eating Disorder Inventory (EDI) in adolescent girls.

Method

The sample comprised 738 participants. The Spanish adaptation of the EDI‐2 was used. The EDI‐2 contains the 64 items of EDI and has the same items as EDI‐3. The dimensional structures hypothesized by Garner for the three EDI versions were assessed via a series of Confirmatory Factor Analyses (CFAs).

Results

The CFA did not confirm Garner's proposed structure in any of the three versions. Consequently it was decided to perform Exploratory Factor Analyses (EFA) of the EDI‐2 and the EDI‐3 to try to indentify the underlying structure. The best theoretical and empirical fit was provided by a 7‐factor structure.

Discussion

This article presents a shortened version of the EDI‐2 which may prove more suitable for use with adolescent girls in the general population than the original questionnaire. Certain practical suggestions for optimizing the use of the different versions of the EDI are also presented. Copyright © 2010 John Wiley & Sons, Ltd and Eating Disorders Association.
Food web bioaccumulation model for polychlorinated biphenyls in San Francisco Bay, California, USA
Authors: Gobas Frank A.P.C. , Arnot Jon A.
Published: March 2010

We document the development and application of a food web bioaccumulation model for polychlorinated biphenyls (PCBs) in San Francisco Bay, California, USA. The model calculates spatial distributions of PCB concentrations in a range of invertebrate, fish, avian, and mammalian organisms, including harbor seals, double-crested cormorants, and Forster's terns. The performance of the model is evaluated against independent empirical PCB concentrations and shows a mean deviation between observed and model-calculated concentrations of 36% for female harbor seals and 5% for benthic invertebrates and jack smelt. The model was applied to produce bay-wide PCB concentration distributions in fish and wildlife species, which were compared with threshold effect concentrations to determine ecological risks and human health risks of fish consumption. Because of their high trophic position in the food web, harbor seals exhibited the highest concentrations of ∑PCBs, which exceeded threshold concentrations for potential adverse effects. The model was also applied to derive bay-wide target sediment concentrations for remediation as part of an ongoing total maximum daily loading characterization. The model calculated bay-wide geometric mean concentrations of ∑PCB in sediments of 1.6 to 73 µg/kg dry weight to meet several ecological and human health risk objectives. The bay-wide geometric ∑PCB concentration in the sediments at the time of the study was 11.6 µg/kg dry weight. The model was developed for assessing the behavior and risks of bioaccumulative substances on an ecosystem level. Environ. Toxicol. Chem. 2010;29:1385–1395. © 2010 SETAC
Spatial Distribution of Electrochemical Performance in a Segmented SOFC: A Combined Modeling and Experimental Study
Authors: Bessler W. G. , Gewies S. , Willich C. , Schiller G. , Friedrich K. A.
Published: March 2010

Spatially inhomogeneous distribution of current density and temperature in solid oxide fuel cells (SOFC) contributes to accelerated electrode degradation, thermomechanical stresses, and reduced efficiency. This paper presents a combined experimental and modeling study of the distributed electrochemical performance of a planar SOFC. Experimental data were obtained using a segmented cell setup that allows the measurement of local current‐voltage characteristics, gas composition and temperature in 4 × 4 segments. Simulations were performed using a two‐dimensional elementary kinetic model that represents the experimental setup in a detailed way. Excellent agreement between model and experiment was obtained for both global and local performance over all investigated operating conditions under varying H2/H2O/N2 compositions at the anode, O2/N2 compositions at the cathode, temperature, and fuel utilization. A strong variation of the electrochemical performance along the flow path was observed when the cell was operated at high fuel utilization. The simulations predict a considerable gradient of gas‐phase concentrations along the fuel channel and through the thickness of the porous anode, while the gradients are lower at the cathode side. The anode dominates polarization losses. The cell may operate locally in critical operating conditions (low H2/H2O ratios, low local segment voltage) without notably affecting globally observed electrochemical behavior.
Characterisation of Nanocarbon‐Based Gas Diffusion Media by Electrochemical Impedance Spectroscopy
Authors: Gallo Stampino P. , Omati L. , Cristiani C. , Dotelli G.
Published: March 2010

A multi‐wall carbon nanotubes (MWCNTs)‐based gas diffusion medium (GDM) was prepared, where carbon black was partially substituted by carbon nanotube (CNT) in the formulation of the micro‐porous layer (MPL). A rheological analysis of the ink used to coat the gas diffusion layer (GDL) was previously performed to correlate viscosities with the slurry composition. Shear thinning inks with viscosity of 0.4 (Pa s–1) were obtained for a composition containing 10 wt.‐% of CNT and 12 wt.‐% of fluorinated polymer. Using the doctor‐blade technique, a coating thickness of about 100–150 μm was obtained.

