bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydroxyurea Suppresses HCV Replication in Humans: A Phase I Trial of Oral Hydroxyurea in Chronic Hepatitis C Patients
Authors: Nozaki Akito , Numata Kazushi , Morimoto Manabu , Kondo Masaaki , Sugimori Kazuya , Morita Satoshi , Miyajima Eiji , Ikeda Masanori , Kato Nobuyuki , Maeda Shin , Tanaka Katsuaki 
Published: October 2010

Background HCV is the main causative agent of chronic liver disease, which could progress to liver cirrhosis and hepatocellular carcinoma. By using a recently developed genome-length HCV RNA replication reporter assay system, we found that hydroxyurea (HU), an inhibitor of DNA synthesis, inhibited HCV RNA replication. Methods To test the hypothesis that HU suppresses HCV replication in humans, we conducted a Phase I trial involving Japanese patients with chronic hepatitis C (CHC) and investigated the safety and effectiveness of a 4-week course of oral HU. Results A total of nine patients were treated with an HU dose level of 500 mg three times daily. Dose-limiting toxicity was not observed at this dose level. Of the nine patients, eight exhibited a moderate decrease in serum HCV RNA levels during the trial. A decrease in HCV RNA levels to nadir levels was achieved for the eight patients (median -0.27 log10 IU/ml [range -0.08– -0.44]) at various times during the 4 weeks after therapy initiation. Conclusions The results of this Phase I trial suggest that HU has potential as an anti-HCV agent that could be effective for the treatment of CHC patients.
Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg in healthy individuals
Authors: Zhu Li , Butterton Joan , Persson Anna , Stonier Michele , Comisar Wendy , Panebianco Deborah , Breidinger Sheila , Zhang Jenny , Bertz Richard 
Published: October 2010

Background Atazanavir plus raltegravir 300/400 mg twice daily is being explored as a ritonavir- and nucleoside- sparing treatment strategy. The pharmaco-kinetics and safety of this combination in healthy individuals were evaluated. Methods A total of 22 healthy individuals received raltegravir 400 mg on days 1–5, atazanavir 300 mg on days 6–12 and atazanavir plus raltegravir 300/400 mg on days 13–26, twice daily with a light meal. Serial blood samples were collected 12 h after the morning dose on days 5, 12 and 26; safety assessments, clinical laboratory data and serial electrocardiograms (ECGs) at 0, 2 and 6 h were obtained. Results Raltegravir coadministration reduced atazanavir geometric mean maximum plasma concentration (Cmax), area under the plasma concentration–time curve from 0 to 12 h post-dose (AUC0–12) and trough plasma concentration (Cmin) by 11%, 17% and 29%, respectively, compared with atazanavir alone. Geometric mean atazanavir Cmin was 817 ng/ml (range 250–1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean Cmax, AUC0–12 and Cmin by 39%, 54% and 48%, respectively. All adverse events were of mild or moderate intensity. Hyperbilirubinaemia and ECG PR increases with atazanavir were similar to those of atazanavir/ritonavir once daily. No corrected QT prolongations were noted. Mean QRS increase from baseline was 11.0 ms (range 2–25) after receiving atazanavir for 7 days; no further QRS increase was noted and no QRS interval was >120 ms with raltegravir coadministration. No ECG changes were observed with raltegravir alone. Conclusions Coadministration of atazanavir and raltegravir 300/400 mg twice daily decreased atazanavir AUC0–12 and Cmin relative to atazanavir alone, and increased AUC0–12 of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.
Effect of boosted fosamprenavir or lopinavir-based combinations on whole-body insulin sensitivity and lipids in treatment-naive HIV-type-1-positive men
Authors: Randell Paul A , Jackson Akil G , Boffito Marta , Back David J , Tjia John F , Taylor Jessica , Mandalia Sundhiya , Moyle Graeme J 
Published: October 2010

Background Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals. Methods HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2. Results A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant. Conclusions In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid pro-file characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.
In Vitroandin VivoAnti-Influenza Virus Activity of Diarylheptanoids Isolated fromAlpinia Officinarum
Authors: Sawamura Rie , Shimizu Tomomi , Sun Yi , Yasukawa Ken , Miura Motofumi , Toriyama Masaharu , Motohashi Shigeyasu , Watanabe Wataru , Konno Katsuhiko , Kurokawa Masahiko 
Published: October 2010

