bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal neurogenesis and ontogenetic changes in the visual system of the brown banded bamboo shark, Chiloscyllium punctatum (hemiscyllidae, elasmobranchii)
Authors: Harahush Blake K. , Hart Nathan S. , Green Kathryn , Collin Shaun P.
Published: December 2008

The development of the eye of the oviparous brown banded bamboo shark, Chiloscyllium punctatum, was monitored from egg deposition through adulthood. The order and timing of retinal cell differentiation were assessed by light and transmission electron microscopy. As in other vertebrates, the ganglion cells are the first to differentiate, in this case by 81 days post‐egg deposition (dpd). The order then deviates from what is typically quoted for vertebrates, with the Müller and amacrine cells differentiating morphologically around the same time, followed by the bipolar cells (101 dpd) and finally the horizontal cells and photoreceptors (124 dpd). The neural retina is fully differentiated and synaptic connections are formed approximately 1 month prior to hatching, which occurs at about 158 dpd. The mature retina is duplex, with a peak rod to cone ratio of approximately 12:1. The eye and lens of C. punctatum continue to grow throughout life and become less aspherical with growth; the equatorial (nasotemporal) lens diameter is 12% larger than the axial (anterior‐posterior) lens diameter in embryos and 8% larger in adults. Access to developmental stages and the protracted gestational period of C. punctatum make it a highly valuable model for developmental studies of the visual system. This study also provides an evolutionary perspective on retinal neurogenesis in an elasmobranch. J. Comp. Neurol. 513:83–97, 2009. © 2008 Wiley‐Liss, Inc.
Molecular targeting with recombinant cytotoxins for the treatment of brain tumors
Authors: Debinski Waldemar
Published: December 2008

Substantial progress has been made in the clinical application of molecularly targeted proteinaceous cytotoxins for the treatment of glioblastoma multiforme (GBM), a primary brain tumor of dismal prognosis. These recombinant cytotoxins are composed of tumor‐targeting ligands and genetically engineered derivatives of extremely toxic to eukaryotic cells bacterial toxins. Several cytotoxins moved relatively quickly, as for novel anti‐cancer drugs, from bench to clinic during the last decade; both clinical studies and laboratory research have brought invaluable translational information. The important factors that are linked to the overall cytotoxins' clinical utility are target specificity, proportion of potential responders to a cytotoxin among patients and an efficient delivery of the cytotoxin directly to the tumor site using convection‐enhanced delivery (CED). Novel, potent, and very specific cytotoxins against GBM are being continuously generated. Moreover, a combinatorial targeting of more than one target in GBM with the cytotoxins emerges as an approach of potentially higher anti‐tumor efficacy and more universal usage. Novel means of recombinant cytotoxins delivery are being envisioned and tested. The next decade should bring more complete and successful clinical application of recombinant cytotoxins, a highly promising class of anti‐GBM drugs. Drug Dev Res 69:407–414, 2008. © 2008 Wiley‐Liss, Inc.
Natural products and colon cancer: current status and future prospects
Authors: Rajamanickam Subapriya , Agarwal Rajesh
Published: December 2008

Carcinogenesis is a multistage process consisting of initiation, promotion, and progression phases. Thus, the multistage sequence of events has many phases for prevention and intervention. Chemoprevention, a novel approach for controlling cancer, involves the use of specific natural products or synthetic chemical agents to reverse, suppress, or prevent premalignancy before the development of invasive cancer. Several natural products including grains, nuts, cereals, spices, fruits, vegetables, beverages, medicinal plants, and herbs, and their various phytochemical constituents including phenolics, flavonoids, carotenoids and alkaloids, as well as organosulfur compounds were suggested to confer protective effects against a wide range of cancers including colon cancer. Since diet has an important role in the etiology of colon cancer, dietary chemoprevention received attention for colon cancer prevention. However, identification of an agent with chemopreventive potential requires in vitro studies, and efficacy and toxicity studies in animal models before embarking on human clinical trials. Recent studies on natural products in colon cancer chemoprevention with respect to multiple molecular mechanisms in various in vitro, in vivo, and clinical studies are described in this overview. Drug Dev Res 69:460–471, 2008. © 2008 Wiley‐Liss, Inc.
Pan‐HER biologics (Hermodulins) for the treatment of cancer
Authors: Maneval Daniel C. , Jin Pei , Shepard H. Michael
Published: December 2008

The four members of the human epidermal growth factor receptor (HER) family and their cognate ligands combine in a complex network to play key roles in normal growth and development. Abnormal expression, mutation, or altered signaling of HER proteins has been linked to the pathogenesis of multiple human malignancies. Clinical benefit for patients with solid tumors of the breast, colon, lung, pancreas, or head and neck has been proven for targeted antagonists directed at a single receptor in the HER family (e.g., trastuzumab, cetuximab, erlotinib). Although effective, tumor resistance to these single‐targeted drugs frequently develops, and efficacy is not as broad as was initially predicted. Redundant signaling of other HER family members provides a likely mechanism for diminished drug activity. An alternative approach to inhibit HER‐mediated tumor growth is to sequester stimulating EGF‐like growth factors with a “ligand‐trap” strategy. Hermodulins are fusion proteins that link the extracellular ligand binding domains of HER family members to the Fc region of human IgG. Data with RB200, a first‐generation Hermodulin, demonstrate effective binding of EGFR and HER3 ligands (e.g., EGF, TGF‐α, NRG1‐β1) and show anti‐tumor activity in preclinical models. An optimized molecule, RB242, has been designed that combines single amino acid changes in the extracellular domains of the EGFR and HER3 domains. Preclinical studies with RB242 are ongoing to enable testing of the pan‐HER ligand‐trap hypothesis in Phase I investigation. Drug Dev Res 69:472–479, 2008. © 2008 Wiley‐Liss, Inc.
Biomimetic Modelling of Copper Enzymes: Synthesis, Characterization, EPR Analysis and Enantioselective Catalytic Oxidations by a New Chiral Trinuclear Copper(II) Complex
Authors: Mutti Francesco G. , Zoppellaro Giorgio , Gullotti Michele , Santagostini Laura , Pagliarin Roberto , Andersson K. Kristoffer , Casella Luigi
Published: December 2008