Moreover, electrochemical performance of a single cell assembled with the CNT‐based GDM was compared with that obtained with a sample without CNTs. In order to better understand the role of CNTs, electrochemical impedance spectroscopy (EIS) of the running fuel cell (FC) was also performed. As a result, it was found that the addition of CNTs sensibly improves single cell performances.
Integrated genomic profiling identifies candidate genes implicated in glioma‐genesis and a novel LEO1‐SLC12A1 fusion gene
Authors: Bralten Linda B. C. , Kloosterhof Nanne K. , Gravendeel Lonneke A. M. , Sacchetti Andrea , Duijm Elza J. , Kros Johan M. , van den Bent Martin J. , Hoogenraad Casper C. , Sillevis Smitt Peter A. E. , French Pim J.
Published: March 2010

We performed genotyping and exon‐level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low‐copy number amplifications (2.5 < n < 7) and high‐copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high‐copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5′‐3′ expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes. © 2010 Wiley‐Liss, Inc.
Characterization of the 12q15 MDM2 and 12q13‐14 CDK4 amplicons and clinical correlations in osteosarcoma
Authors: Mejia‐Guerrero Salvador , Quejada Michael , Gokgoz Nalan , Gill Mona , Parkes Robert K. , Wunder Jay S. , Andrulis Irene L.
Published: March 2010

The chromosomal region 12q13‐15 is recurrently amplified in osteosarcoma (OS), but its importance in bone tumor development remains unknown. Although there are two major candidate genes (MDM2, a TP53 downregulator, and CDK4, involved in cell cycle progression) considered to be the driving genes in this region, the size of the amplicon and number of genes involved have not been determined. In this study, we used 130 classical OS and 15 parosteal OS to determine MDM2 and CDK4 amplification frequency in OS. Tumors in which these genes were amplified were used to map the 12q13‐15 amplified region and to determine its correlation with clinical prognosis. The 12q13‐15 amplification was more prevalent in parosteal OS (67% of cases) than in high‐grade classical OS (12%). Quantitative real‐time PCR of MDM2, CDK4, and 25 other genes showed that this region contains two different amplicons: one at 12q15 centered on MDM2 and one at 12q13‐14 centered on CDK4. Both regions were frequently coamplified in both types of OS, and MDM2 and CDK4 amplification was correlated with higher expression levels for both genes. Univariate and multivariate analyses of clinical data indicated that classical OS patients whose tumors exhibited MDM2 amplification were more likely to be older at diagnosis (median age 32.6 vs. 17.8 years) and female (66.7 vs. 33.3%) than those without gene amplification. There was no association with other clinical parameters. In conclusion, coamplification of MDM2 and CDK4 in two separate amplicons occurs frequently in parosteal OS and less so in classical high‐grade OS. © 2010 Wiley‐Liss, Inc.
Preventing Hepatitis C Virus Recurrence in Liver Transplant Recipients: A Role for Adoptive Immunotherapy?
Authors: Pawlotsky Jean-Michel , Chevaliez Stéphane
Published: March 2010

Abstract

After liver transplantation in HCV-infected patients, the virus load inevitably exceeds pretransplantation levels. This phenomenon reflects suppression of the host-effector immune responses that control HCV replication by the immunosuppressive drugs used to prevent rejection of the transplanted liver. Here, we describe an adoptive immunotherapy approach, using lymphocytes extracted from liver allograft perfusate (termed herein liver allograft–derived lymphocytes), which includes an abundance of NK/NKT cells that mounted an anti-HCV response in HCV-infected liver transplantation recipients, despite the immunosuppressive environment. This therapy involved intravenously injecting patients 3 days after liver transplantation with liver allograft–derived lymphocytes treated with IL-2 and the CD3-specific mAb OKT3. During the first month after liver transplantation, the HCV RNA titers in the sera of recipients who received immunotherapy were markedly lower than those in the sera of recipients who did not receive immunotherapy. We further explored these observations in human hepatocyte–chimeric mice, in which mouse hepatocytes were replaced by human hepatocytes. These mice unfailingly developed HCV infections after inoculation with HCV-infected human serum. However, injection of human liver-derived lymphocytes treated with IL-2/OKT3 completely prevented HCV infection. Furthermore, an in vitro study using genomic HCV replicon–containing hepatic cells revealed that IFN-γ–secreting cells played a pivotal role in such anti-HCV responses. Thus, our study presents what we believe to be a novel paradigm for the inhibition of HCV replication in HCV-infected liver transplantation recipients. © 2010 American Society for Clinical Investigation.
the Chicken or the Egg: Adipocytes and Hepatic Insulin Resistance
Authors: Hebbard Lionel , George Jacob
Published: March 2010