Background:Diarylheptanoids (AO-0002 [7-(4″-hydroxy-3″-methoxyphenyl)-1-phenyl-4 E-hepten-3-one] and AO-0011 [(5 S)-5-hydroxy-7-(4″-hydroxyphenyl)-1-phenyl-3-heptanone]) isolated from Alpinia officinarum have been reported to exhibit anti-influenza virus activity in vitro. Hence, efficacies against influenza virus infection and the mode of antiviral action were evaluated in vivo and in vitro, respectively.Methods:In a murine influenza virus infection model, diarylheptanoids were orally administered three times daily to mice infected with influenza A/PR/8/34 virus for 6 days after infection. AO-0002 was examined for its antiviral activity against the wild types of influenza viruses A/PR/8/34 (H1N1), oseltamivir-resistant A/PR/8/34 (H1N1), A/Bangkok/93/03 (H1N1), A/Ishikawa/7/82 (H3N2), A/Fukushima/13/43 (H3N2), B/Singapore/222/79 and B/Fukushima/15/93 in plaque reduction or yield reduction assays. The mode of anti-influenza virus action was assessed by a virus adsorption assay, immunofluorescence assay of viral antigens, and inhibition of viral messenger RNA synthesis using real-time reverse transcriptase PCR. Results: AO-0002 at 100 mg/kg was significantly effective in reducing the body weight loss and prolonging survival times of infected mice without toxicity, but AO-0011 was not. AO-0002 at 30 and 100 mg/kg significantly reduced virus titres in bronchoalveolar lavage fluids of the lungs on days 3 and 6 after infection. AO-0002 exhibited anti-influenza virus activity against all viruses used, including the oseltamivir-resistant strain in vitro. The compound had no effect on virus adsorption or invasion into cells, but dose-dependently suppressed the expression of viral messenger RNA and antigens.Conclusions:AO-0002 was suggested to have a different anti-influenza virus action to that of oseltamivir and was verified to show anti-influenza activity in vitro and in vivo.
Profile of HBV antiviral resistance mutations with distinct evolutionary pathways against nucleoside/ nucleotide analogue treatment among Chinese chronic hepatitis B patients
Authors: Yang Jing-Xian , Liu Bao-Ming , Li Xiao-Guang , Yan Chun-Hui , Xu Jie , Sun Xie-Wen , Wang Yu-Hua , Jiao Xiu-Juan , Yan Ling , Dong Jian-Ping , Hou Chun-Sheng , Abuduheilili Xiernayi , Li Tong , Zhuang Hui 
Published: October 2010

Background Antiviral drug-resistant HBV mutants under a variety of treatment protocols are complex and only partly understood. Here, a population-based cross-sectional study was performed to analyse the profile of resistance mutations in distinct evolutionary pathways refractory to different nucleoside/nucleotide analogues (NAs). Methods Serum samples of 199 chronic hepatitis B patients undergoing NA treatment from five hospitals in four northern cities of China were obtained between January 2007 and July 2009. The genotypic resistance of HBV in these samples was characterized. The full-length HBV reverse transcriptase region was amplified, sequenced and analysed with particular focus on the following NA-resistant changes: rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtN236 and rtM250. Results Among 199 HBV isolates, 30 (15.08%) and 169 (84.92%) were genotypes B and C, respectively, and 65 (32.66%) harboured NA-resistant mutations. The prevalence of mutations at rtM204 was 34.33% in 134 patients who had received or who had been exposed to lamivudine-based therapy. Five cases of rtN236 mutations were detected exclusively among 75 patients receiving adefovir-dipivoxil-based therapies. A total of 19 cases of multidrug resistance rtA181 mutations were observed in those with lamivudine-, adefovir-dipivoxil- or telbivudine-based treatment (186 cases), but not in those undergoing entecavir treatment (13 cases). Mutations were not found at rtI169, rtT184, rtA194 or rtS202. rtM204 mutations (27 rtM204I, 15 rtM204V and 5 rtM204I/V cases) were detected at the highest frequency among 65 mutants (72.30% [47/65]) and found to display 16 combination mutation patterns, in which rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively ( P<0.01). Conclusions One-third of the studied population harboured NA-resistant HBV with complicated mutation patterns. Monitoring HBV genotypic resistance mutation markers and patterns is therefore shown to be beneficial for optimizing antiviral therapies and for avoiding clinical deterioration.
Nano-NRTIs: Efficient Inhibitors of HIV Type-1 in Macrophages with a Reduced Mitochondrial Toxicity
Authors: Vinogradov Serguei V , Poluektova Larisa Y , Makarov Edward , Gerson Trevor , Senanayake Madapathage T 
Published: October 2010

