bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental determination of laws of color harmony. Part 3: Harmony content of different hue pairs
Authors: Nemcsics Antal
Published: December 2008

At the Budapest University of Technology and Economics in 1956, we decided to start large‐scale experiments on color harmony. The experiments and the processing of the experimental data were completed in 2006. The experiments described in this article were based on a long established experience that harmony content of different hue pairs greatly differ from each other. The vast majority of former research activities on the subject of color harmony narrowed down mostly to investigations of saturated color pairs. Color samples of our experiments have been defined within the color space of the Coloroid color system, built on harmony thresholds. The compositions, prepared for the experiments, always consisted of two saturated hues and three low saturation colors of each hue at varying brightness, making it a total of eight colors. Within the framework of the experiments, 48 hues were used. Out of these, each of the 24 was formed into composition pairs with the remaining 48 hues, forming a total of 852 compositions. The paired‐comparison experiments were conducted with the use of the compositions prepared by collage technique. Color samples made of painted paper, between 1980 and 1985, have been repeated between 2002 and 2006 with the same color selection but with computer‐generated pseudorandom patch system compositions. It has been established that harmony content of hue pairs can be expressed by the relative angle of their hue planes in the Coloroid color space. The harmony content of hue pairs exceeds that of other pairs, when this angle is below 10°, between 30° and 40°, between 130° and 140° or near to 180°. Those color pairs of which hue planes are between 60° and 90° to each other in Coloroid color space, exhibit the least harmony content. © 2008 Wiley Periodicals, Inc. Col Res Appl, 34, 33–44, 2009.
Using Appearance Maps drawn from goniocolorimetric profiles to predict sensory appreciation of red and blue paints
Authors: Eterradossi Olivier , Perquis Stéphane , Mikec Véronique
Published: December 2008

In this article, we test the ability of a sensorialy calibrated version of Appearance Maps, a recently suggested tool based on Multidimensional Scaling and Procrustes Analysis, to understand and predict the sensory evaluation of automotive paints by trained subjects. This tool has been applied to a set of 13 industrial samples representing three shades: two effect shades, both at 4 levels of quality, and one solid shade at 5 levels of quality, which were evaluated for their overall appearance relative to the distinctness of image and the “Orange Peel” effect. The results of descriptive analysis performed on the samples by a panel of 15 trained panelists (paint experts and sensory assessors) are compared with information taken from the maps. One of the Appearance Map coordinates is shown to correlate well with mean sensory evaluations. Different relations (either sigmoid curves or power laws) between map coordinate considered as a stimulus and sensory scores taken as perception are found for the different shades, and comments on possible similarities between the observed relations and known models are made. © 2008 Wiley Periodicals, Inc. Col Res Appl, 34, 68–74, 2009.
The Effects of Starting Materials in the Synthesis of (Ga1−xZnx)(N1−xOx) Solid Solution on Its Photocatalytic Activity for Overall Water Splitting under Visible Light
Authors: Hisatomi Takashi , Maeda Kazuhiko , Lu Daling , Domen Kazunari
Published: December 2008

It all depends on the ingredients: The physicochemical properties of (Ga1−xZnx)(N1−xOx), including its particle size, are dependent on the particle size of the ZnO precursor. The relationship between the physicochemical properties and photocatalytic performance of (Ga1−xZnx)(N1−xOx) for overall water splitting under visible light was investigated to identify suitable starting materials of the catalyst.

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The influence of starting materials on the physicochemical and photocatalytic properties of (Ga1−xZnx)(N1−xOx) were investigated in an attempt to optimize the preparation conditions. The catalyst was successfully prepared by nitriding a starting mixture of ZnO and Ga2O3. A mixture of metallic zinc and GaN, however, did not afford the desired compound. The crystallinity, surface area, composition, and absorption characteristics of the resultant (Ga1−xZnx)(N1−xOx) solid solution are found to be dependent on the morphology of ZnO but largely insensitive to the choice of Ga2O3 polymorph. The use of coarser‐grained ZnO results in a coarser‐grained catalyst with elevated zinc and oxygen content and reduced uniformity in composition and crystallinity. The results demonstrate the importance of selecting appropriate ZnO and Ga2O3 starting materials for maximizing the photocatalytic activity of (Ga1−xZnx)(N1−xOx) for overall water splitting under visible light.
Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle
Authors: De Vos Winnok H. , Hoebe R. A. , Joss G. H. , Haffmans W. , Baatout S. , Van Oostveldt P. , Manders E. M. M.
Published: December 2008

Telomeres are complex end structures that confer functional integrity and positional stability to human chromosomes. Despite their critical importance, there is no clear view on telomere organization in cycling human cells and their dynamic behavior throughout the cell cycle. We investigated spatiotemporal organization of telomeres in living human ECV‐304 cells stably expressing telomere binding proteins TRF1 and TRF2 fused to mCitrine using four dimensional microscopy. We thereby made use of controlled light exposure microscopy (CLEM), a novel technology that strongly reduces photodamage by limiting excitation in parts of the image where full exposure is not needed. We found that telomeres share small territories where they dynamically associate. These territories are preferentially positioned at the interface of chromatin domains. TRF1 and TRF2 are abundantly present in these territories but not firmly bound. At the onset of mitosis, the bulk of TRF protein dissociates from telomere regions, territories disintegrate and individual telomeres become faintly visible. The combination of stable cell lines, CLEM and cytometry proved essential in providing novel insights in compartment‐based nuclear organization and may serve as a model approach for investigating telomere‐driven genome‐instability and studying long‐term nuclear dynamics. © 2008 International Society for Advancement of Cytometry
Quantification of cardiomyocyte contraction based on image correlation analysis
Authors: Kamgoué A. , Ohayon J. , Usson Y. , Riou L. , Tracqui P.
Published: December 2008