Abstract

Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting death-promoting effects, the death receptor Fas (also known as CD95) can activate inflammatory pathways in several cell lines and tissues, although little is known about the metabolic consequence of Fas activation in adipose tissue. We therefore sought to investigate the contribution of Fas in adipocytes to obesity-associated metabolic dysregulation. Fas expression was markedly increased in the adipocytes of common genetic and diet-induced mouse models of obesity and insulin resistance, as well as in the adipose tissue of obese and type 2 diabetic patients. Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were protected from deterioration of glucose homeostasis induced by high-fat diet (HFD). Adipocytes in AFasKO mice were more insulin sensitive than those in wild-type mice, and mRNA levels of proinflammatory factors were reduced in white adipose tissue. Moreover, AFasKO mice were protected against hepatic steatosis and were more insulin sensitive, both at the whole-body level and in the liver. Thus, Fas in adipocytes contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity and may constitute a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes. © 2010 American Society for Clinical Investigation.
Regulation of Multidrug Resistance-Associated Protein 2 by Calcium Signaling in Mouse Liver
Authors: Cruz Laura N. , Guerra Mateus T. , Kruglov Emma , Mennone Albert , Garcia Celia R. S. , Chen Ju , Nathanson Michael H.
Published: March 2010

Multidrug resistance associated protein 2 (Mrp2) is a canalicular transporter responsible for organic anion secretion into bile. Mrp2 activity is regulated by insertion into the plasma membrane; however, the factors that control this are not understood. Calcium (Ca2+) signaling regulates exocytosis of vesicles in most cell types, and the type II inositol 1,4,5-triphosphate receptor (InsP3R2) regulates Ca2+ release in the canalicular region of hepatocytes. However, the role of InsP3R2 and of Ca2+ signals in canalicular insertion and function of Mrp2 is not known. The aim of this study was to determine the role of InsP3R2-mediated Ca2+ signals in targeting Mrp2 to the canalicular membrane. Livers, isolated hepatocytes, and hepatocytes in collagen sandwich culture from wild-type (WT) and InsP3R2 knockout (KO) mice were used for western blots, confocal immunofluorescence, and time-lapse imaging of Ca2+ signals and of secretion of a fluorescent organic anion. Plasma membrane insertion of green fluorescent protein (GFP)-Mrp2 expressed in HepG2 cells was monitored by total internal reflection microscopy. InsP3R2 was concentrated in the canalicular region of WT mice but absent in InsP3R2 KO livers, whereas expression and localization of InsP3R1 was preserved, and InsP3R3 was absent from both WT and KO livers. Ca2+ signals induced by either adenosine triphosphate (ATP) or vasopressin were impaired in hepatocytes lacking InsP3R2. Canalicular secretion of the organic anion 5-chloromethylfluorescein diacetate (CMFDA) was reduced in KO hepatocytes, as well as in WT hepatocytes treated with 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA). Moreover, the choleretic effect of tauroursodeoxycholic acid (TUDCA) was impaired in InsP3R2 KO mice. Finally, ATP increased GFP-Mrp2 fluorescence in the plasma membrane of HepG2 cells, and this also was reduced by BAPTA.

Conclusion:

InsP3R2-mediated Ca2+ signals enhance organic anion secretion into bile by targeting Mrp2 to the canalicular membrane. Hepatology 2010
Bile Acid Changes After High-Dose Ursodeoxycholic Acid Treatment in Primary Sclerosing Cholangitis: Relation to Disease Progression
Authors: Sinakos Emmanouil , Marschall Hanns-Ulrich , Kowdley Kris V. , Befeler Alex , Keach Jill , Lindor Keith
Published: March 2010

High-dose (28-30 mg/kg/day) ursodeoxycholic acid (UDCA) treatment improves serum liver tests in patients with primary sclerosing cholangitis (PSC) but does not improve survival and is associated with increased rates of serious adverse events. The mechanism for the latter undesired effect remains unclear. High-dose UDCA could result in the production of hepatotoxic bile acids, such as lithocholic acid (LCA), because of limited small bowel absorption of UDCA and conversion of UDCA by bacteria in the colon. We determined the serum bile acid composition in 56 patients with PSC previously enrolled in a randomized, double-blind controlled trial of high-dose UDCA versus placebo. Samples for analysis were obtained at the baseline and at the end of treatment. The mean changes in the UDCA level (16.86 versus 0.05 μmol/L) and total bile acid level (17.21 versus −0.55 μmol/L) were significantly higher in the UDCA group (n = 29) versus the placebo group (n = 27) when pretreatment levels were compared (

P

< 0.0001). LCA was also markedly increased (0.22 versus 0.01 μmol/L) in the UDCA group compared to the placebo group (

P

= 0.001). No significant changes were detected for cholic acid, deoxycholic acid, or chenodeoxycholic acid. Patients (n = 9) in the UDCA group who reached clinical endpoints of disease progression (the development of cirrhosis, varices, liver transplantation, or death) tended to have greater increases in their posttreatment total bile acid levels (34.99 versus 9.21 μmol/L,

P

< 0.08) in comparison with those who did not.