Background: Macrophages serve as a depot for HIV type-1 (HIV-1) in the central nervous system. To efficiently target macrophages, we developed nanocarriers for potential brain delivery of activated nucleoside reverse transcriptase inhibitors (NRTIs) called nano-NRTIs. Methods: Nanogel carriers consisting of poly(ethylene glycol) (PEG)- or Pluronic-polyethylenimine (PEI) biodegradable networks, star PEG-PEI or poly(amidoamine) dendrimer-PEI-PEG dendritic networks, as well as nanogels decorated with brain-targeting peptide molecules, specifically binding to the apolipoprotein E receptor, were synthesized and evaluated. Nano-NRTIs were obtained by mixing aqueous solutions of zidovudine 5′-triphosphate or didanosine 5′-triphosphate and nanocarriers, followed by freeze-drying. Intracellular accumulation, cytotoxicity and antiviral activity of nano-NRTIs were monitored in monocyte-derived macrophages (MDMs). HIV-1 viral activity in infected MDMs was measured by a reverse transcriptase activity assay following treatment with nano-NRTIs. Mitochondrial DNA depletion in MDMs and human HepG2 cells was assessed by quantitative PCR. Results: Nanogels were efficiently captured by MDMs and demonstrated low cytotoxicity, and no antiviral activity without drugs. All nano-NRTIs demonstrated high efficacy of HIV-1 inhibition at drug levels as low as 1 μmol/l, representing a 4.9- to 14-fold decrease in 90% effective drug concentrations as compared with NRTIs, whereas 50% cytotoxicity effects started at 200x higher concentrations. Nano-NRTIs with a core-shell structure and decorated with brain-targeting peptides displayed the highest antiviral efficacy. Mitochondrial DNA depletion, a major cause of NRTI neurotoxicity, was reduced threefold compared with NRTIs at application of selected nano-NRTIs. Conclusions: Nano-NRTIs demonstrated a promising antiviral efficacy against HIV-1 in MDMs and showed strong potential as nanocarriers for delivery of antiviral drugs to macrophages harbouring in the brain.
CCR2 Identifies a Stable Population of Human Effector Memory CD4+ T Cells Equipped for Rapid Recall Response
Authors: Zhang Hongwei H. , Song Kaimei , Rabin Ronald L. , Hill Brenna J. , Perfetto Stephen P. , Roederer Mario , Douek Daniel C. , Siegel Richard M. , Farber Joshua M. 
Published: October 2010

Abstract
Because T cells act primarily through short-distance interactions, homing receptors can identify colocalizing cells that serve common functions. Expression patterns for multiple chemokine receptors on CD4+ T cells from human blood suggested a hierarchy of receptors that are induced and accumulate during effector/memory cell differentiation. We characterized CD4+CD45RO+ T cells based on expression of two of these receptors, CCR5 and CCR2, the principal subsets being CCR5−CCR2− (∼70%), CCR5+CCR2− (∼25%), and CCR5+CCR2+ (∼5%). Relationships among expression of CCR5 and CCR2 and CD62L, and the subsets’ proliferation histories, suggested a pathway of progressive effector/memory differentiation from the CCR5−CCR2− to CCR5+CCR2− to CCR5+CCR2+ cells. Sensitivity and rapidity of TCR-mediated activation, TCR signaling, and effector cytokine production by the subsets were consistent with such a pathway. The subsets also showed increasing responsiveness to IL-7, and the CCR5+CCR2+ cells were CD127bright and invariably showed the greatest response to tetanus toxoid. CCR5+CCR2+ cells also expressed the largest repertoire of chemokine receptors and migrated to the greatest number of chemokines. By contrast, the CCR5+CCR2− cells had the greatest percentages of regulatory T cells, activated/cycling cells, and CMV-reactive cells, and were most susceptible to apoptosis. Our results indicate that increasing memory cell differentiation can be uncoupled from susceptibility to death, and is associated with an increase in chemokine responsiveness, suggesting that vaccination (or infection) can produce a stable population of effector-capable memory cells that are highly enriched in the CCR5+CCR2+ subset and ideally equipped for rapid recall responses in tissue.
Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism
Authors: Elsheikh Ayman , Lavergne Sidonie N. , Castrejon J. Luis , Farrell John , Wang Haiyi , Sathish Jean , Pichler Werner J. , Park B. Kevin , Naisbitt Dean J. 
Published: October 2010