The new octadentate ligand (R)‐(+)‐N,N′‐dimethyl‐N,N′‐bis{‐2‐[bis(1‐methyl‐2‐benzimidazolylmethyl)]‐2‐methylaminoethyl}‐1,1′‐binaphthyl‐2,2′diamine [(R)‐(+)‐DABN‐L‐Ala‐Bz4; L] was employed for the synthesis of dinuclear and trinuclear copper(II) complexes. The ligand design is based on the insertion of chiral residues derived from L‐alanine between the diaminobinaphthyl (R)‐(+)‐DABN spacer and the aminobis(benzimidazole) metal binding units. The chiroptical properties of the ligand and the complexes are described. EPR experiments were performed on [Cu2L]4+ and [Cu3L]6+ at low temperatures. In the case of [Cu2L]4+, a weak dipolar interaction between the two spin centres was found. A similar weak spin interaction occurred in the trinuclear copper cluster, which could be treated likewise as a weakly coupled three‐spin system. The analysis was substantiated by studying the complex EPR temperature behaviour, where population of the quartet state occurred only at high temperature (77 K), whereas at cryogenic temperatures (4 K) the system adopted a doublet state as a ground‐state spin configuration. Titration with sodium azide of [Cu2L]4+ was consistent with terminal binding of one N3– molecule to each copper ion. Furthermore, dipolar interactions between spin centres were strongly suppressed in this case. For [Cu3L]6+, the adduct formed by the interaction with two azido molecules induced formation of a μ‐azido bridges among the three Cu2+ ions and led to population of the quartet state even at cryogenic temperatures. This bridged configuration was, however, lost upon further addition of azido molecules. The copper(II) complexes were tested as catalysts in the oxidation of biogenic catechols and flavonoids by dioxygen to give the corresponding quinones, which were trapped as adducts with MBTH. The dinuclear complex [Cu2L]4+ displays poor substrate enantiodifferentiating ability, even though it exhibits catalytic activity comparable to that of [Cu3L]6+. The trinuclear complex [Cu3L]6+ exhibits significant enantioselectivity in the oxidations of the catecholamines L‐/D‐dopa methyl ester and L‐/D‐norepinephrine. The origin of this enantioselectivity must be associated with the mode of substrate binding, as it depends almost entirely on KM.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Study of the Effects of Nonlinear Potential Sweeps on Voltammetry
Authors: Ogurtsov Vladimir I. , Beni Valerio , Strutwolf Jörg , Arrigan Damien W. M.
Published: December 2008

Voltammetric methods use a constant sweep rate during the course of a scan. This paper reports a study of the influence of a nonconstant sweep rate on the voltammetric response. In this approach, either continuously increasing or continuously decreasing potential scan rates can be employed, unlike presently available methods which rely on a constant sweep rate. The voltammetric response of potassium ferrocyanide at a glassy carbon electrode was used as a model system to test the new method. The responses obtained using traditional staircase voltammetry (linear staircase voltammetry) and the new approach (nonlinear staircase voltammetry) were compared by experiment and by simulation. The new approach offers capability for signal enhancement, whereby enhanced current or enhanced peak shape can be obtained by choice of appropriate waveform parameters.
Micellar electrokinetic chromatography: Methodological and instrumental advances focused on practical aspects
Authors: Silva Manuel
Published: December 2008

This article reviews the latest methodological and instrumental improvements for enhancing sensitivity and resolution in MEKC‐based determinations. On‐line sample concentration (stacking, sweeping and combination of two protocols) and other on‐capillary approaches such as in‐capillary derivatization and the coupling of flow‐injection systems with MEKC are the most relevant methodological approaches discussed for improving sensitivity. At the same time, changes in the BGE through the use of organic modifiers, ionic liquids, cations, CDs, non‐ionic and zwitterionic surfactants, mixed micelles, vesicles and carbon nanostructures as well as 2‐D CE and chemometric techniques for enhancing resolution are also considered in detail. Two instrumental approaches such as MS and LIF are also discussed, covering the proposals for overcoming the difficulties arising from the direct coupling of MEKC with MS and the excellent detection sensitivity achieved by LIF using the typical argon‐ion laser and recent growth in the use of diode lasers as excitation sources. Some thoughts on potential future directions are also expressed.
Urinary levels of oxidative DNA and RNA damage among workers exposed to polycyclic aromatic hydrocarbons in silicon production: Comparison with 1‐hydroxypyrene
Authors: Marie Caroline , Ravanat Jean‐Luc , Badouard Carine , Marques Marie , Balducci Franck , Maître Anne
Published: December 2008