Conclusion:

High-dose UDCA treatment in PSC patients results in marked UDCA enrichment and significant expansion of the total serum bile acid pool, including LCA. Hepatology 2010
Risk of Malignant Neoplasms of Liver and Biliary Tract in Diabetic Patients With Different Age and Sex Stratifications
Authors: Chen Hua-Fen , Chen Peter , Li Chung-Yi
Published: March 2010

We prospectively investigated 615,532 diabetic patients and 614,871 age-matched and sex-matched control subjects selected from National Health Insurance claims for malignant neoplasms of liver and biliary tract (International Statistical Classification of Diseases and Related Health Problems, 9th edition, codes 155 and 156, respectively) between 2000 and 2006. The person-year approach with Poisson assumption was used to estimate the hazard rates. We also evaluated the age-specific and sex-specific relative risks of these two malignancies in relation to diabetes with Cox proportional hazard regression model with adjustment for potential confounders. The overall hazard rate of malignant neoplasm of the liver was 32.76 and 17.41 per 10,000 patient-years, respectively, for diabetic men and women; the corresponding figures for biliary tract neoplasm were much lower at 1.42 and 1.60 per 10,000 patient-years. Compared with control subjects, diabetic patients had a two-fold increased risk of malignant neoplasm of the liver, but this risk was attenuated by adjusting for selected clinical risk factors (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.17-1.25). Additionally, diabetic patients were associated with increased risk of biliary neoplasms with an approximate magnitude of 20%-30%, but the HR was attenuated and became insignificant after adjustment for clinical risk factors (HR 1.07; 95% CI 0.95-1.21). Diabetic patients with cirrhosis had the highest relative risk of liver neoplasm (HR 85.25; 95% CI 76.84-94.58), whereas those with cholangitis had the highest risk of biliary tract neoplasm (HR 70.30; 95% CI 51.95-95.12) compared with control subjects without any clinical risk factors.

Conclusion:

This population-based study confirms the association of diabetes with liver neoplasm and suggests that diabetic patients with certain clinical risk factors should be educated for strict adherence of liver neoplasm screening. (Hepatology 2010)
Individual and combined roles of CYP3A, P‐glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) in the pharmacokinetics of docetaxel
Authors: van Waterschoot Robert A.B. , Lagas Jurjen S. , Wagenaar Els , Rosing Hilde , Beijnen Jos H. , Schinkel Alfred H.
Published: March 2010

Docetaxel is one of the most widely used anticancer drugs. A major problem with docetaxel treatment, however, is the considerable interpatient variability in docetaxel exposure. Another disadvantage of the drug is that it has a very low oral bioavailability and can, therefore, only be administered intravenously. The drug‐metabolizing enzyme CYP3A and the drug transporter MDR1 (P‐glycoprotein) are major determinants of docetaxel pharmacokinetics. In vitro studies have indicated that docetaxel is also a substrate for the drug transporter MRP2, but the in vivo importance of MRP2 for docetaxel is currently unknown. We, therefore, investigated the role of MRP2 in the pharmacokinetics of docetaxel by utilizing Mrp2−/− mice. We also generated and characterized Cyp3a/Mdr1a/b/Mrp2−/− combination knockout mice to get more insight into how these drug‐handling systems work together in determining docetaxel pharmacokinetics. The systemic exposure in Mrp2−/− mice was not significantly different from wild‐type, after either oral or intravenous administration. Strikingly, however, in Cyp3a/Mdr1a/b/Mrp2−/− mice, systemic docetaxel exposure was increased 166‐fold after oral administration when compared with wild‐type mice, and 2.3‐fold when compared with Cyp3a/Mdr1a/b−/− mice. Interestingly, this 166‐fold increase was disproportionate compared with that for the separate Cyp3a (12‐fold) or Mdr1a/b/Mrp2 (4‐fold) knockouts. The oral bioavailability was increased to 73% in the Cyp3a/Mdr1a/b/Mrp2−/− strain, versus only 10% in wild‐type mice. Our data thus indicate that in the absence of CYP3A and Mdr1a/b activity, Mrp2 has a marked impact on docetaxel pharmacokinetics. These findings could have important implications for improving the oral bioavailability and reducing the variability in docetaxel exposure.
Synergistic antitumor activity of the SN‐38‐incorporating polymeric micelles NK012 with S‐1 in a mouse model of non‐small cell lung cancer
Authors: Nagano Tatsuya , Yasunaga Masahiro , Goto Koichi , Kenmotsu Hirotsugu , Koga Yoshikatsu , Kuroda Jun‐ichiro , Nishimura Yoshihiro , Sugino Takashi , Nishiwaki Yutaka , Matsumura Yasuhiro
Published: March 2010