AbstractRecognition of drugs by immune cells is usually explained by the hapten model, which states that endogenous metabolites bind irreversibly to protein to stimulate immune cells. Synthetic metabolites interact directly with protein-generating antigenic determinants for T cells; however, experimental evidence relating intracellular metabolism in immune cells and the generation of physiologically relevant Ags to functional immune responses is lacking. The aim of this study was to develop an integrated approach using animal and human experimental systems to characterize sulfamethoxazole (SMX) metabolism-derived antigenic protein adduct formation in immune cells and define the relationship among adduct formation, cell death, costimulatory signaling, and stimulation of a T cell response. Formation of SMX-derived adducts in APCs was dose and time dependent, detectable at nontoxic concentrations, and dependent on drug-metabolizing enzyme activity. Adduct formation above a threshold induced necrotic cell death, dendritic cell costimulatory molecule expression, and cytokine secretion. APCs cultured with SMX for 16 h, the time needed for drug metabolism, stimulated T cells from sensitized mice and lymphocytes and T cell clones from allergic patients. Enzyme inhibition decreased SMX-derived protein adduct formation and the T cell response. Dendritic cells cultured with SMX and adoptively transferred to recipient mice initiated an immune response; however, T cells were stimulated with adducts derived from SMX metabolism in APCs, not the parent drug. This study shows that APCs metabolize SMX; subsequent protein binding generates a functional T cell Ag. Adduct formation above a threshold stimulates cell death, which provides a maturation signal for dendritic cells.
T Cell Polarity at the Immunological Synapse Is Required for CD154-Dependent IL-12 Secretion by Dendritic Cells
Authors: Tourret Marie , Guégan Sarah , Chemin Karine , Dogniaux Stéphanie , Miro Francesc , Bohineust Armelle , Hivroz Claire 
Published: October 2010

Abstract
Ag-specific interaction between T lymphocytes and dendritic cells (DCs) leads to both T cell and DC activation. CD154 (CD40 ligand)/CD40 interactions have been shown to play a major, although not exclusive, role in this functional cross-talk. Interactions between T cells and DCs are structured by an immunological synapse (IS), characterized by polarization of the T cell microtubule cytoskeleton toward the interacting DCs. Yet the role T cell polarization may play in T cell-induced DC activation is mostly unknown. In this study, we address the role of T cell polarity in CD154-dependent activation of DCs in a human model, using two different tools to block T cell polarity (i.e., a microtubule depolymerizing drug and an inhibitor of atypical protein kinase C). We show that CD154 is recruited and concentrated at the IS formed between human primary T cells and autologous DCs and that this recruitment requires T cell polarity at the IS. Moreover, we show that T cell polarization at the IS controls T cell-dependent CD154–CD40 signaling in DCs as well as CD154-dependent IL-12 secretion by DCs. This study shows that T cell polarity at the IS plays a key role in CD154/CD40-dependent cross-talk between CD4+ T cells and DCs.
Umbilical Cord-Derived Mesenchymal Stromal Cells Modulate Monocyte Function to Suppress T Cell Proliferation
Authors: Cutler Antony J. , Limbani Vasanti , Girdlestone John , Navarrete Cristina V. 
Published: October 2010