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous occupational and environmental pollutants and the urinary excretion of 1‐hydroxypyrene (1‐OHP) is classically measured for the determination of PAH exposure internal dose. Some of PAH are tumorigenic due to their metabolites ability to generate DNA adducts and oxidative DNA damage through the production of reactive oxygen species during metabolism. 8‐hydroxy‐7,8‐dihydro‐2′‐deoxyguanosine (8‐OHdGuo) is one of the major oxidative DNA lesions and its use as a potential biomarker of genotoxic PAH occupational exposure should be evaluated. Indeed conflicting results are frequently reported in occupational studies in terms of correlation between 8‐OHdGuo urinary levels and PAH exposure. The aim of our study was therefore to determine the potential for PAH occupational exposure to increase urinary oxidative DNA damage. The population consisted of 68 male workers employed in silicon production. The urinary concentrations of 8‐OHdGuo and its homologue in RNA, 8‐hydroxy‐7,8‐dihydroguanosine (8‐OHGuo) were determined using high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry, whereas those of 1‐OHP were measured using HPLC with fluorescence detection. Individual variation rates were calculated on a working day and a working week. The results indicated that, while 1‐OHP levels strongly increased on a working day and even more on a working week, 8‐OHdGuo and 8‐OHGuo urinary levels did not show similar significant increases. Moreover, no correlation between 1‐OHP and oxidative DNA and RNA lesions was found. Consequently, urinary 8‐OHdGuo and 8‐OHGuo did not seem to be relevant biomarkers of genotoxic PAH exposure in the case of the silicon plant studied. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
Cigarette smoke extract induces expression of cell adhesion molecules in HUVEC via actin filament reorganization
Authors: Chen Haw‐Wen , Lii Chong‐Kuei , Ku Hua‐Jung , Wang Tsu‐Shing
Published: December 2008

Epidemiologic studies have shown a strong association between cigarette smoking and cardiovascular diseases. Various oxidative species and free radicals are produced during cigarette smoking and these lead to endothelial dysfunction and inflammation. Expression of adhesion molecules, such as intercellular adhesion molecule‐1 (ICAM‐1), E‐selectin, and vascular cell adhesion molecule‐1, and adhesion of leukocytes are present in atherosclerosis. We showed previously that a nonfractionated cigarette smoke extract (CSE) induces surface expression of ICAM‐1 and E‐selectin in human umbilical vein endothelial cells (HUVEC). We then investigated the role of the MAPKs (ERK1/2, JNK, and p38) and AP‐1 and the role of actin cytoskeleton reorganization in the CSE‐induced expression of ICAM‐1 and E‐selectin. Western blot analysis showed that CSE treatment rapidly and significantly caused phosphorylation of JNK and ERK1/2 but not of p38. Cytochalasin D (an actin filament disruptor) partially inhibited CSE‐induced ICAM‐1 and E‐selectin surface expression. However, inhibitors of ERK1/2 (PD98059) and JNK (SP600125) did not attenuate the CSE‐induced ICAM‐1 and E‐selectin surface expression. The results of electrophoretic mobility shift assay showed that CSE enhanced AP‐1 binding activity. Therefore, CSE activated AP‐1 and upregulated ICAM‐1 and E‐selectin surface expression in HUVEC seem to be via an MAPK‐independent pathway. Moreover, the dynamic reorganization of the actin cytoskeleton seems to be required for the CSE‐induced surface expression of ICAM‐1 and E‐selectin. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
A note on the Hertz contact model with nonlinear damping for pounding simulation
Authors: Ye Kun , Li Li , Zhu Hongping
Published: December 2008

Structural pounding during earthquakes has been recently investigated extensively by using different models of impact force. In this paper, reexamination of the Hertz contact model with nonlinear damping is made. Based on this reexamination, the formula used to determine the damping constant in terms of the spring stiffness, the coefficient of restitution and relative approaching velocity of two colliding bodies is found to be incorrect for pounding simulation in structural engineering. In order to correct this problem, a more accurate approximating formula for the damping constant is theoretically derived. The correctness of the derived analytical formula has been confirmed through numerical simulations. Copyright © 2008 John Wiley & Sons, Ltd.
Complex multiple cosmogenic nuclide concentration and histories in the arid Rio Lluta catchment, northern Chile
Authors: Kober F. , Ivy‐Ochs S. , Zeilinger G. , Schlunegger F. , Kubik P. W. , Baur H. , Wieler R.
Published: December 2008

Terrestrial cosmogenic nuclide (TCN) concentrations measured in river sediments can be used to estimate catchment‐wide denudation rates. By investigating multiple TCN the steadiness of sediment generation, transport and depositional processes can be tested. Measurements of 10Be, 21Ne and 26Al from the hyper‐ to semi‐arid Rio Lluta catchment, northern Chile, yield average single denudation rates ranging from 12 to 75 m Myr–1 throughout the catchment. Paired nuclide analysis reveals complex exposure histories for most of the samples and thus the single nuclide estimates do not exclusively represent catchment‐wide denudation rates. The lower range of single nuclide denudation rates (12–17 m Myr–1), established with the noble gas 21Ne, is in accordance with palaeodenudation rates derived from 21Ne/10Be and 26Al/10Be ratio analysis. Since this denudation rate range is measured throughout the system, it is suggested that a headwater signal is transported downstream but modulated by a complex admixture of sediment that has been stored and buried at proximal hillslope or terrace deposits, which are released during high discharge events. That is best evidenced by the stable nuclide 21Ne, which preserves the nuclide concentration even during storage intervals.