Quantification of cardiomyocyte contraction is usually obtained by measuring globally cell shortening from the displacement of cell extremities. We developed a correlation‐based optical flow method, which correlates the whole‐cell temporal pattern with a precise quantification of the intracellular strain wave at the sarcomeres level. A two‐dimensional image correlation analysis of cardiomyocytes phase‐contrast images was developed to extract local cell deformations from videomicroscopy time‐lapse sequences. Test images, synthesized from known intensity displacement fields, were first used to validate the method. Intracellular strain fields were then computed from videomicroscopy time‐lapse sequences of single adult and neonatal cardiomyocytes. The propagation of the sarcomeres contraction–relaxation wave during cell contraction has been successfully quantified. The time‐varying patterns of intracellular displacement were obtained accurately, even when cardiomyocyte bending occurred in pace with contraction. Interestingly, the characterization of the successive 2D displacement fields show a direct quantification of the variation with time of intracellular strains anywhere in the cell. The proposed method enables a quantitative analysis of cardiomyocyte contraction without requiring wave tracking with the use of fluorescent calcium probes. Thus, our algorithmic approach provides a fast and efficient tool for analyzing the correlation between global cell dynamical behavior and mechanosensitive intracellular processes. © 2008 International Society for Advancement of Cytometry
Novel agents to override imatinib resistance mechanisms
Authors: Yokota Asumi , Kimura Shinya
Published: December 2008

Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells that results from the Philadelphia chromosome (Ph) created through translocation of human chromosomes 9 and 22. The resulting Bcr‐Abl fusion protein has constitutively high tyrosine kinase activity that causes transformation of hematopoietic stem cells. Imatinib mesylate (IM) was developed as a specific Bcr‐Abl kinase inhibitor and is efficacious in treating Ph‐chromosome‐positive (Ph+) leukemias such as CML and Ph+ acute lymphoblastic leukemia (ALL). Within a few years of its introduction to the clinic, IM has dramatically altered the first‐line therapy for CML. Although most newly diagnosed CML patients in the chronic phase (CP) achieved durable responses when treated with IM, resistance to IM has become a major problem in patients with advanced‐stage disease. The most important mechanism of IM resistance are point mutations within the Abl kinase domain; therefore, there is an urgent need for novel agents that can inhibit mutated Bcr‐Abl. In this review, we describe novel Bcr‐Abl tyrosine kinase inhibitors, the so‐called “Super Gleevec” inhibitors. Drug Dev Res 69:398–406, 2008. © 2008 Wiley‐Liss, Inc.
Development of drugs against hormone‐refractory prostate cancer
Authors: Kageyama Yukio
Published: December 2008

The development of novel drugs for prostate cancer refractory to androgen deprivation therapy has been of great interest due to the lack of effective treatment modalities that can prolong the survival of such patients. The recent introduction of docetaxel‐based combination chemotherapy has been a breakthrough with a modest, but significant, survival benefit. However, the improved survival period measured in months is far from ideal considering the non‐negligible adverse events associated with docetaxel. Thus, numerous preclinical and clinical studies have been conducted to explore more favorable approaches to hormone‐refractory prostate cancer. The novel agents under investigation include new chemotherapeutic drugs, drugs targeting signal transduction pathways, apoptosis modulators, drugs targeting the tumor microenvironment, molecular chaperone inhibitors, and dietary ingredients. Unfortunately, none of these agents have shown superior single‐agent activity relative to docetaxel‐based therapy to date. Therefore, developing the most effective combination therapies of new agents and docetaxel‐based chemotherapy seems to be a reasonable approach until novel agents that can overcome the drug resistance of hormone‐refractory prostate cancer cells emerge. Drug Dev Res 69:431–450, 2008. © 2008 Wiley‐Liss, Inc.
Persistent Alkylgallium Peroxides – Synthesis of the Cage Compound Na4[(Ga‐R)3(O2)3(O)]2(Et2O)(DABCO) [R = CH(SiMe3)2]
Authors: Uhl Werner , Halvagar Mohammad R. , Rogel Friedhelm , Massa Werner
Published: December 2008

Reaction of Na[H3Ga‐CH(SiMe3)2] (1) with the adduct (H2O2)2·DABCO affords the alkylgallium peroxide Na4[(Ga‐R)3(O2)3(O)]2(Et2O)(DABCO) (2) [R = CH(SiMe3)2] by hydrogen release. Compound 2 possesses oxidizing peroxo groups in close proximity to reducing Ga–C bonds and a higher thermal stability than the analogous lithium peroxo complex. In the solid state a cage compound is formed in which two Ga3(O2)3 heterocycles are bridged by four sodium atoms. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Advances in enantioselective separations using electromigration capillary techniques
Authors: Preinerstorfer Beatrix , Lämmerhofer Michael , Lindner Wolfgang
Published: December 2008

