bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blocking Herpes Simplex Virus 2 Glycoprotein E Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine for Genital Herpes
Authors: Awasthi Sita , Huang Jialing , Shaw Carolyn , Friedman Harvey M. 
Published: May 2014

ABSTRACTHerpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion.IMPORTANCEHerpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease, and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections.
Highly Diverse Morbillivirus-Related Paramyxoviruses in Wild Fauna of the Southwestern Indian Ocean Islands: Evidence of Exchange between Introduced and Endemic Small Mammals
Authors: Wilkinson David A. , Mélade Julien , Dietrich Muriel , Ramasindrazana Beza , Soarimalala Voahangy , Lagadec Erwan , le Minter Gildas , Tortosa Pablo , Heraud Jean-Michel , de Lamballerie Xavier , Goodman Steven M. , Dellagi Koussay , Pascalis Herve 
Published: May 2014

ABSTRACT

The
Paramyxoviridae
form an increasingly diverse viral family, infecting a wide variety of different hosts. In recent years, they have been linked to disease emergence in many different animal populations and in humans. Bats and rodents have been identified as major animal populations capable of harboring paramyxoviruses, and host shifting between these animals is likely to be an important driving factor in the underlying evolutionary processes that eventually lead to disease emergence. Here, we have studied paramyxovirus circulation within populations of endemic and introduced wild small mammals of the southwestern Indian Ocean region and belonging to four taxonomic orders: Rodentia, Afrosoricida, Soricomorpha, and Chiroptera. We report elevated infection levels as well as widespread paramyxovirus dispersal and frequent host exchange of a newly emerging genus of the
Paramyxoviridae
, currently referred to as the unclassified morbillivirus-related viruses (UMRVs). In contrast to other genera of the
Paramyxoviridae
, where bats have been shown to be a key host species, we show that rodents (and, in particular,
Rattus rattus
) are significant spreaders of UMRVs. We predict that the ecological particularities of the southwestern Indian Ocean, where small mammal species often live in densely packed, multispecies communities, in combination with the increasing invasion of
R. rattus
and perturbations of endemic animal communities by active anthropological development, will have a major influence on the dynamics of UMRV infection.

IMPORTANCE
Identification of the infectious agents that circulate within wild animal reservoirs is essential for several reasons: (i) infectious disease outbreaks often originate from wild fauna; (ii) anthropological expansion increases the risk of contact between human and animal populations and, as a result, the risk of disease emergence; (iii) evaluation of pathogen reservoirs helps in elaborating preventive measures to limit the risk of disease emergence. Many paramyxoviruses for which bats and rodents serve as major reservoirs have demonstrated their potential to cause disease in humans and animals. In the context of the biodiversity hot spot of southwestern Indian Ocean islands and their rich endemic fauna, we show that highly diverse UMRVs exchange between various endemic animal species, and their dissemination likely is facilitated by the introduced
Rattus rattus
. Hence, many members of the
Paramyxoviridae
appear well adapted for the study of the viral phylodynamics that may be associated with disease emergence.
Newcastle Disease Virus (NDV) Recombinants Expressing Infectious Laryngotracheitis Virus (ILTV) Glycoproteins gB and gD Protect Chickens against ILTV and NDV Challenges
Authors: Zhao Wei , Spatz Stephen , Zhang Zhenyu , Wen Guoyuan , Garcia Maricarmen , Zsak Laszlo , Yu Qingzhong 
Published: May 2014