The catchment‐wide single 21Ne denudation rates and the palaeodenuation rates contrast with previous TCN‐derived erosion rates from bedrock exposures at hillslope interfluves by being at least one order of magnitude higher, especially in the lower river course. These results support earlier studies that identified a coupling of erosional processes in the Western Cordillera contrasting with decoupled processes in the Western Escarpment and in the Coastal Cordillera. Copyright © 2008 John Wiley & Sons, Ltd.
Probabilistic sinkhole modelling for hazard assessment
Authors: Galve J. P. , Gutiérrez F. , Lucha P. , Guerrero J. , Bonachea J. , Remondo J. , Cendrero A.
Published: December 2008

A method for quantitatively assessing sinkhole susceptibility (spatial probability) and hazard (spatio‐temporal probability) has been developed and independently tested in a 50 km2 sector of the Ebro Valley evaporite karst. Three genetic types of sinkholes have been mapped in the floodplain and a terrace surface: 947 small cover‐collapse sinkholes (type 1, terrace), large collapse sinkholes (type 2, floodplain) and large subsidence depressions (type 3, floodplain). The type 1 sinkhole inventory includes two temporal populations: 447 sinkholes formed before 24 November 2005, and 500 between that date and 2 November 2006. Sinkhole susceptibility models have been elaborated analysing the statistical relationships between the sinkholes of the 2005 inventory and a set of potential conditioning factors. The independent evaluation (validation) of the susceptibility models by means of several strategies (random, sequentially excluded, and temporal) has allowed us to select the most significant variables for each sinkhole type and assess quantitatively the quality of models; which are reasonable for the three sinkhole types. Validation has also provided information on the contribution of specific variables and the effect of changing their accuracy to the prediction capability of models. Susceptibility models for type 3 sinkholes have been validated satisfactorily with the 2006 sinkhole inventory (temporal validation). The best susceptibility model has been transformed into a hazard map considering the frequency of sinkholes that occurred in each susceptibility class between 2005 and 2006, as well as their average size. The susceptibility and hazard models obtained could be used as an objective basis for the application of mitigation measures, either of preventive or corrective nature. Copyright © 2008 John Wiley & Sons, Ltd.
A higher‐order accuracy lattice Boltzmann model for the wave equation
Authors: Zhang Jianying , Yan Guangwu , Dong Yinfeng
Published: December 2008

A lattice Boltzmann model with higher‐order accuracy for the wave motion is proposed. The new model is based on the technique of the higher‐order moment of equilibrium distribution functions and a series of lattice Boltzmann equations in different time scales. The forms of moments are derived from the binary wave equation by designing the higher‐order dissipation and dispersion terms. The numerical results agree well with classical ones. Copyright © 2008 John Wiley & Sons, Ltd.
Linearity of the fMRI response in category‐selective regions of human visual cortex
Authors: Horner Aidan J. , Andrews Timothy J.
Published: December 2008

The goal of this study was to determine the linearity of the blood oxygen level‐dependent (BOLD) response, as measured by functional magnetic resonance imaging (fMRI), in category‐selective regions of human visual cortex. We defined regions of the temporal lobe that were selective to faces (fusiform face area, FFA) and places (parahippocampal place area, PPA). We then determined the linearity of the BOLD response in these regions to their preferred and nonpreferred stimuli. First, we tested the principle of scaling. As we increased the visibility of the stimulus, there was a corresponding linear increase in the fMRI signal in the FFA and PPA to their preferred stimulus (face and place, respectively). In contrast, responses in the FFA and PPA to the nonpreferred stimulus did not conform to the principle of scaling. Next, we asked whether the fMRI response in these regions of visual cortex conformed to the principle of additivity. To assess this, we determined whether the response to a long stimulus block could be predicted by adding the response to multiple shorter duration blocks. Although the fMRI response in the FFA and PPA was generally linear to the preferred stimulus, a more nonlinear response was apparent to the nonpreferred stimulus. In conclusion, the linearity of the BOLD response in the human ventral visual pathway varied across cortical region and stimulus category. This suggests that measures of linearity may provide a useful indication of neural selectivity in the brain. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
Model driven EEG/fMRI fusion of brain oscillations
Authors: Valdes‐Sosa Pedro A. , Sanchez‐Bornot Jose Miguel , Sotero Roberto Carlos , Iturria‐Medina Yasser , Aleman‐Gomez Yasser , Bosch‐Bayard Jorge , Carbonell Felix , Ozaki Tohru
Published: December 2008

