bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Woodchuck Hepatitis Virus (WHV) Transgene Mouse Models Show Sex-Dependent WHV Replicative Activity and Development of Spontaneous Immune Responses to WHV Proteins
Authors: Meng Zhongji , Ma Zhiyong , Zhang Ejuan , Kosinska Anna D. , Liu Jia , Zhang Xiaoyong , Zhou Tianlun , Wu Jun , Dahmen Uta , Dirsch Olaf , Yang Dongliang , Roggendorf Michael , Lu Mengji 
Published: November 2013

ABSTRACT
The woodchuck model is an informative model for studies on hepadnaviral infection. In this study, woodchuck hepatitis virus (WHV) transgenic (Tg) mouse models based on C57BL/6 mice were established to study the pathogenesis associated with hepadnaviral infection. Two lineages of WHV Tg mice, harboring the WHV wild-type genome (lineage 1217) and a mutated WHV genome lacking surface antigen (lineage 1281), were generated. WHV replication intermediates were detected by Southern blotting. DNA vaccines against WHV proteins were applied by intramuscular injection. WHV-specific immune responses were analyzed by flow cytometry and enzyme-linked immunosorbent assays (ELISAs). The presence of WHV transgenes resulted in liver-specific but sex- and age-dependent WHV replication in Tg mice. Pathological changes in the liver, including hepatocellular dysplasia, were observed in aged Tg mice, suggesting that the presence of WHV transgenes may lead to liver diseases. Interestingly, Tg mice of lineage 1281 spontaneously developed T- and B-cell responses to WHV core protein (WHcAg). DNA vaccination induced specific immune responses to WHV proteins in WHV Tg mice, indicating a tolerance break. The magnitude of the induced WHcAg-specific immune responses was dependent on the effectiveness of different DNA vaccines and was associated with a decrease in WHV loads in mice. In conclusion, sex- and age-dependent viral replication, development of autoimmune responses to viral antigens, pathological changes in the liver in WHV Tg mice, and the possibility of breaking immune tolerance to WHV transgenes will allow future studies on pathogenesis related to hepadnaviral infection and therapeutic vaccines.
Assessing the Susceptibility of Transgenic Mice Overexpressing Deer Prion Protein to Bovine Spongiform Encephalopathy
Authors: Vickery Christopher M. , Lockey Richard , Holder Thomas M. , Thorne Leigh , Beck Katy E. , Wilson Christina , Denyer Margaret , Sheehan John , Marsh Sarah , Webb Paul R. , Dexter Ian , Norman Angela , Popescu Emma , Schneider Amanda , Holden Paul , Griffiths Peter C. , Plater Jane M. , Dagleish Mark P. , Martin Stuart , Telling Glenn C. , Simmons Marion M. , Spiropoulos John 
Published: November 2013

ABSTRACT

Several transgenic mouse models have been developed which facilitate the transmission of chronic wasting disease (CWD) of cervids and allow prion strain discrimination. The present study was designed to assess the susceptibility of the prototypic mouse line, Tg(CerPrP)1536
+/−
, to bovine spongiform encephalopathy (BSE) prions, which have the ability to overcome species barriers. Tg(CerPrP)1536
+/−
mice challenged with red deer-adapted BSE resulted in 90% to 100% attack rates, and BSE from cattle failed to transmit, indicating agent adaptation in the deer.
Activation of Peripheral Blood Mononuclear Cells by Dengue Virus Infection Depotentiates Balapiravir
Authors: Chen Yen-Liang , Abdul Ghafar Nahdiyah , Karuna Ratna , Fu Yilong , Lim Siew Pheng , Schul Wouter , Gu Feng , Herve Maxime , Yokohama Fumiaki , Wang Gang , Cerny Daniela , Fink Katja , Blasco Francesca , Shi Pei-Yong 
Published: November 2013