The most recent literature dealing with enantioselective separations and stereoselective analyses of chiral entities including especially pharmaceuticals, phytochemicals, biochemicals, agrochemicals, fine chemicals and specific test compounds by electromigration techniques such as CE, MEKC, MEEKC, CEC and microchip CE is reviewed. The review covers literature from 2007 until mid‐2008, i.e. studies that were published after the appearance of the latest review article on that topic in Electrophoresis by Gübitz and Schmid (see Electrophoresis 2007, 28, 114). Particular attention is given to the description of new chiral selector systems, studies on separation mechanisms and applications in the above‐specified electromigration techniques.
Heart‐cutting 2‐D CE using multiple detection points for chiral analysis of native amino acids
Authors: Anouti Suzanne , Vandenabeele‐Trambouze Odile , Koval Dušan , Cottet Hervé
Published: December 2008

A new methodology based on heart‐cutting 2‐D CE in a single capillary was developed for the chiral separation of a mixture of 22 underivatized amino acids. The first dimension is performed in an achiral BGE (2.3 M acetic acid, pH 2.1) allowing the separation of the analytes as a function of their charge‐to‐radius ratio. A selected fraction from the first dimension is then separated in the second dimension in the presence of a chiral selector (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid. Since the introduction of the second electrolyte is performed by pressure mobilization, capillaries with small id of 10 μm are used to limit the peak broadening due to Taylor dispersion. Double capacitively coupled contactless conductivity detector is used for monitoring the selection and the isolation of the fraction at the different steps of the analysis (voltage and pressure mobilization steps). This double detection allows calculating the voltage and pressure stop times in real‐time analysis. This new methodology is applied with success for the chiral separation of different amino acids (d,l‐Tyr, d,l‐Trp and d,l‐Thr) contained in a mixture of 22 native amino acids.
Radiation‐induced bystander effects in vivo are epigenetically regulated in a tissue‐specific manner
Authors: Ilnytskyy Yaroslav , Koturbash Igor , Kovalchuk Olga
Published: December 2008

Exposure of animal body parts to ionizing radiation (IR) can lead to molecular changes in distant shielded “bystander” tissues and organs. Nevertheless, tissue specificity of bystander responses within the same organism has not been examined in detail. Studies on in vivo bystander effect conducted so far analyzed changes induced by single‐dose exposure. The potential of fractionated irradiation to induce bystander effects in vivo has never been studied. We analyzed changes in global DNA methylation and microRNAome in skin and spleen of animals subjected to single‐dose (acute or fractionated) whole‐body or cranial exposure to 0.5 Gy of X‐rays. We found that IR‐induced DNA methylation changes in bystander spleen and skin were distinct. Acute radiation exposure resulted in a significant loss of global DNA methylation in the exposed and bystander spleen 6 hr, 96 hr, and 14 days after irradiation. Fractionated irradiation led to hypomethylation in bystander spleen 6 hr after whole‐body exposure, and 6 hr, 96 hr, and 14 days after cranial irradiation. Contrarily, changes in the skin of the same animals were seen only 6 hr after acute whole‐body and head exposure. DNA hypomethylation observed in spleen was paralleled by a reduction of methyl‐binding protein MeCP2 expression. Irradiation also induced tissue‐specific microRNAome alterations in skin and spleen. For the first time, we have shown that IR‐induced epigenetic bystander effects that occur in the same organism are triggered by both acute and fractionated exposure and are very distinct in different bystander organs. Future studies are clearly needed to address organismal and carcinogenic repercussions of those changes. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
A novel germline mutation in Big Blue® mice
Authors: Crabbe Rory A. , Prtenjaca Anita , Tarnowski Heather E. , Hill Kathleen A.
Published: December 2008

The Big Blue® lacI mutation detection assay is well validated and has permitted detailed analysis of spontaneous mutations in individual tissues over the lifespan of the mouse. In a recent assay of spontaneous mutations, a novel lacI mutation (C354T) recurred in six of seven mutants with a second mutation. The frequency of spontaneous doublets (mutants with two nontandem mutations) was elevated 2.7‐fold over that previously reported (Hill KA et al., [2004b]: Mutat Res 554:223–240) for normal tissues (6.3 × 10−7 herein vs. 2.36 × 10−7). The average spacing between mutations in the doublets (237 bp) was greater than previously reported for spontaneous doublets. The frequency of C354T as a “hitchhiker” mutation in doublets was consistent with a germline mutation in one of 38 mutation targets in the Big Blue mouse genome. C354T is a missense mutation at a CpG dinucleotide producing a conservative amino acid change (Ala109Val) and a very light blue mutant phenotype. Mutant phenotypes of doublets with C354T were typical of the second mutation. C354T was observed in mutants from five tissues of five Big Blue mice. A bidirectional‐PCR amplification of specific alleles (Bi‐PASA) assay detected C354T in genomic DNA from multiple tissues of five Big Blue mice. These observations are consistent with a novel lacI C354T germline mutation in Big Blue mice that introduces a significant artifact in the analysis of spontaneous mutations. This finding reiterates the importance of identifying all mutations and examining new mutations in the context of our increasingly detailed knowledge of features of spontaneous murine mutations. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
Evaluation capacity building in complex organizations
Authors: Taylor‐Powell Ellen , Boyd Heather H.
Published: December 2008