This article reviews progress and challenges in model driven EEG/fMRI fusion with a focus on brain oscillations. Fusion is the combination of both imaging modalities based on a cascade of forward models from ensemble of post‐synaptic potentials (ePSP) to net primary current densities (nPCD) to EEG; and from ePSP to vasomotor feed forward signal (VFFSS) to BOLD. In absence of a model, data driven fusion creates maps of correlations between EEG and BOLD or between estimates of nPCD and VFFS. A consistent finding has been that of positive correlations between EEG alpha power and BOLD in both frontal cortices and thalamus and of negative ones for the occipital region. For model driven fusion we formulate a neural mass EEG/fMRI model coupled to a metabolic hemodynamic model. For exploratory simulations we show that the Local Linearization (LL) method for integrating stochastic differential equations is appropriate for highly nonlinear dynamics. It has been successfully applied to small and medium sized networks, reproducing the described EEG/BOLD correlations. A new LL‐algebraic method allows simulations with hundreds of thousands of neural populations, with connectivities and conduction delays estimated from diffusion weighted MRI. For parameter and state estimation, Kalman filtering combined with the LL method estimates the innovations or prediction errors. From these the likelihood of models given data are obtained. The LL‐innovation estimation method has been already applied to small and medium scale models. With improved Bayesian computations the practical estimation of very large scale EEG/fMRI models shall soon be possible. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
Phase III randomized study: Oral pilocarpine versus submandibular salivary gland transfer protocol for the management of radiation‐induced xerostomia
Authors: Jha Naresh , Seikaly Hadi , Harris Jeffrey , Williams David , Sultanem Khalil , Hier Michael , Ghosh Sunita , Black Martin , Butler James , Sutherland Donna , Kerr Paul , Barnaby Pam
Published: December 2008

Background.

Xerostomia is a serious morbidity of radiation treatment in head and neck cancer.

Methods.

We conducted a prospective phase III multicenter randomized study comparing submandibular salivary gland transfer (SGT) procedure with pilocarpine during and for 3 months after XRT. Salivary flow (baseline, stimulated) and University of Washington Quality of Life Questionnaire (U of W QOL) scores were measured.

Results.

An interim intent to treat analysis (120 patients) at 6 months shows superior results in SGT arm: median baseline salivary flow for SGT (0.04 mL/minute) versus pilocarpine (0.01 mL/minute), p = .001; median stimulated salivary flow (0.18 mL/minute) for SGT versus (0.05 mL/minute) for pilocarpine, p = .003. Scores (U of W QOL) for amount (p = .017) and consistency of saliva (p = .005) in favor of SGT leading to premature closure of study.

Conclusions.

Submandibular SGT procedure is superior to pilocarpine in management of radiation‐induced xerostomia. © 2008 Wiley Periodicals, Inc. Head Neck, 2009
Effect of induction chemotherapy on speech and swallowing function in patients with oral tongue cancer
Authors: Barringer Denise A. , Hutcheson Katherine A. , Sturgis Erich M. , Kies Merrill S. , Lewin Jan S.
Published: December 2008

Background.

Swallowing physiology, diet, and patient‐reported outcomes were evaluated after induction chemotherapy for oral tongue cancer.

Methods.

Fifteen of 23 patients enrolled in a phase II clinical trial of induction chemotherapy followed by surgical resection for oral tongue cancer underwent instrumental and perceptual analysis of speech and swallowing. Oropharyngeal swallow efficiency (OPSE) was calculated. Patient‐reported outcomes were collected. We compared pre‐ and postchemotherapy results.

Results.

OPSE scores were not significantly different (p > .05) after induction chemotherapy; however, patient‐reported swallowing and diet levels were significantly higher (p < .001 and p = .015, respectively). Diet levels improved from soft‐chewable to full diet in most patients. Speech intelligibility did not change (p = .328).

Conclusion.

It appears that induction chemotherapy has a negligible effect on speech and swallowing physiology but may provide symptomatic improvement of pain and swallowing after treatment. Further investigations are needed to corroborate these findings. © 2008 Wiley Periodicals, Inc. Head Neck, 2009
ABC-transporters are localized in caveolin-1-positive and reggie-1-negative and reggie-2-negative microdomains of the canalicular membrane in rat hepatocytes #
Authors: Ismair Manfred G. , Häusler Stephanie , Stuermer Claudia A. , Guyot Christelle , Meier Peter J. , Roth Jürgen , Stieger Bruno
Published: December 2008

The canalicular plasma membrane is constantly exposed to bile acids acting as detergents. Bile acids are essential to mediate release of biliary lipids from the canalicular membrane. Membrane microdomains (previously called lipid rafts) are biochemically defined by their resistance to detergent solubilization at cold temperature. We aimed to investigate the canalicular plasma membrane for the presence of microdomains, which could protect this membrane against the detergent action of bile acids. Highly purified rat liver canalicular plasma membrane vesicles were extracted with 1% Triton X-100 or 1% Lubrol WX at 4°C and subjected to flotation through sucrose step gradients. Both detergents yielded detergent-resistant membranes containing the microdomain markers alkaline phosphatase and sphingomyelin. However, cholesterol was resistant to Lubrol WX solubilization, whereas it was only marginally resistant to solubilization by Triton X-100. The microdomain marker caveolin-1 was localized to the canalicular plasma membrane domain and was resistant to Lubrol WX, but to a large extent solubilized by Triton X-100. The two additional microdomain markers, reggie-1 and reggie-2, were localized to the basolateral and canalicular plasma membrane and were partially resistant to Lubrol WX but resistant to Triton X-100. The canalicular transporters bile salt export pump, multidrug resistance protein 2, multidrug resistance-associated protein 2, and Abcg5 were largely resistant to Lubrol WX but were solubilized by Triton X-100. Conclusion: These results indicate the presence of two different types of microdomains in the canalicular plasma membrane: “Lubrol-microdomains” and “Triton-microdomains”. “Lubrol-microdomains” contain the machinery for canalicular bile formation and may be the starting place for canalicular lipid secretion. (Hepatology 2009.)
Elevations in alanine aminotransferase levels late in the course of antiviral therapy in hepatitis C virus RNA–negative patients are associated with virological relapse # †
Authors: Basso Monica , Giannini Edoardo G. , Torre Francesco , Blanchi Sabrina , Savarino Vincenzo , Picciotto Antonino
Published: December 2008