The combination therapy of CPT‐11, a prodrug of SN‐38, with S‐1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non‐small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN‐38‐incorporating polymeric micelles NK012 over CPT‐11 in combination with S‐1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity.In vitrocytotoxic effects were examined in human NSCLC cell lines (A549, PC‐9, PC‐14, EBC‐1 and H520).In vivoantitumor effects were evaluated in PC‐14‐ and EBC‐1‐bearing mice after NK012 or CPT‐11 administration on Days 0 and 7 and S‐1 administration on Days 0–13. Pathological changes in the small intestine were also investigated. Thein vitrogrowth inhibitory effects of NK012 were 56.8‐ to 622‐fold more potent than those of CPT‐11. NK012/S‐1 treatment showed significantly higher antitumor activity both in PC‐14‐bearing (p= 0.0007) and EBC‐1‐bearing mice (p< 0.0001) than CPT‐11/S‐1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT‐11/S‐1‐treated mice than in NK012/S‐1‐treated mice. NK012/S‐1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants clinical evaluation.
Immune evasion of microsatellite unstable colorectal cancers
Authors: Kloor Matthias , Michel Sara , von Knebel Doeberitz Magnus
Published: March 2010

Colorectal cancers (CRC) develop through 2 major pathways of genetic instability. In contrast to the majority of CRCs, which are characterized by chromosomal instability, high‐level microsatellite unstable (MSI‐H) CRCs arise as a consequence of the loss of DNA mismatch repair (MMR) functions and show accumulation of insertion and deletion mutations particularly in microsatellite sequences. MSI‐H occurs in about 15% of CRCs, and virtually all CRCs occurring in the context of the hereditary cancer‐predisposing Lynch syndrome. These tumors are characterized by a comparably good prognosis and a low frequency of distant metastases. Because of the expression of a defined set of tumor‐specific antigens, MSI‐H CRCs elicit a strong local and systemic antitumoral immune response of the host and therefore use different strategies to evade the control of the immune system. In this review, we will summarize novel molecular mechanisms that at the same time drive pathogenesis, immunogenicity and immune evasion during the development and progression of MSI‐H CRCs. We will focus on the current knowledge about alterations in human leukocyte antigen (HLA) antigen presentation and discuss how immune evasion—while offering protection against local antitumoral immune responses—paradoxically might interfere with the ability of the tumor to form distant organ metastases.
miR‐145, miR‐133a and miR‐133b: Tumor‐suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma
Authors: Kano Masayuki , Seki Naohiko , Kikkawa Naoko , Fujimura Lisa , Hoshino Isamu , Akutsu Yasunori , Chiyomaru Takeshi , Enokida Hideki , Nakagawa Masayuki , Matsubara Hisahiro
Published: March 2010

MicroRNAs (miRNAs), noncoding RNAs 21–25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor‐suppressive function in esophageal squamous cell carcinoma (ESCC) was performed using the miRNA expression signatures obtained from ESCC clinical specimens. A subset of 15 miRNAs was significantly downregulated in ESCC. A comparison of miRNA signatures from ESCC and our previous report identified 4 miRNAs that are downregulated in common (miR‐145, miR‐30a‐3p, miR‐133a and miR‐133b), suggesting that these miRNAs are candidate tumor suppressors. Gain‐of‐function analysis revealed that 3 transfectants (miR‐145, miR‐133a and miR‐133b) inhibit cell proliferation and cell invasion in ESCC cells. These miRNAs (miR‐145, miR‐133a and miR‐133b), which have conserved sequences in the 3′UTR of FSCN1 (actin‐binding protein, Fascin homolog 1), inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR‐145 target sites and 1 miR‐133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss‐of‐function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor‐suppressive miRNAs, miR‐145, miR‐133a and miR‐133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.
Optimization of culture conditions for an efficient xeno‐feeder free limbal cell culture system towards ocular surface regeneration
Authors: Varghese Viji Mary , Prasad Tilak , Kumary T.V.
Published: March 2010

Ex vivo expansion of limbal stem cells from a small biopsy and its subsequent transplantation is the golden choice of treatment for limbal stem cell deficiency. Use of murine 3T3 feeder layer is a prerequisite for this ex vivo expansion. There is an ever‐increasing demand for feeder free cultures to avoid xenotoxicity and transmission of xeno‐diseases to human system. This study was aimed to establish an efficient xeno‐feeder free limbal culture system towards ocular surface regeneration. To study the effect of initial dispase treatment and culture system used, migratory distance of cells from explants was analyzed from phase contrast images using “interactive measurements” of Qwin software (Leica). Expression of p63 in different culture systems was studied by immunofluorescent staining, followed by quantitative confocal microscopy (Carl Zeiss). Results showed dispase treatment was not necessary for establishing limbal explant culture. A combination of Iscove's modified Dulbecco's medium and Panserin 801 resulted in formation of autofeeder layer with maintenance of progenitor characteristics, thus mimicking natural tissue architecture. Further analysis of this culture system showed that cells could be cultured till confluency. Immunofluorescent staining of ABCG2 revealed presence of stem cell marker in the confluent cell layer. Scanning Electron Micrographs demonstrated homogenous population of tightly packed cells in this culture system. Replacement of bovine serum with autologous serum did not affect morphology or growth of cells in this culture system. This study will be a major step in the development of xeno‐feeder free epithelial equivalents towards ocular surface reconstruction. Microsc. Res. Tech. 73:1045–1052, 2010. © 2010 Wiley‐Liss, Inc.
A scanning electron microscopy specimen holder for viewing different angles of a single specimen
Authors: Pohl Hans
Published: March 2010