Evaluation capacity building, or ECB, is an area of great interest within the field of evaluation as well as in Extension evaluation. Internal Extension evaluators have long offered training and technical assistance to help Extension educators conduct evaluation. Today ECB in Extension encompasses myriad activities and processes to advance evaluation practice and evaluative thinking. They can be described in a three‐component framework: professional development, resources and supports, and organizational environment. This chapter describes the Extension experience, highlighting practices and challenges within each component, and presents the case of logic model dissemination as an illustration. The authors discuss the distinction between evaluator and ECB practitioner and call for clarity in purpose, role delineation, and expectations. They include a simple logic model for evaluating ECB, which focuses on linking ECB investments to individual, team, program, and organizational change. The authors conclude with a list of their own learnings and reflections as they have faced the challenges and many rewards of building evaluation capacity in complex organizations. © Wiley Periodicals, Inc.
White‐matter abnormalities in attention deficit hyperactivity disorder: A diffusion tensor imaging study
Authors: Silk Timothy J. , Vance Alasdair , Rinehart Nicole , Bradshaw John L. , Cunnington Ross
Published: December 2008

Current evidence suggests that attention deficit hyperactivity disorder (ADHD) involves dysfunction in wide functional networks of brain areas associated with attention and cognition. This study examines the structural integrity of white‐matter neural pathways, which underpin these functional networks, connecting fronto‐striatal and fronto‐parietal circuits, in children with ADHD. Fifteen right‐handed 8 to 18‐year‐old males with ADHD‐combined type and 15 right‐handed, age, verbal, and performance IQ‐matched, healthy males underwent diffusion tensor imaging. A recent method of tract‐based spatial statistics was used to examine fractional anisotropy (FA) and mean diffusivity within major white‐matter pathways throughout the whole‐brain. White‐matter abnormalities were found in several distinct clusters within left fronto‐temporal regions and right parietal‐occipital regions. Specifically, participants with ADHD showed greater FA in white‐matter regions underlying inferior parietal, occipito‐parietal, inferior frontal, and inferior temporal cortex. Secondly, eigenvalue analysis suggests that the difference in FA in ADHD may relate to a lesser degree of neural branching within key white‐matter pathways. Tractography methods showed these regions to generally form part of white‐matter pathways connecting prefrontal and parieto‐occipital areas with the striatum and the cerebellum. Our findings demonstrate anomalous white‐matter development in ADHD in distinct cortical regions that have previously been shown to be dysfunctional or hypoactive in fMRI studies of ADHD. These data add to an emerging picture of abnormal development within fronto‐parietal cortical networks that may underpin the cognitive and attentional disturbances associated with ADHD. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
Is a preserved functional reserve a mechanism limiting clinical impairment in pediatric MS patients?
Authors: Rocca Maria A. , Absinta Martina , Ghezzi Angelo , Moiola Lucia , Comi Giancarlo , Filippi Massimo
Published: December 2008

We evaluated the functional magnetic resonance imaging (fMRI) correlates of simple movement performance in patients with pediatric multiple sclerosis (MS) and their relation with the extent of T2 lesion volume (LV), to improve our understanding of the mechanisms leading to their short/medium term favorable clinical course. We obtained fMRI during repetitive flexion‐extension of the last four fingers of the right hand and brain dual‐echo scans from 17 right‐handed patients with pediatric relapsing‐remitting MS and 9 sex‐ and age‐matched right‐handed healthy controls. T2 LV was measured using a local thresholding segmentation technique. fMRI activations and functional connectivity analysis were performed using SPM2. Compared to controls, pediatric MS patients had an increased recruitment of the left (L) primary sensorimotor cortex (SMC). They also showed reduced functional connectivity between the L primary SMC and the L thalamus (P = 0.03), the L insula and the L secondary sensorimotor cortex (SII) (P = 0.02), the supplementary motor area and the L SII (P = 0.02), the L thalamus and the L insula (P = 0.01) and the L thalamus and the L SII (P = 0.003). In patients with pediatric MS, the activity of the L primary SMC was significantly correlated with brain T2 LV (r = 0.78). No correlation was found between coefficients of abnormal connectivity and structural MRI measures. The maintenance of a selective and strictly lateralized pattern of movement‐associated brain activations and a modulation of its functional connections suggest a preserved functional reserve in patients with pediatric MS, which, in turn, might contribute to explain their favorable clinical evolution at short/medium term. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen–positive and hepatitis B e antigen–negative hepatitis B virus strains #
Authors: Amini-Bavil-Olyaee Samad , Herbers Ulf , Sheldon Julie , Luedde Tom , Trautwein Christian , Tacke Frank
Published: December 2008