The incidence and clinical meaning of elevated alanine aminotransferase (ALT) in chronic hepatitis C patients who are hepatitis C virus (HCV)-RNA negative during pegylated interferon (PEG-IFN) and ribavirin therapy have not been completely characterized. In this study our aim was to assess the incidence, pattern, predictive factors, and clinical meaning of elevated ALT in a cohort of 173 chronic hepatitis C patients who obtained viral clearance during either PEG-IFNα2a or α2b and weight-based ribavirin therapy. Patients were defined sustained viral responders (SVRs) or relapser responders (RRs) on the basis of a serum HCV-RNA result at 24-week follow-up. SVR and RR were obtained in 141 (58%) and 32 patients (13%), respectively. Among the 173 study patients, 57 patients (33%) had undetectable serum HCV-RNA and elevated ALT in at least one evaluation (weeks 2, 4, 12, 24 in all genotypes, and week 48 in HCV genotype 1 and 4 alone), and this phenomenon was not differently distributed between SVRs and RRs. No pretreatment demographic (age, gender), clinical (ALT levels, histological grade and stage, body mass index) and viral (load, genotype) parameter was associated with this phenomenon. The incidence of elevated ALT levels was not associated with type of PEG-IFN and ribavirin dose. Elevated ALT levels showed a different longitudinal pattern, occurring more frequently between week 12 and the end of treatment in RR as compared to SVR patients (90% versus 9%, P = 0.000001). Conclusion: The occurrence of elevated ALT levels in HCV-RNA-negative patients during PEG-IFN and ribavirin therapy is a fairly frequent and unpredictable phenomenon. Although ALT elevation per se is not associated with a greater risk of relapse, its occurrence in the later phases of therapy is more common in relapsing patients. (Hepatology 2009.)
Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride #
Authors: Park Ogyi , Jeong Won-IL , Wang Lei , Wang Hua , Lian Zhe-Xiong , Gershwin Eric M. , Gao Bin
Published: December 2008

Liver fibrosis is a common scarring response to all forms of chronic liver injury and is always associated with inflammation that contributes to fibrogenesis. Although a variety of cell populations infiltrate the liver during inflammation, it is generically clear that CD8 T lymphocytes promote while natural killer (NK) cells inhibit liver fibrosis. However, the role of invariant natural killer T (iNKT) cells, which are abundant in the liver, in hepatic fibrogenesis, remains obscure. Here we show that iNKT-deficient mice are more susceptible to carbon tetrachloride (CCl4)-induced acute liver injury and inflammation. The protective effect of naturally activated iNKT in this model is likely mediated via suppression of the proinflammatory effect of activated hepatic stellate cells. Interestingly, strong activation of iNKT through injection of iNKT activator α-galactosylceramide (α-GalCer) accelerates CCl4-induced acute liver injury and fibrosis. In contrast, chronic CCl4 administration induces a similar degree of liver injury in iNKT-deficient and wild-type mice, and only a slightly higher grade of liver fibrosis in iNKT-deficient mice than wild-type mice 2 weeks but not 4 weeks after CCl4 injection, although iNKT cells are able to kill activated stellate cells. An insignificant role of iNKT in chronic liver injury and fibrosis may be attributable to hepatic iNKT cell depletion. Finally, chronic α-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after α-GalCer injection. Conclusion: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by α-GalCer accelerates CCl4-induced acute liver injury, inflammation, and fibrosis. During chronic liver injury, hepatic iNKT cells are depleted and play a role in inhibiting liver fibrosis in the early stage but not the late stage of fibrosis. (Hepatology 2009.)
Circulating prediagnostic interleukin‐6 and C‐reactive protein and prostate cancer incidence and mortality
Authors: Stark Jennifer Rider , Li Haojie , Kraft Peter , Kurth Tobias , Giovannucci Edward L. , Stampfer Meir J. , Ma Jing , Mucci Lorelei A.
Published: December 2008

Interleukin‐6 (IL‐6) and C‐reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case‐control study to evaluate the relation between prediagnostic levels of IL‐6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL‐6 (−174 G/C) polymorphism in relation to circulating levels of IL‐6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL‐6 nor CRP plasma levels varied significantly by IL‐6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL‐6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL‐6 and BMI on prostate cancer incidence (pinteraction < 0.01). Increasing IL‐6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in overweight men. Further, prediagnostic IL‐6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (ptrend = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL‐6 level. Our study suggests that IL‐6 may potentially be involved in the development or progression of prostate cancer. © 2008 Wiley‐Liss, Inc.
Fatty acid synthase is over‐expressed in large aberrant crypt foci in rats treated with azoxymethane
Authors: Lau Dominic S.Y. , Archer Michael C.
Published: December 2008