The specimen holder for scanning electron microscopy described herein allows a single specimen to be examined in any possible view and significantly improves object illumination. The specimen is glued to a fine pin and flexibly mounted on a double‐sided adhesive conductive pad on a rotatable pivot. A milled pot placed beneath the specimen acts as an electron trap. This provides a homogeneous black image background by minimizing noisy signals from the specimen's surroundings. Microsc. Res. Tech. 73:1073–1076, 2010. © 2010 Wiley‐Liss, Inc.
Characterization and de novo sequencing of snow crab tropomyosin enzymatic peptides by both electrospary ionization and matrix‐assisted laser desorption ionization QqToF tandem mass spectrometry
Authors: Abdel Rahman Anas M. , Lopata Andreas L. , O'Hehir Robyn E. , Robinson John J. , Banoub Joseph H. , Helleur Robert J.
Published: March 2010

The protein tropomyosin (TM) is a known major allergen present in shellfish causing frequent food allergies. TM is also an occupational allergen generated in the working environment of snow crab (Chionoecetes opilio) processing plants. The TM protein was purified from both claw and leg meats of snow crab and analyzed by electrospray ionization and matrix‐assisted laser desorption/ionization (MALDI) using hybrid quadruple time‐of‐flight tandem mass spectrometry (QqToF‐MS). The native polypeptide molecular weight of TM was determined to be 32 733 Da. The protein was further characterized using the ‘bottom‐up’ MS approach. A peptide mass fingerprinting was obtained by two different enzymatic digestions and de novo sequencing of the most abundant peptides performed. Any post‐translational modifications were identified by searching their calculated and predicted molecular weights in precursor ion spectra. The immunological reactivity of snow crab extract was evaluated using specific antibodies and allergenic reactivity assessed with serum of allergic patients. Subsequently, a signature peptide for TM was identified and evaluated in terms of identity and homology using the basic local alignment search tool (BLAST). The identification of a signature peptide for the allergen TM using MALDI‐QqToF‐MS will be critical for the sensitive and specific quantification of this highly allergenic protein in the work place. Copyright © 2010 John Wiley & Sons, Ltd.
The carbon versus mass diagram to visualize and exploit FTICR‐MS data of natural organic matter
Authors: Reemtsma Thorsten
Published: March 2010

A two‐dimensional diagram is proposed, in which the carbon number of each formula is plotted against its nominal mass, to visualize large sets of molecular formula data that can be derived from data generated by ultrahigh‐resolution Fourier transform ion cyclotron resonance‐MS. In such a carbon versus mass (CvM) diagram, each formula (CcHhOo) is unambiguously described by c, its (nominal) mass and the parameter i = c + o. Calculations of chemically allowable formulas illustrate that organic molecules occupy only certain spaces in such a diagram. The extension of these spaces increases with molecular mass in x‐direction (hydrogenation) and y‐direction (oxygenation). The data sets of molecules determined in natural organic matter(NOM) occupy only a certain range of the allowable space. The intensity of the mass spectrometric signals can be included as the third dimension into a CvM diagram. Separate CvM diagrams can be plotted for NOM molecules that include different heteroatoms. The benefits of the CvM diagram are illustrated by application onto data sets of fulvic acids from riverine and marine origin, of secondary organic aerosol, including organosulfates and organonitrates, as well as of ozonation of fulvic acids. The CvM diagram is a useful tool to visualize the elemental regularities in NOM isolates as well as the differences between isolates. It may also be applicable to large sets of molecular formula data generated in other disciplines such as petroleum biogeochemistry or metabolomics. Copyright © 2010 John Wiley & Sons, Ltd.
An objective and automatic method for identification of pattern changes in wind direction time series
Authors: Klausner Ziv , Fattal Eyal
Published: March 2010

Finding the point in time at which the wind pattern changes its direction is an important problem with a broad scope of application in atmospheric boundary layer modelling. In many cases such a change of pattern can be extracted using subjective methods, which involves a subjective post analysis of the measured time series. A considerably more difficult task is identifying such a change using an objective and automated method. This task is usually treated by smoothing the original time series, extracting threshold parameters using a statistical analysis of the past wind data, and setting threshold values via trial and error. We present here an objective and automatic method for solving this problem. The method identifies extrema and bending points in the cumulative sum terms of sine and cosine of the wind direction time series, which are based on the directional cumulative sum principle. Our method is non‐parametric, and needs neither prior calibration of threshold values nor smoothing of the data. Furthermore, our method is unique in its ability to detect the pattern change even if the direction change occurs gradually. An example of the application of the method is presented using 6 months of data collected at a single meteorological station located on the central coastal plain of Israel. The method was applied to identify the timing of the occurrence of the nocturnal land wind period (beginning and end). Out of 176 days examined, the method identified correctly more than 90% of the periods. Copyright © 2010 Royal Meteorological Society
Spatial distribution of recent rainfall trends in Spain (1961–2006)
Authors: Río S. del , Herrero L. , Fraile R. , Penas A.
Published: March 2010