ABSTRACT

Infectious laryngotracheitis (ILT) is a highly contagious acute respiratory disease of chickens caused by infectious laryngotracheitis virus (ILTV). The disease is controlled mainly through biosecurity and vaccination with live attenuated strains of ILTV and vectored vaccines based on turkey herpesvirus (HVT) and fowlpox virus (FPV). The current live attenuated vaccines (chicken embryo origin [CEO] and tissue culture origin [TCO]), although effective, can regain virulence, whereas HVT- and FPV-vectored ILTV vaccines are less efficacious than live attenuated vaccines. Therefore, there is a pressing need to develop safer and more efficacious ILTV vaccines. In the present study, we generated Newcastle disease virus (NDV) recombinants, based on the LaSota vaccine strain, expressing glycoproteins B (gB) and D (gD) of ILTV using reverse genetics technology. These recombinant viruses, rLS/ILTV-gB and rLS/ILTV-gD, were slightly attenuated
in vivo
yet retained growth dynamics, stability, and virus titers
in vitro
that were similar to those of the parental LaSota virus. Expression of ILTV gB and gD proteins in the recombinant virus-infected cells was detected by immunofluorescence assay. Vaccination of specific-pathogen-free chickens with these recombinant viruses conferred significant protection against virulent ILTV and velogenic NDV challenges. Immunization of commercial broilers with rLS/ILTV-gB provided a level of protection against clinical disease similar to that provided by the live attenuated commercial vaccines, with no decrease in body weight gains. The results of the study suggested that the rLS/ILTV-gB and -gD viruses are safe, stable, and effective bivalent vaccines that can be mass administered via aerosol or drinking water to large chicken populations.

IMPORTANCE
This paper describes the development and evaluation of novel bivalent vaccines against chicken infectious laryngotracheitis (ILT) and Newcastle disease (ND), two of the most economically important infectious diseases of poultry. The current commercial ILT vaccines are either not safe or less effective. Therefore, there is a pressing need to develop safer and more efficacious ILT vaccines. In the present study, we generated Newcastle disease virus (NDV) recombinants expressing glycoproteins B (gB) and D (gD) of infectious laryngotracheitis virus (ILTV) using reverse genetics technology. These recombinant viruses were safe, stable, and immunogenic and replicated efficiently in birds. Vaccination of chickens with these recombinant viruses conferred complete protection against ILTV and NDV challenge. These novel bivalent vaccines can be mass administered via aerosol or drinking water to large chicken populations at low cost, which will have a direct impact on poultry health, fitness, and performance.
Single-Domain Antibodies Targeting Neuraminidase Protect against an H5N1 Influenza Virus Challenge
Authors: Cardoso Francisco Miguel , Ibañez Lorena Itatí , Van den Hoecke Silvie , De Baets Sarah , Smet Anouk , Roose Kenny , Schepens Bert , Descamps Francis J. , Fiers Walter , Muyldermans Serge , Depicker Ann , Saelens Xavier 
Published: May 2014

ABSTRACT

Influenza virus neuraminidase (NA) is an interesting target of small-molecule antiviral drugs. We isolated a set of H5N1 NA-specific single-domain antibodies (N1-VHHm) and evaluated their
in vitro
and
in vivo
antiviral potential. Two of them inhibited the NA activity and
in vitro
replication of clade 1 and 2 H5N1 viruses. We then generated bivalent derivatives of N1-VHHm by two methods. First, we made N1-VHHb by genetically joining two N1-VHHm moieties with a flexible linker. Second, bivalent N1-VHH-Fc proteins were obtained by genetic fusion of the N1-VHHm moiety with the crystallizable region of mouse IgG2a (Fc). The
in vitro
antiviral potency against H5N1 of both bivalent N1-VHHb formats was 30- to 240-fold higher than that of their monovalent counterparts, with 50% inhibitory concentrations in the low nanomolar range. Moreover, single-dose prophylactic treatment with bivalent N1-VHHb or N1-VHH-Fc protected BALB/c mice against a lethal challenge with H5N1 virus, including an oseltamivir-resistant H5N1 variant. Surprisingly, an N1-VHH-Fc fusion without
in vitro
NA-inhibitory or antiviral activity also protected mice against an H5N1 challenge. Virus escape selection experiments indicated that one amino acid residue close to the catalytic site is required for N1-VHHm binding. We conclude that single-domain antibodies directed against influenza virus NA protect against H5N1 virus infection, and when engineered with a conventional Fc domain, they can do so in the absence of detectable NA-inhibitory activity.