Fatty acid synthase (FAS) is over‐expressed in many human cancers including colon. High levels of FAS expression have also been observed in a number of lesions that are precursors to invasive colorectal cancer. However, FAS expression in aberrant crypt foci (ACF), the earliest identifiable lesions in colon cancer development, has not been investigated. In this study, we treated Fisher rats with a single dose of the colon carcinogen azoxymethane then evaluated ACF 100 days later. We showed that large ACF (≥4 crypts/focus) have a significantly higher level of immunohistochemical staining for FAS than either small ACF (≤3 crypts/focus) or normal crypts. Furthermore, the severity of nuclear atypia in ACF was positively associated with increased expression of FAS. These findings suggest that the genes associated with FAS over‐expression are activated early in the stepwise development of colon cancer, though not until the ACF have reached a critical size with a level of nuclear atypia indicative of dysplasia. © 2008 Wiley‐Liss, Inc.
Liposomal honokiol inhibits VEGF‐D‐induced lymphangiogenesis and metastasis in xenograft tumor model
Authors: Wen Jing , Fu A‐fu , Chen Li‐Juan , Xie Xing‐Jiang , Yang Guang‐Li , Chen Xian‐Cheng , Wang Yong‐Sheng , Li Jiong , Chen Ping , Tang Ming‐Hai , Shao Xi Ming , Lu You , Zhao Xia , Wei Yu‐Quan
Published: December 2008

Lymph nodes metastasis of tumor could be a crucial early step in the metastatic process. Induction of tumor lymphangiogenesis by vascular endothelial growth factor‐D may play an important role in promoting tumor metastasis to regional lymph nodes and these processes can be inhibited by inactivation of the VEGFR‐3 signaling pathway. Honokiol has been reported to possess potent antiangiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor‐associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we established lymph node metastasis models by injecting overexpressing VEGF‐D Lewis lung carcinoma cells into C57BL/6 mice to explore the effect of honokiol on tumor‐associated lymphangiogenesis and related lymph node metastasis. The underlying mechanisms were systematically investigated in vitro and in vivo. In in vivo study, liposomal honokiol significantly inhibited the tumor‐associated lymphangiogenesis and metastasis in Lewis lung carcinoma model. A remarkable delay of tumor growth and prolonged life span were also observed. In in vitro study, honokiol inhibited VEGF‐D‐induced survival, proliferation and tube‐formation of both human umbilical vein endothelial cells (HUVECs) and lymphatic vascular endothelial cells (HLECs). Western blotting analysis showed that liposomal honokiol‐inhibited Akt and MAPK phosphorylation in 2 endothelial cells, and downregulated expressions of VEGFR‐2 of human vascular endothelial cells and VEGFR‐3 of lymphatic endothelial cells. Thus, we identified for the first time that honokiol provided therapeutic benefit not only by direct effects on tumor cells and antiangiogenesis but also by inhibiting lymphangiogenesis and metastasis via the VEGFR‐3 pathway. The present findings may be of importance to investigate the molecular mechanisms underlying the spread of cancer via the lymphatics and explore the therapeutical strategy of honokiol on antilymphangiogenesis and antimetastasis. © 2008 Wiley‐Liss, Inc.
Ag‐doped manganite nanoparticles: New materials for temperature‐controlled medical hyperthermia
Authors: Melnikov O. V. , Gorbenko O. Yu. , M̌arkelova M. N. , Kaul A. R. , Atsarkin V. A. , Demidov V. V. , Soto C. , Roy E. J. , Odintsov B. M.
Published: December 2008

The purpose of this study was to introduce newly synthesized nanomaterials as an alternative to superparamagnetic ironoxide based particles (SPIO) and thus to launch a new platform for highly controllable hyperthermia cancer therapy and imaging. The new material that forms the basis for this article is lanthanum manganite particles with silver ions inserted into the perovskite lattice: La1−xAgxMnO3+δ. Adjusting the silver doping level, it is possible to control the Curie temperature (Tc) in the hyperthermia range of interest (41–44°C). A new class of nanoparticles based on silver‐doped manganites La1–xAgxMnO3+δ is suggested. New nanoparticles are stable, and their properties were not affected by the typical ambient conditions in the living tissue. It is possible to monitor the particle uptake and retention by MRI. When these particles are placed into an alternating magnetic field, their temperature increases to the definite value near Tc and then remains constant if the magnetic field is maintained. During the hyperthermia procedure, the temperature can be restricted, thereby preventing the necrosis of normal tissue. A new class of nanoparticles based on silver‐doped manganites La1–xAgxMnO3+δ was suggested. Ag‐doped perovskite manganites particles clearly demonstrated the effect of adjustable Curie temperature necessary for highly controllable cellular hyperthermia. The magnetic relaxation properties of the particles are comparable with that of SPIO, and so we were able to monitor the particle movement and retention by MRI. Thus, the new material combines the MRI contrast enhancement capability with targeted hyperthermia treatment. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009
In vivo production of nanosized metal wear debris formed by tribochemical reaction as confirmed by high‐resolution TEM and XPS analyses
Authors: Milošev Ingrid , Remškar Maja
Published: December 2008

High‐resolution transmission electron microscopy (TEM) and X‐ray photoelectron spectroscopy (XPS) were used to establish the link between particles isolated from periprosthetic tissue of metal‐on‐metal (MOM) bearing and the solid deposit at the surface of retrieved MOM hip components. The high resolution of TEM made it possible to identify individual CoCrMo wear particles. Two shapes were observed. Needle‐shaped particles ranged from 40 to 120 nm and contained both Co and Cr. Globular particles ranged up to 90 nm and contained high levels of Cr and no Co. Ti‐ and Ca‐based particles were also identified. XPS analysis of the areas of thick solid deposit on the retrieved femoral head showed that the base alloy was covered by up to nearly 1‐μm thick layer containing carbon, nitrogen, and oxygen. This layer was organic in nature, presumably protein‐related. In areas with a thinner deposit, an organic‐related layer was mixed with layers of metal oxides, the latter being much thinner than the extensive organic, carbon‐rich layer. Outside the area of the deposit, the passive oxidized chromium layer was thinner, less than 20 nm, and carbon was bound to nonorganic oxygen. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009
Polymeric particle formation through electrospraying at low atmospheric pressure
Authors: Wu Yiquan , Kennedy Scott J. , Clark Robert L.
Published: December 2008