Annual, seasonal and monthly rainfall trends from 1961 to 2006 period were analysed in this study by applying various statistical tools to data from 553 Spanish weather stations. The magnitude of the trends was derived from the slopes of the regression lines using the least squares method, while the statistical significance was determined using the non‐parametric Mann‐Kendall test. Geostatistical interpolation techniques were applied to generate rainfall trend surfaces. Combining classic trends tests and spatially interpolated precipitation permits the spatio‐temporal visualization of detected trends. Updated trends reveal that rainfall is generally decreasing in January, February, March, April, and June. Around 61, 44 and 12% of the whole territory is evidencing significant negative trends in February, June and March, respectively. Significant precipitation decreases are also noted in more than 28% of Spain in summer and winter. On the contrary, rainfall is significantly increasing in October in more than 21% of Spain and areas mainly located in north‐western areas. May, August, September and autumn also show significant positive trends in the period 1961–2006, although the percentages are lower than for negative trends. Finally, the annual precipitation is significantly decreasing in 11% of the territory. Copyright © 2010 Royal Meteorological Society
Dating of raised marine and lacustrine deposits in east Greenland using beryllium‐10 depth profiles and implications for estimates of subglacial erosion
Authors: Goehring Brent M. , Kelly Meredith A. , Schaefer Joerg M. , Finkel Robert C. , Lowell Thomas V.
Published: March 2010

Here we combine 10Be depth profile techniques applied to late glacial ice‐contact marine and lacustrine deltas, as well as boulder exposure dating of associated features in the Scoresby Sound region, east Greenland, to determine both the surface age and the magnitude of cosmogenic nuclide inheritance. Boulder ages from an ice‐contact delta in northern Scoresby Sund show scatter typical of polar regions and yield an average age of 12.8 ± 0.5 ka – about 2 ka older than both our average profile surface age of 10.9 ± 0.7 ka from three depth profiles and a radiocarbon‐based estimate. On the other hand, boulder exposure ages from a set of moraines in southern Scoresby Sund show excellent internal consistency for polar regions and yield an average age of 11.6 ± 0.2 ka. The profile surface age from a corresponding ice‐contact delta is 8.1 ± 0.9 ka, while a second delta yields an age of 10.0 ± 0.4 ka. Measured 10Be inheritance concentrations from all depth profiles are internally consistent and are between 10% and 20% of the surface concentrations, suggesting a regional cosmogenic inheritance signal for the Scoresby Sound landscape. Based on the profile inheritance concentrations, we explore the first‐order catchment‐averaged bedrock erosion under the Greenland ice sheet, yielding estimates of total erosion during the last glacial cycle of the order of 2–30 m. Copyright © 2010 John Wiley & Sons, Ltd.
Destination image differences between visitors and non‐visitors: a case of New York city
Authors: Phillips WooMi J. , Jang SooCheong
Published: March 2010

This note discusses the influences of previous visits on tourists' destination images. The cognitive and affective images of New York City (NYC) appear to change in certain directions after visiting. The results also found that city images have a significant influence on tourists' visit intention. However, previous visits to NYC did not play any moderating effect between destination images and visiting intention. Copyright © 2010 John Wiley & Sons, Ltd.
Late reuse of liver allografts from brain-dead graft recipients: The Munich experience and a review of the literature
Authors: Rentsch Markus , Meyer Jens , Andrassy Joachim , Fischer-Fröhlich Carl-Ludwig , Rust Christan , Mueller Susanna , Angele Martin , Löhe Florian , Jauch Karl-Walter , Graeb Christian
Published: March 2010

The increasing donor organ shortage requires the consideration of any possible organ donor in order to meet the current demand. However, the growing number of long-term survivors of liver transplantation may create a situation in which former organ recipients may experience brain death with a functioning graft and therefore become organ donors themselves. Previous reports concerning this rare situation predominantly refer to the reuse of donor organs within the first 8 days after primary liver transplantation. So far, only a single case of late reuse of a donor liver has been published, with 2 additional cases mentioned in a summary of the United Network for Organ Sharing database. Here we report the case of a 43-year-old female donor who had received a liver graft for complications of Budd-Chiari syndrome 5 years before becoming an organ donor herself after cerebral infarction with consecutive brain death. Liver Transpl 16:701-704, 2010. © 2010 AASLD.
Contrast-enhanced ultrasound for the evaluation of hepatic artery stenosis after liver transplantation: potential role in changing the clinical algorithm
Authors: Zheng Rong-Qin , Mao Ren , Ren Jie , Xu Er-Jiao , Liao Mei , Wang Ping , Lu Min-Qiang , Yang Yang , Cai Chang-Jie , Chen Gui-Hua
Published: March 2010