Tenofovir is a new effective treatment option for patients with chronic hepatitis B, but could be potentially hampered by mutations in the hepatitis B virus (HBV) polymerase conferring drug resistance. Drug resistance may occur preferentially if long-term administration is required, for example, in patients with hepatitis B e antigen (HBeAg)-negative HBV infection bearing precore (PC) and basal core promoter (BCP) mutations. The rtA194T polymerase mutation has been found in HBV/HIV coinfected patients during tenofovir treatment and may be associated with tenofovir resistance. We generated replication-competent HBV constructs harboring rtA194T alone or in addition to lamivudine (LAM) resistance (rt180M + rtM204V), PC mutations, and BCP mutations and assessed their replicative capacity after transient transfection in human hepatoma cells. The rtA194T polymerase mutation alone or in conjunction with LAM resistance reduced the replication efficiency as compared with wild-type (WT) HBV. In contrast, combination of rtA194T (± LAM resistance) with HBeAg-negative PC or BCP mutants increased the replication capacity of the drug-resistant polymerase mutants, thereby restoring the viral replication to similar levels as WT clones. Clones harboring rtA194T showed partial resistance to tenofovir in vitro and also to LAM but remained susceptible to telbivudine and entecavir. Conclusion: The rtA194T polymerase mutation is associated with partial tenofovir drug resistance and negatively impacts replication competence of HBV constructs. Viral replication, however, can be restored to WT levels, if these polymerase mutations occur together with precore or basic core promoter substitutions as found in HBeAg-negative hepatitis B. Patients with HBeAg-negative chronic HBV infection may therefore be at particular risk when developing drug resistance to tenofovir. Telbivudine or entecavir should be considered as effective alternative treatment options for these patients. (Hepatology 2009.)
Bile salt–induced pro-oxidant liver damage promotes transplanted cell proliferation for correcting Wilson disease in the Long-Evans Cinnamon rat model #
Authors: Joseph Brigid , Kapoor Sorabh , Schilsky Michael L. , Gupta Sanjeev
Published: December 2008

Insights into disease-specific mechanisms for liver repopulation are needed for cell therapy. To understand the efficacy of pro-oxidant hepatic perturbations in Wilson disease, we studied Long-Evans Cinnamon (LEC) rats with copper toxicosis under several conditions. Hepatocytes from healthy Long-Evans Agouti (LEA) rats were transplanted intrasplenically into the liver. A cure was defined as lowering of copper to below 250 μg/g liver, presence of ATPase, Cu++ transporting, beta polypeptide (atp7b) messenger RNA (mRNA) in the liver and improvement in liver histology. Treatment of animals with the hydrophobic bile salt, cholic acid, or liver radiation before cell transplantation produced cure rates of 14% and 33%, respectively; whereas liver radiation plus partial hepatectomy followed by cell transplantation proved more effective, with cure in 55%, P < 0.01; and liver radiation plus cholic acid followed by cell transplantation was most effective, with cure in 75%, P < 0.001. As a group, cell therapy cures in rats preconditioned with liver radiation plus cholic acid resulted in less hepatic copper, indicating greater extent of liver repopulation. We observed increased hepatic catalase and superoxide dismutase activities in LEC rats, suggesting chronic oxidative stress. After liver radiation or cholic acid, hepatic lipid peroxidation levels increased, indicating further oxidative injury, although we did not observe overt additional cytotoxicity. This contrasted with healthy animals in which liver radiation and cholic acid produced hepatic steatosis and loss of injured hepatocytes. We concluded that pro-oxidant perturbations were uniquely effective for cell therapy in Wilson disease because of the nature of preexisting hepatic damage. (Hepatology 2009.)
Association between hypothyroidism and hepatocellular carcinoma: A case-control study in the United States #
Authors: Hassan Manal M. , Kaseb Ahmed , Li Donghui , Patt Yehuda Z. , Vauthey Jean-Nicolas , Thomas Melanie B. , Curley Steven A. , Spitz Margaret R. , Sherman Steven I. , Abdalla Eddie K. , Davila Marta , Lozano Richard D. , Hassan Deena M. , Chan Wenyaw , Brown Thomas D. , Abbruzzese James L.
Published: December 2008

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus–negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC. (Hepatology 2009;49:1563–1570.)
HBV superinfection in HCV chronic carriers: A disease that is frequently severe but associated with the eradication of HCV #
Authors: Sagnelli Evangelista , Coppola Nicola , Pisaturo Mariantonietta , Masiello Addolorata , Tonziello Gilda , Sagnelli Caterina , Messina Vincenzo , Filippini Pietro
Published: December 2008