ABSTRACT

In a recent clinical trial, balapiravir, a prodrug of a cytidine analog (R1479), failed to achieve efficacy (reducing viremia after treatment) in dengue patients, although the plasma trough concentration of R1479 remained above the 50% effective concentration (EC
50
). Here, we report experimental evidence to explain the discrepancy between the
in vitro
and
in vivo
results and its implication for drug development. R1479 lost its potency by 125-fold when balapiravir was used to treat primary human peripheral blood mononuclear cells (PBMCs; one of the major cells targeted for viral replication) that were preinfected with dengue virus. The elevated EC
50
was greater than the plasma trough concentration of R1479 observed in dengue patients treated with balapiravir and could possibly explain the efficacy failure. Mechanistically, dengue virus infection triggered PBMCs to generate cytokines, which decreased their efficiency of conversion of R1479 to its triphosphate form (the active antiviral ingredient), resulting in decreased antiviral potency. In contrast to the cytidine-based compound R1479, the potency of an adenosine-based inhibitor of dengue virus (NITD008) was much less affected. Taken together, our results demonstrate that viral infection in patients before treatment could significantly affect the conversion of the prodrug to its active form; such an effect should be calculated when estimating the dose efficacious for humans.
Human Cytotoxic T Lymphocytes Directed to Seasonal Influenza A Viruses Cross-React with the Newly Emerging H7N9 Virus
Authors: van de Sandt Carolien E. , Kreijtz Joost H. C. M. , de Mutsert Gerrie , Geelhoed-Mieras Martina M. , Hillaire Marine L. B. , Vogelzang-van Trierum Stella E. , Osterhaus Albert D. M. E. , Fouchier Ron A. M. , Rimmelzwaan Guus F. 
Published: November 2013

ABSTRACTIn February 2013, zoonotic transmission of a novel influenza A virus of the H7N9 subtype was reported in China. Although at present no sustained human-to-human transmission has been reported, a pandemic outbreak of this H7N9 virus is feared. Since neutralizing antibodies to the hemagglutinin (HA) globular head domain of the virus are virtually absent in the human population, there is interest in identifying other correlates of protection, such as cross-reactive CD8+T cells (cytotoxic T lymphocytes [CTLs]) elicited during seasonal influenza A virus infections. These virus-specific CD8+T cells are known to recognize conserved internal proteins of influenza A viruses predominantly, but it is unknown to what extent they cross-react with the newly emerging H7N9 virus. Here, we assessed the cross-reactivity of seasonal H3N2 and H1N1 and pandemic H1N1 influenza A virus-specific polyclonal CD8+T cells, obtained from HLA-typed study subjects, with the novel H7N9 virus. The cross-reactivity of CD8+T cells to H7N9 variants of known influenza A virus epitopes and H7N9 virus-infected cells was determined by their gamma interferon (IFN-γ) response and lytic activity. It was concluded that, apart from recognition of individual H7N9 variant epitopes, CD8+T cells to seasonal influenza viruses display considerable cross-reactivity with the novel H7N9 virus. The presence of these cross-reactive CD8+T cells may afford some protection against infection with the new virus.
MiR-134/487b/655 Cluster Regulates TGF-β–Induced Epithelial–Mesenchymal Transition and Drug Resistance to Gefitinib by Targeting MAGI2 in Lung Adenocarcinoma Cells
Authors: Kitamura Kazuhiro , Seike Masahiro , Okano Tetsuya , Matsuda Kuniko , Miyanaga Akihiko , Mizutani Hideaki , Noro Rintaro , Minegishi Yuji , Kubota Kaoru , Gemma Akihiko 
Published: November 2013

Abstract
Epithelial–mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non–small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA)-related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in NSCLC. miRNA expression profiles were examined before and after transforming growth factor β1 (TGF-β1) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. miRNA array and real-time quantitative reverse transcription PCR (qRT-PCR) revealed that TGF-β1 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW, and PDZ domain–containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN, was diminished in A549 cells with EMT after the TGF-β1 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-β1–induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-β1–induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, in which suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be a new therapeutic target in patients with advanced lung adenocarcinoma, depending on the EMT phenomenon. Mol Cancer Ther; 13(2); 444–53. ©2013 AACR.
Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress
Authors: Aoi Jun , Endo Motoyoshi , Kadomatsu Tsuyoshi , Miyata Keishi , Ogata Aki , Horiguchi Haruki , Odagiri Haruki , Masuda Tetsuro , Fukushima Satoshi , Jinnin Masatoshi , Hirakawa Satoshi , Sawa Tomohiro , Akaike Takaaki , Ihn Hironobu , Oike Yuichi 
Published: November 2013

Abstract
Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to “preneoplastic change” and “malignant conversion” in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.
Implications: Angptl2-induced inflammation increases susceptibility to microenvironmental changes, allowing increased oxidative stress and decreased Msh2 expression; therefore, Angptl2 might be a target to develop new strategies to antagonize these activities in premalignant tissue. Mol Cancer Res; 12(2); 239–49. ©2013 AACR.
Should oral anticoagulants be restarted after warfarin-associated cerebral haemorrhage in patients with atrial fibrillation?
Authors: Agnelli Giancarlo , Paciaroni Maurizio 
Published: November 2013