Electrospraying is a simple and versatile technique capable of producing polymeric particles. However, most investigations carried out thus far have been performed at ambient atmospheric pressure without studying the influences of pressure on the formation of polymeric particles. Here, we report our investigation on the effects of varying the pressure and the solution concentration on the microstructures of electrosprayed polymeric particles. Pressures are varied from ambient atmospheric pressure to 380 mmHg below ambient pressure, and solution concentrations are varied over a range of 3–7 w/v %. By varying these parameters, we manipulated the rate of solvent evaporation and the solidification of the electrosprayed particles. The results show that changes to the pressure had significant effects on the microstructure and morphology of poly(ε‐caprolactone) (PCL) particles. The average particle size became larger as the chamber pressure decreased. At a solution concentration of 5 w/v % and a pressure 150 mmHg below ambient pressure, uniform and spherical PCL particles were generated. Electrospun fibers were formed when a solution concentration of 7 w/v % was used. The developed technique can be applied to prepare polymeric drug delivery carriers though a low‐pressure‐assisted spray‐drying method, and is particularly suitable for fabricating delivery microspheres encapsulated with temperature‐sensitive drugs and biomolecules. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
Biomechanical and histomorphometric evaluation of a thin ion beam bioceramic deposition on plateau root form implants: An experimental study in dogs
Authors: Granato Rodrigo , Marin Charles , Suzuki Marcelo , Gil Jose N. , Janal Malvin N. , Coelho Paulo G.
Published: December 2008

The aim of this study was to evaluate the biomechanical fixation, bone‐to‐implant contact, and bone morphology of an ion beam assisted deposition of a 300–500 nm thick Ca‐ and P‐based bioceramic surface on a previously alumina‐blasted/acid‐etched Ti‐6Al‐4V implant surface in a dog model. Materials and Methods: Thirty‐six 4.5 × 11 mm plateau root form implants, control (alumina‐blasted/acid‐etched‐AB/AE) and test groups (AB/AE+300–500 nm bioceramic coating, Nanotite™) were placed along a proximal tibia of six beagle dogs remaining for 2 and 4 weeks (n = 3 animals per implantation time). Following euthanization, the implants were torqued to interface fracture at ∼0.196 radians/sec until a 10% maximum load drop was detected. The implants in bone were nondecalcified processed to ∼30 μm thickness slides for histomorphologic and bone‐to‐implant contact (BIC) assessment. Statistical analyses for torque to interface fracture were performed using a mixed model ANOVA, and BIC was evaluated by the χ2 test at 95% level of significance. Results: At 4 weeks, significantly higher torque to interface fracture was observed for the Test implant surface. Histomorphologic analysis showed higher degrees of bone organization for test implants compared to control at 2 and 4 weeks. Significantly higher BIC was observed at 4 weeks compared to 2 weeks (no statistical differences between control and test implants). Conclusion: The higher torque to interface fracture and increased bone maturity obtained in this study support that the surface modification comprising a 300–500 nm Ca‐ and P‐based bioceramic coating positively influenced healing around pleateau root form implants. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
Feeding kinematics and performance of Hawaiian stream gobies, Awaous guamensis and Lentipes concolor: Linkage of functional morphology and ecology
Authors: Maie Takashi , Wilson Megan P. , Schoenfuss Heiko L. , Blob Richard W.
Published: December 2008

Distributions of Hawaiian stream fishes are typically interrupted by waterfalls that divide streams into multiple segments. Larvae hatch upstream, are flushed into the ocean, and must climb these waterfalls to reach adult habitats when returning back to freshwater as part of an amphidromous life cycle. Stream surveys and studies of climbing performance show that Lentipes concolor Gill can reach fast‐flowing upper stream segments but that Awaous guamensis Valenciennes reaches only slower, lower stream segments. Gut content analyses for these two species indicate considerable overlap in diet, suggesting that feeding kinematics and performance of these two species might be comparable. Alternatively, feeding kinematics and performance of these species might be expected to differ in relation to the different flow regimes in their habitat (feeding in faster stream currents for L. concolor versus in slower currents for A. guamensis). To test these alternative hypotheses, we compared food capturing kinematics and performance during suction feeding behaviors of A. guamensis and L. concolor using morphological data and high‐speed video. Lentipes concolor showed both a significantly larger gape angle and faster jaw opening than A. guamensis. Geometric models calculated that despite the inverse relationship of gape size and suction pressure generation, the fast jaw motions of L. concolor allow it to achieve higher pressure differentials than A. guamensis. Such elevated suction pressure would enhance the ability of L. concolor to successfully capture food in the fast stream reaches it typically inhabits. Differences in jaw morphology may contribute to these differences in performance, as the lever ratio for jaw opening is about 10% lower in L. concolor compared with A. guamensis, suiting the jaws of L. concolor better for fast opening. J. Morphol. 2009. © 2008 Wiley‐Liss, Inc.