The impact of hepatitis B virus (HBV) superinfection in hepatitis C virus (HCV) chronic carriers was evaluated in a long-term follow-up study on 29 chronic anti-HCV carriers with acute hepatitis B (AVH-B) (Case group BC) and 29 anti-HCV negative patients with AVH-B (Control group B), pair-matched for age (±5 years), sex, and risk factors for the acquisition of HBV infection. Patients in Case group BC and those in Control group B showed similar initial HBV viral load and a similar trend of becoming negative for HBV-DNA. AVH-B showed a severe course more frequently in Case group BC than in Control group B (34.5% versus 6.9%, P < 0.05). Of the 28 patients in Case group BC alive at the end of the acute illness (one death from liver failure), 24 were followed up for 2-6 years, median 5 years: 22 patients became HBsAg-negative and two progressed to HBsAg-positive chronic hepatitis. HCV-RNA was undetectable in all patients during AVH-B; in the 24 patients with a long-term follow-up, HCV-RNA was detected in seven (29.2%) after 1 year, in 14 (58.3%) after 2 years, and in 18 (75%) after 3-6 years. The six patients who eradicated chronic HCV infection, compared with 18 showing reactivation of HCV replication, had higher values of aspartate aminotransferase and alanine aminotransferase and a higher prevalence of cases with severe AVH-B (83.3% versus 22.2%, P < 0.05). Conclusions: Although it can be life-threatening, HBV superinfection in HCV chronic carriers may lead to clearance of chronic HCV infection, especially in patients with severe AVH-B. (Hepatology 2009.)
Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model #
Authors: Kamili Saleem , Sozzi Vitini , Thompson Geoff , Campbell Katie , Walker Christopher M. , Locarnini Stephen , Krawczynski Krzysztof
Published: December 2008

Hepatitis B virus (HBV) mutants resistant to treatment with nucleoside or nucleotide analogs and those with the ability to escape from HBV-neutralizing antibody have the potential to infect HBV-vaccinated individuals. To address this potential serious public health challenge, we tested the efficacy of immunity induced by a commercial hepatitis B vaccine against a tissue culture-derived, clonal HBV polymerase mutant in HBV seronegative chimpanzees. The polymerase gene mutant contained a combination of three mutations (rtV173L, rtL180M, rtM204V), two of which resulted in changes to the overlapping viral envelope of the hepatitis B surface antigen (sE164D, sI195M). Prior to the HBV mutant challenge of vaccinated chimpanzees, we established virologic, serologic, and pathologic characteristics of infections resulting from intravenous inoculation of the HBV polymerase gene mutant and the sG145R vaccine-escape surface gene mutant. Cloning and sequencing experiments determined that the three mutations in the polymerase gene mutant remained stable and that the single mutation in the surface gene mutant reverted to the wild-type sequence. Immunological evidence of HBV replication was observed in the vaccinated chimpanzees after challenge with the polymerase gene mutant as well as after rechallenge with serum-derived wild-type HBV (5,000 chimpanzee infectious doses administered intravenously), despite robust humoral and cellular anti-HBV immune responses after hepatitis B vaccination. Conclusion: Our data showing successful experimental infection by HBV mutants despite the presence of high anti-HBs levels considered protective in the vaccinated host are consistent with clinical reports on breakthrough infection in anti-HBs-positive patients infected with HBV mutants. In the absence of a protective humoral immunity, adaptive cellular immune responses elicited by infection may limit HBV replication and persistence. (Hepatology 2009.)
Changes in stream water quality due to logging of the boreal forest in the Montmorency Forest, Québec
Authors: Tremblay Yohann , Rousseau Alain N. , Plamondon André P. , Lévesque Denis , Prévost Marcel
Published: December 2008

Summer stream water quality was monitored before and following the logging of 50% of the boreal forest within three small watersheds (<50 ha) nested in the ‘Ruisseau des Eaux‐Volées’ Experimental Watershed, Montmorency Forest (Québec, Canada). Logging was conducted in winter, on snow cover according to recommended best management practices (BMPs) to minimize soil disturbance and protect advance growth. A 20‐m forest buffer was maintained along perennial streams. In watershed 7·2, cut‐blocks were located near the stream network and logging was partially allowed within the riparian buffer zone. In watersheds 7·5 and 7·7, logging occurred farther away from the stream network. Observations were also made for watershed 7·3 that collected the runoff from watersheds 7·2 and 7·5, and watershed 7·6, the uproad portion of watershed 7·7. The control watershed 0·2 was contiguous to the impacted watersheds and remained undisturbed. Following clearcutting, changes in summer daily maximum and minimum stream temperatures remained within ± 1 °C while changes in diurnal variation did not decrease by more than 0·5 °C. Concentrations of NO3− greatly increased by up to 6000% and concentrations of K+ increased by up to 300% during the second summer after logging. Smaller increases were observed for Fetotal (up to 71%), specific conductance (up to 26%), and Mg2+ (up to 19%). Post‐logging pH decreased slightly by no more than 7% while PO43− concentration remained relatively constant. Suspended sediment concentrations appeared to increase during post‐logging, but there was not enough pre‐logging data to statistically confirm this result. Logging of moderate intensity and respecting established BMPs may account for the limited changes of water quality parameters and the low exceedances of the criteria for the protection of aquatic life. The proximity of the cutover to the stream network and logging within the riparian zone did not appear to affect water quality. Copyright © 2008 John Wiley & Sons, Ltd.
Large genomic rearrangements and germline epimutations in Lynch syndrome
Authors: Gylling Annette , Ridanpää Maaret , Vierimaa Outi , Aittomäki Kristiina , Avela Kristiina , Kääriäinen Helena , Laivuori Hannele , Pöyhönen Minna , Sallinen Satu‐Leena , Wallgren‐Pettersson Carina , Järvinen Heikki J. , Mecklin Jukka‐Pekka , Peltomäki Paivi
Published: December 2008