Abstract
Mesenchymal stromal cells (MSCs) may be derived from a variety of tissues, with human umbilical cord (UC) providing an abundant and noninvasive source. Human UC-MSCs share similar in vitro immunosuppressive properties as MSCs obtained from bone marrow and cord blood. However, the mechanisms and cellular interactions used by MSCs to control immune responses remain to be fully elucidated. In this paper, we report that suppression of mitogen-induced T cell proliferation by human UC-, bone marrow-, and cord blood-MSCs required monocytes. Removal of monocytes but not B cells from human adult PBMCs (PBMNCs) reduced the immunosuppressive effects of MSCs on T cell proliferation. There was rapid modulation of a number of cell surface molecules on monocytes when PBMCs or alloantigen-activated PBMNCs were cultured with UC-MSCs. Indomethacin treatment significantly inhibited the ability of UC-MSCs to suppress T cell proliferation, indicating an important role for PGE2. Monocytes purified from UC-MSC coculture had significantly reduced accessory cell and allostimulatory function when tested in subsequent T cell proliferation assays, an effect mediated in part by UC-MSC PGE2 production and enhanced by PBMNC alloactivation. Therefore, we identify monocytes as an essential intermediary through which UC-MSCs mediate their suppressive effects on T cell proliferation.
Elevated Levels of Soluble TNF Receptors 1 and 2 Correlate with Plasmodium falciparum Parasitemia in Pregnant Women: Potential Markers for Malaria-Associated Inflammation
Authors: Thévenon Audrey Davidson , Zhou James A. , Megnekou Rosette , Ako Simon , Leke Rose G. F. , Taylor Diane Wallace 
Published: October 2010

Abstract
Plasmodium falciparum-infected erythrocytes (IEs) sequester in the intervillous space (IVS) of the placenta causing placental malaria (PM), a condition that increases a woman’s chances of having a low-birth-weight baby. Because IEs sequester, they frequently are not observed in peripheral blood smears, resulting in women with PM being misdiagnosed and thus not treated. Because sequestered IEs induce inflammation in the IVS, detection of inflammatory mediators in the peripheral blood may provide an approach for diagnosing PM. Two counterregulatory molecules, TNF-αR (TNFR) 1 and TNFR2, modulate the pathological effects of TNF-α. Levels of these soluble TNFRs (sTNFRs) are reported to be elevated in children with severe malaria, but it is unclear if they are increased in the peripheral blood of PM-positive women with asymptomatic infections. In this study, sTNFR levels were measured throughout the course of pregnancy, as well as at delivery, in women with asymptomatic infections and those who remained uninfected. Results showed that both sTNFRs were significantly increased in the peripheral blood of women with asymptomatic malaria (p &lt; 0.0001) and were positively correlated with parasitemia (p &lt; 0.0001 for sTNFR1 and p = 0.0046 for sTNFR2). Importantly, levels of sTNFR2 were elevated in the peripheral blood of women who were PM-positive but peripheral blood-smear negative (p = 0.0017). Additionally, sTNFR2 levels were elevated in the blood of malaria-positive women who delivered low-birth-weight babies. In vitro studies demonstrated that syncytiotrophoblasts were not a major source of sTNFR. These data suggest that sTNFR2 may be a valuable biomarker for detection of malaria-associated inflammation.
Aportación de los planificadores estratégicos españoles a la eficacia publicitaria
Authors: Sánchez Blanco Cristina 
Published: October 2010

El presente artículo tiene como propósito examinar las funciones que tiene el planificador estratégico en la actualidad y en concreto definir el papel que ejerce en la consecución de la eficacia de la comunicación de los anunciantes. La Planificación Estratégica nació en Londres en 1968 en dos agencias de publicidad en el contexto mediático y de marketing de aquella época. En el entorno actual, caracterizado por el protagonismo del consumidor y la necesidad de una comunicación integrada, su papel adquiere mayor protagonismo como defensor del consumidor para que la comunicación comercial esté basada en una investigación profunda sobre él. Así, su trabajo aporta valor a los anunciantes porque se ocupa de realizar un posicionamiento de la marca correcto y una estrategia de comunicación eficaz porque está enfocada en un conocimiento seguro del consumidor.
Esta reflexión teórica adquiere más realce al adaptarla al análisis de la realidad de los profesionales españoles hoy en día a través de un estudio empírico basado en una encuesta a los planificadores que trabajan en España. La Planificación Estratégica es una disciplina reciente en dicho país ya que es a principios de los años 90 cuando algunas agencias empezaron a contar con profesionales dedicados en exclusiva a esta función. Sin embargo, en menos de veinte años se ha convertido en un departamento clave en el entorno de comunicación comercial.