Hepatic artery stenosis (HAS) is a common complication in liver transplant patients. Conventional angiography remains the gold standard for diagnosis. Recently, contrast-enhanced ultrasound (CEUS) has begun providing real-time angiographic-like images of vessels and allowing the accurate diagnosis of arterial diseases such as hepatic artery thrombosis. The purpose of this study was to evaluate the efficacy of CEUS in depicting HAS after liver transplantation. Forty-seven liver transplant recipients underwent CEUS examinations with the intravenous injection of microbubble contrast agents. The reference standard was conventional angiography for 15 patients and computed tomographic angiography for 32 patients. The presence, degree, location, and type of HAS were evaluated. For the detection of HAS by CEUS, the following was found: an accuracy of 91.5% (43/47), a sensitivity of 92.3% (36/39), a specificity of 87.5% (7/8), a positive predictive value of 97.3% (36/37), and a negative predictive value of 70% (7/10). CEUS corrected false-positive findings on color Doppler ultrasound in 7 of 47 cases (14.9%). The accuracy of CEUS in identifying the location and type of HAS was 92.3% (36/39) and 84.6% (33/39), respectively. CEUS is a useful noninvasive technique for the detection of HAS in liver transplant patients because it provides comprehensive information, including the presence, location, degree, and type. A positive CEUS finding suggests angiography as the next step rather than a computed tomography scan and may thereby alter the clinical imaging algorithm. Liver Transpl 16:729-735, 2010. © 2010 AASLD.
Injectable Biodegradable Hydrogels
Authors: Nguyen Minh Khanh , Lee Doo Sung
Published: March 2010

Injectable biodegradable copolymer hydrogels, which exhibit a sol–gel phase transition in response to external stimuli, such as temperature changes or both pH and temperature (pH/temperature) alterations, have found a number of uses in biomedical and pharmaceutical applications, such as drug delivery, cell growth, and tissue engineering. These hydrogels can be used in simple pharmaceutical formulations that can be prepared by mixing the hydrogel with drugs, proteins, or cells. Such formulations are administered in a straightforward manner, through site‐specific control of release behavior, and the hydrogels are compatible with biological systems. This review will provide a summary of recent progress in biodegradable temperature‐sensitive polymers including polyesters, polyphosphazenes, polypeptides, and chitosan, and pH/temperature‐sensitive polymers such as sulfamethazine‐, poly(β‐amino ester)‐, poly(amino urethane)‐, and poly(amidoamine)‐based polymers. The advantages of pH/temperature‐sensitive polymers over simple temperature‐sensitive polymers are also discussed. A perspective on the future of injectable biodegradable hydrogels is offered.

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4‐Chloro‐benzoic acid [1,2,4]triazol‐1‐ylmethyl ester as an effective inhibitor of mild steel corrosion in HCl solution
Authors: Tao Z. , Zhang S. , Li W. , Hou B.
Published: March 2010

4‐Chloro‐benzoic acid [1,2,4]triazol‐1‐ylmethyl ester (CBT) was synthesized and its inhibiting action on the corrosion of mild steel in 1 M hydrochloric acid solutions was investigated by means of weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), and scanning electron microscope (SEM). The results showed that CBT is an excellent inhibitor for mild steel in acid medium and its inhibition efficiency (IE%) is up to 90.2% at a concentration of 10−3 M at 298 K. EIS showed that the charge transfer controls the corrosion process in the uninhibited and inhibited solutions. Potentiodynamic polarization studies clearly reveal that CBT acts essentially as mixed‐type inhibitor. Thermodynamic parameters such as adsorption heat ($\Delta {\rm H}_{ads}^0$), adsorption entropy ($\Delta {\rm S}_{ads}^0$), and adsorption free energy ($\Delta {\rm G}_{ads}^0$) were obtained and discussed from experimental data of the temperature studies of the inhibition process at four temperatures ranging from 298 to 333 K. Kinetic parameters activation such as $E_a$, $\Delta H^ *$, $\Delta S^ *$, and pre‐exponential factor have been calculated and discussed. Adsorption of the inhibitor on the mild steel surface followed Langmuir adsorption isotherm. The values of the free energy of adsorption $\Delta G_{ads}^0$ indicated that the adsorption of CBT molecule was a spontaneous process, and was typical of chemisorption.
Atmospheric corrosion of aluminium in the northern Taklamakan Desert environment
Authors: Sun S. , Zheng Q. , Wen J. , Li D.
Published: March 2010

Atmospheric corrosion of aluminium in the northern Taklamakan Desert environment in China was investigated through the field exposure over a period of 2 years and the laboratory‐accelerated test of dry‐wet cycles. The results demonstrated that aluminium 1050 suffered serious atmospheric corrosion in the field exposure, which resulted from high soluble salt content and a high pH value of surface desert soil deposited on the samples. The soluble salt in surface desert soil could sufficiently decrease the relative humidity at which corrosion current density suddenly increased. Moreover, aluminium suffered more serious corrosion when there was more soluble salt content in surface desert soil. Among those salts, magnesium chloride caused the most serious corrosion attack.