In one‐third of families fulfilling the Amsterdam criteria for hereditary nonpolyposis colorectal cancer/Lynch syndrome, and a majority of those not fulfilling these criteria point mutations in DNA mismatch repair (MMR) genes are not found. The role of large genomic rearrangements and germline epimutations in MLH1, MSH2 and MSH6 was evaluated in 2 such cohorts. All 45 index patients were mutation‐negative by genomic sequencing and testing for a prevalent population‐specific founder mutation, and selectively lacked MMR protein expression in tumor tissue. Eleven patients (“research cohort”) represented 11 mutation‐negative families among 81 verified or putative Lynch syndrome families from the nation‐wide Hereditary Colorectal Cancer Registry of Finland. Thirty‐four patients from 33 families (“clinic‐based cohort”) represented suspected Lynch syndrome patients tested for MMR gene mutations in a diagnostic laboratory during 2004–2007. Multiplex ligation‐dependent probe amplification (MLPA) and methylation‐specific (MS)‐MLPA were used to detect rearrangements and epimutations, respectively. Large genomic deletions occurred in 12/45 patients (27%), being present in 3/25 (12%), 9/16 (56%) and 0/4 (0%) among index patients lacking MLH1, MSH2 or MSH6 expression, respectively. Germline epimutations of MLH1, one of which coexisted with a genomic deletion, occurred in 2 patients (4%) and were accompanied by monoallelic expression in mRNA. Large genomic deletions (mainly MSH2) and germline epimutations (MLH1) together explain a significant fraction of point mutation‐negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of such families. © 2008 Wiley‐Liss, Inc.
The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells
Authors: Probst Olivia C. , Puxbaum Verena , Svoboda Barbara , Leksa Vladimir , Stockinger Hannes , Mikula Mario , Mikulits Wolfgang , Mach Lukas
Published: December 2008

The mannose 6‐phosphate/insulin‐like growth factor II receptor (M6P/IGF2R) mediates biosynthetic sorting and endocytosis of various factors that impinge on the proliferation, migration and invasiveness of tumour cells. The gene encoding M6P/IGF2R is frequently lost or mutated in a wide range of malignant tumours including squamous cell carcinomas. We have previously shown that M6P/IGF2R‐deficient SCC‐VII murine squamous cell carcinoma cells secrete large amounts of pro‐invasive lysosomal proteinases. Furthermore, the formation of mature lysosomes is impaired in SCC‐VII cells. To assess the link between M6P/IGF2R status and tumour invasion, we have now generated SCC‐VII lines stably transfected with human M6P/IGF2R cDNA. Reconstitution of functional M6P/IGF2R expression in SCC‐VII cells strongly improves the intracellular retention of lysosomal proteinases and restores the formation of mature lysosomes. In addition, the presence of heterologous M6P/IGF2R compromises the growth of SCC‐VII cells both in vitro and in vivo. Remarkably, M6P/IGF2R expression also reduces the invasive capacity of SCC‐VII cells in response to various chemoattractants. These results indicate that the M6P/IGF2R status influences the metastatic propensity of squamous cell carcinomas. © 2008 Wiley‐Liss, Inc.
Endometrial cancer invasion depends on cancer‐derived tumor necrosis factor‐α and stromal derived hepatocyte growth factor
Authors: Choi Dong Soon , Kim Hyun‐Jin , Yoon Jong‐Hyuck , Yoo Seung‐Chul , Jo Hantae , Lee So Yeon , Min Churl K. , Ryu Hee‐Sug
Published: December 2008

Cancer invasion is an outcome of interactions of the cancer and the host cell. It is now becoming increasingly clear that ovarian hormones have a huge influence on such intercommunications in various types of cancers. Estrogen is known to aggravate the aggressiveness of the endometrial cancer whereas progesterone seems to act as a negative factor. Insight into the mode of ovarian hormonal actions could come from the studies of its regulation of the paracrine interactions between the endometrial cancer and the normal stromal cells during the cancer invasion. In this context, we report here that estrogen promotes the endometrial cancer invasion by inducing humoral interactions between the cancer and the stromal cells, i.e., estrogen stimulates tumor necrosis factor‐α expression from the endometrial cancer cells, which, in turn, induces the stromal expression of hepatocyte growth factor (HGF), conferring the enhanced NK4 (HGF‐antagonist/angiogenesis inhibitor)‐sensitive invasion characteristic of the endometrial cancer cells. Additionally, we demonstrate a close correlation of the invasion of endometrial cancer cells with the expression and dimerization of integrin αvβ5 as well as the activation of focal adhesion kinase as the consequences of paracrine interactions. Thus, understanding of paracrine interactions of cancer cells with host stromal cells can yield new insight into the architecture and function of cancer invasion and metastasis, leading to a development of a new cancer therapeutic intervention. © 2008 Wiley‐Liss, Inc.
Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule‐dependency
Authors: Mikkelsen Tom , Brodie Chaya , Finniss Susan , Berens Michael E. , Rennert Jessica L. , Nelson Kevin , Lemke Nancy , Brown Stephen L. , Hahn Diane , Neuteboom Berend , Goodman Simon L.
Published: December 2008