SummaryIntracranial haemorrhage (ICH), which affects up to 1% of patients on oral anticoagulation per year, is the most feared and devastating complication of this treatment. After such an event, it is unclear whether anticoagulant therapy should be resumed. Such a decision hinges upon the assessment of the competing risks of haematoma growth or recurrent ICH and thromboembolic events. ICH location and the risk for ischaemic cerebrovascular event seem to be the key factors that lead to risk/benefit balance of restarting anticoagulation after ICH. Patients with lobar haemorrhage or cerebral amyloid angiopathy remain at higher risk for anticoagulant-related ICH recurrence than thromboembolic events and, therefore would be best managed without anticoagulants. Patients with deep hemispheric ICH and a baseline risk of ischemic stroke >6.5% per year, that corresponds to CHADS2 ≥ 4 or CHA2DS2-VASc ≥ 5, may receive net benefit from restarting anticoagulation. To date, a reasonable recommendation regarding time to resumption of anticoagulation therapy would be after 10 weeks. Available data regarding the role of magnetic resonance imaging in assessing the risks of both ICH and warfarin-related ICH do not support the use of this test for excluding anticoagulation in patients with atrial fibrillation.
Eulerian and Lagrangian Isopycnal Eddy Diffusivities in the Southern Ocean of an Eddying Model
Authors: Griesel A. , McClean J. L. , Gille S. T. , Sprintall J. , Eden C. 
Published: November 2013

Abstract
Lagrangian isopycnal diffusivities quantify the along-isopycnal mixing of any tracer with mean gradients along isopycnal surfaces. They are studied in the Southern Ocean of the 1/10° Parallel Ocean Program (POP) model using more than 50 000 float trajectories. Concurrent Eulerian isopycnal diffusivities are estimated directly from the eddy fluxes and mean tracer gradients. Consistency, spatial variation, and relation to mean jets are evaluated. The diffusivities are calculated in bins large enough to reduce contributions from the rotational components that do not lead to net tracer mixing. Because the mean jets are nonzonal and nonparallel, meridional dispersion includes standing eddies and is significantly different from cross-stream dispersion. With the subtraction of the local Eulerian mean, the full Lagrangian diffusivity tensor can be estimated. Along-stream diffusivities are about 6 times larger than cross-stream diffusivities. Along-streamline averages of Eulerian and Lagrangian isopycnal diffusivities are similar in that they are larger north of the Antarctic Circumpolar Current (ACC) and smaller in the ACC in the upper 500 m. Eulerian diffusivities are often twice as large as the Lagrangian diffusivities below 500 m. There is large longitudinal variability in the diffusivities and in their relation to the mean flow. In bins with one prominent jet, diffusivities are reduced at the surface in the jet and increased to the north and south of the jet. There is a local maximum at depths of 500–1000 m. In other bins where mean jets merge and diverge because of topography, there is no consistent relation of the diffusivities with the mean flow. Eulerian fluxes are upgradient in about 15% of the bins.
Diabetes Peer Coaching
Authors: Rogers Elizabeth A. , Hessler Danielle M. , Bodenheimer Thomas S. , Ghorob Amireh , Vittinghoff Eric , Thom David H. 
Published: November 2013

Purpose The purpose of this study was to identify characteristics of peer coaches associated with improvement in diabetes control among low-income patients with type 2 diabetes. Methods Low-income patients with type 2 diabetes who spoke English or Spanish from 6 urban clinics in San Francisco, California, were invited to participate in the study. Twenty participants received training and provided peer coaching to 109 patients over a 6-month peer coaching intervention. Primary outcome was average change in patient glycosylated hemoglobin (A1C). Characteristics of peer coaches included age, gender, years with diabetes, A1C, body mass index (BMI), levels of diabetes-related distress, self-efficacy in diabetes self-management, and depression. Results Patient improvement in A1C was associated with having a coach with a lower sense of self-efficacy in diabetes management ( P < .001), higher level of diabetes-related distress ( P = .01), and lower depression score ( P = .03). Conclusions Coach characteristics are associated with patient success in improving A1C. “Better” levels of coach diabetes self-efficacy and distress were not helpful and, in fact, were associated with less improvement in patient A1C, suggesting that some coach uncertainty about his or her own diabetes might foster improved patient self-management. These coach characteristics should be considered when recruiting peer coaches.
Genetic differences in cytochrome P450 enzymes and antidepressant treatment response
Authors: Hodgson Karen , Tansey Katherine , Dernovšek Mojca Zvezdana , Hauser Joanna , Henigsberg Neven , Maier Wolfgang , Mors Ole , Placentino Anna , Rietschel Marcella , Souery Daniel , Smith Rebecca , Craig Ian W , Farmer Anne E , Aitchison Katherine J , Belsy Sarah , Davis Oliver SP , Uher Rudolf , McGuffin Peter 
Published: November 2013

Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline:nortrip-tyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.
Expression and clinical significance of the programmed cell death 5 gene and protein in laryngeal squamous cell carcinoma
Authors: Xu Fenglei , Wu Kai , Zhao Miaoqing , Qin Yejun , Xia Ming 
Published: November 2013

Objective To determine the expression of the gene programmed cell death 5 ( PDCD5) and its protein PDCD5 in laryngeal squamous cell carcinoma and to analyse possible correlations with clinicopathological parameters. Methods PDCD5 mRNA expression was assessed using reverse transcription–polymerase chain reaction and expression of PDCD5 protein was studied using Western blot analysis and immunohistochemistry in laryngeal squamous cell carcinoma and morphologically normal para-carcinoma tissue. Results A total of 41 laryngeal squamous cell carcinoma and 29 normal para-carcinoma tissue specimens were examined. Expression of both PDCD5 mRNA and PDCD5 protein was significantly reduced in laryngeal squamous cell carcinoma compared with normal tissue. Expression was correlated with clinical stage and histological grade, but was not associated with age, sex, location of primary tumour or the presence of lymph node metastases. Conclusion The expression of PDCD5 and its protein were shown to be reduced in laryngeal squamous cell carcinoma. The functional importance of PDCD5 as a regulating agent in cell apoptosis suggests that it may play a key role in tumour pathogenesis and development.
Ivabradine, a novel treatment for clozapine-induced sinus tachycardia: a case series
Authors: Lally John , Brook Jennifer , Dixon Thomas , Gaughran Fiona , Shergill Sukhi , Melikian Narbeh , MacCabe James H. 
Published: November 2013

Objectives: Clozapine is the most efficacious treatment for treatment-resistant schizophrenia; however its use can be limited by intolerability. Sinus tachycardia is a common adverse event associated with clozapine use, which may lead to the premature discontinuation of clozapine. Traditionally, β blockers are used to treat clozapine-associated tachycardia, though problems with intolerability and ineffectiveness can limit their utility. Methods: In this article, we present two cases of patients with treatment-resistant schizophrenia who developed symptomatic tachycardia associated with clozapine therapy. Results: We demonstrate that the novel heart rate controlling agent ivabradine can be effectively and safely used to control the heart rate and to allow for continued treatment with clozapine. Conclusion: This is the first report in the literature demonstrating that ivabradine appears to be a well tolerated agent, which should be considered as a symptomatic treatment of clozapine-induced tachycardia if the use of a β blocker fails due to a lack of response or intolerability.
Allogeneic platelet transfusions prevent murine T-cell–mediated immune thrombocytopenia
Authors: Guo Li , Yang Lei , Speck Edwin R. , Aslam Rukhsana , Kim Michael , McKenzie Christopher G. J. , Lazarus Alan H. , Ni Heyu , Hou Ming , Freedman John , Semple John W. 
Published: November 2013

Key PointsAllogeneic platelet MHC class I transfusions can both prevent and/or alleviate anti-CD61 (GPIIIa) T-cell–mediated ITP. The transfusions reverse abnormal bone marrow megakaryocyte histology and inhibit CD61-induced cytotoxicity.
Perceived neighborhood problems: multilevel analysis to evaluate psychometric properties in a Southern adult Brazilian population
Authors: Höfelmann Doroteia Aparecida , Diez-Roux Ana V , Antunes José Leopoldo Ferreira , Peres Marco Aurélio 
Published: November 2013

Abstract

Background
Physical attributes of the places in which people live, as well as their perceptions of them, may be important health determinants. The perception of place in which people dwell may impact on individual health and may be a more telling indicator for individual health than objective neighborhood characteristics. This paper aims to evaluate psychometric and ecometric properties of a scale on the perceptions of neighborhood problems in adults from Florianopolis, Southern Brazil.

Methods
Individual, census tract level (per capita monthly familiar income) and neighborhood problems perception (physical and social disorders) variables were investigated. Multilevel models (items nested within persons, persons nested within neighborhoods) were run to assess ecometric properties of variables assessing neighborhood problems.

Results
The response rate was 85.3%, (1,720 adults). Participants were distributed in 63 census tracts. Two scales were identified using 16 items: Physical Problems and Social Disorder. The ecometric properties of the scales satisfactory: 0.24 to 0.28 for the intra-class correlation and 0.94 to 0.96 for reliability. Higher values on the scales of problems in the physical and social domains were associated with younger age, more length of time residing in the same neighborhood and lower census tract income level.

Conclusions
The findings support the usefulness of these scales to measure physical and social disorder problems in neighborhoods.