We investigated whether cilengitide could amplify the antitumor effects of radiotherapy in an orthotopic rat glioma xenograft model. Cilengitide is a specific inhibitor of αv series integrins, and acts as an antiangiogenic. U251 human glioma cells express αvβ3 and αvβ5 integrins. We used in vitro assays of adhesion and growth of tumor and endothelial cells to evaluate cytotoxicity and the potential for cilengitide to enhance radiation toxicity. Treatment was then evaluated in an orthotopic model to evaluate synergy with therapeutic radiation in vivo. In vitro, cilengitide blocked cell adhesion, but did not influence the effects of radiation on U251 cells; cilengitide strongly amplified radiation effects on endothelial cell survival. In vivo, radiotherapy prolonged the survival of U251 tumor‐bearing rats from 50 to over 110 days. Cotreatment with cilengitide and radiation dramatically amplified the effects of radiation, producing survival over 200 days and triggering an enhanced apoptotic response and suppression of tumor growth by histology at necropsy. Signaling pathways activated in the tumor included NFκb, a documented mediator of cellular response to radiation. Because cilengitide has a short plasma half‐life (t½ ∼ 20 min), antiangiogenic scheduling typically uses daily injections. We found that a single dose of cilengitide (4 mg/kg) given between 4 and 12 hr prior to radiation was sufficient to produce the same effect. Our results demonstrate that blockade of αv integrins mediates an unanticipated rapid potentiation of radiation, and suggests possible clinical translation for glioma therapy. © 2008 Wiley‐Liss, Inc.
Induction of myeloid‐derived suppressor cells by tumor exosomes
Authors: Xiang Xiaoyu , Poliakov Anton , Liu Cunren , Liu Yuelong , Deng Zhong‐bin , Wang Jianhua , Cheng Ziqiang , Shah Spandan V. , Wang Gui‐Jun , Zhang Liming , Grizzle William E. , Mobley Jim , Zhang Huang‐Ge
Published: December 2008

Myeloid‐derived suppressor cells (MDSCs) promote tumor progression. The mechanisms of MDSC development during tumor growth remain unknown. Tumor exosomes (T‐exosomes) have been implicated to play a role in immune regulation, however the role of exosomes in the induction of MDSCs is unclear. Our previous work demonstrated that exosomes isolated from tumor cells are taken up by bone marrow myeloid cells. Here, we extend those findings showing that exosomes isolated from T‐exosomes switch the differentiation pathway of these myeloid cells to the MDSC pathway (CD11b+Gr‐1+). The resulting cells exhibit MDSC phenotypic and functional characteristics including promotion of tumor growth. Furthermore, we demonstrated that in vivo MDSC mediated promotion of tumor progression is dependent on T‐exosome prostaglandin E2 (PGE2) and TGF‐β molecules. T‐exosomes can induce the accumulation of MDSCs expressing Cox2, IL‐6, VEGF, and arginase‐1. Antibodies against exosomal PGE2 and TGF‐β block the activity of these exosomes on MDSC induction and therefore attenuate MDSC‐mediated tumor‐promoting ability. Exosomal PGE2 and TGF‐β are enriched in T‐exosomes when compared with exosomes isolated from the supernatants of cultured tumor cells (C‐exosomes). The tumor microenvironment has an effect on the potency of T‐exosome mediated induction of MDSCs by regulating the sorting and the amount of exosomal PGE2 and TGF‐β available. Together, these findings lend themselves to developing specific targetable therapeutic strategies to reduce or eliminate MDSC‐induced immunosuppression and hence enhance host antitumor immunotherapy efficacy. © 2008 Wiley‐Liss, Inc.
Correlation between rate of bony ingrowth to stainless steel, pure titanium, and titanium alloy implants in vivo and formation of hydroxyapetite on their surfaces in vitro
Authors: Oron A. , Agar G. , Oron U. , Stein A.
Published: December 2008

The rate of bony ingrowth to identical metal implants made of either pure titanium (cpTi), titanium alloy (Ti‐6Al‐4V), or stainless steel 316L (SS) inserted to the medullar canal of the femur in rats was investigated. The kinetics of spontaneous deposition of hydroxyapatite (HA) globules on the aforementioned metals in vitro during incubation in simulated body fluid (SBF) was also studied. It was found that the rate of increased bonding strength between the cpTi implants and the host bone was the highest, whereas around the SS implants it was the slowest. At 10 days postimplant insertion, the shear strength of the cpTi implants was 2.2‐ and 4‐fold significantly higher than for the Ti‐6Al‐4V and the SS implants, respectively. Spontaneous formation of the HA globules on the cpTi and Ti‐6Al‐4V implants that were incubated in the SBF was observed as early as 6 and 10 days after incubation in SBF, respectively, whereas on SS implants, deposition of HA was evident only after 2 weeks of in vitro incubation in SBF. It is concluded that the chemical surface characteristics and the biocompatibility of the implants probably play a key role in the process of bone growth next to them, during the formation of bone in vivo. The rate of bony ingrowth to various metal implants alloys inserted into the medullar canal of rats correlates well with the induction of apatite formation on them during incubation in vitro with SBF. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009