IMPORTANCE
Highly pathogenic H5N1 viruses are a zoonotic threat. Outbreaks of avian influenza caused by these viruses occur in many parts of the world and are associated with tremendous economic loss, and these viruses can cause very severe disease in humans. In such cases, small-molecule inhibitors of the viral NA are among the few treatment options for patients. However, treatment with such drugs often results in the emergence of resistant viruses. Here we show that single-domain antibody fragments that are specific for NA can bind and inhibit H5N1 viruses
in vitro
and can protect laboratory mice against a challenge with an H5N1 virus, including an oseltamivir-resistant virus. In addition, plant-produced VHH fused to a conventional Fc domain can protect
in vivo
even in the absence of NA-inhibitory activity. Thus, NA of influenza virus can be effectively targeted by single-domain antibody fragments, which are amenable to further engineering.
Analysis of occupational radiation exposure during cerebral angiography utilizing a new real time radiation dose monitoring system
Authors: James Robert F , Wainwright Kristin JoAnn , Kanaan Hilal A , Hudson Suzanne , Wainwright Mark Edison , Hightower Jerome H , Delaney John J 
Published: May 2014

BackgroundThermoluminescent dosimeter badges currently utilized to monitor occupational radiation exposures are limited in their ability to provide timely feedback, restricting workers' ability to identify unnecessary exposure. New real time radiation monitoring systems provide an opportunity for workers to immediately identify and alter problematic behaviors in the neuroangiography suite, decreasing unnecessary exposures, lowering risk, and maximizing safety efforts.MethodsReal time radiation monitoring was performed for 120 diagnostic cerebral angiography procedures. Data were collected in two phases, for procedures performed by two physician participants (30 procedures per physician per phase). Workers were blinded to their real time dose in phase I, and unblinded in phase II. Individual exposures (Sv) and the incidence of red events (exposure rates ≥2.0 mSv/h) were collected for each assigned participating role (physician A, physician B, nurse, scrubbed technologist, and circulating technologist). The dose area product was collected for each procedure to standardize against variations in procedure duration or intensity.ResultsIn phase II, significant decreased radiation exposure was observed for all roles except physician A. Physician B decreased most from 24.3×10−8to 6.9×10−8Sv/Gy-cm2(p<0.0001). Rates of red events decreased similarly for all roles except physician A, and were significant for all roles except the nurse role.ConclusionsReal time radiation dose monitoring during diagnostic cerebral angiography may help to reduce occupational radiation exposures for healthcare workers.
In Vivo Imaging as a Pharmacodynamic Marker
Authors: van der Veldt Astrid A.M. , Lammertsma Adriaan A. 
Published: May 2014

Abstract
Although numerous anticancer drugs are widely used in the clinic, many questions remain about pharmacokinetics, biodistribution, toxicities, and efficacy. Positron emission tomography (PET) using radiolabeled drugs is a promising method to further understand the clinical behavior of anticancer agents. In addition, it may contribute to better guided treatment planning in individual patients with cancer. Among the available anticancer drugs, considerable experience has been gained with radiolabeling taxanes. At present, two radiolabeled taxanes, paclitaxel and docetaxel, are available as PET tracers. In the present review, data available for the labeled taxanes [18F]paclitaxel and [11C]docetaxel are discussed and linked to clinical observations following paclitaxel and docetaxel therapy, respectively. In addition, the review discusses the applications and the future of PET using radiolabeled drugs. Experience gained with [18F]paclitaxel and [11C]docetaxel may be extrapolated to other taxanes and may provide a framework for the development and clinical implementation of other radiolabeled anticancer drugs, even outside the taxane era.
See all articles in this CCR Focus section, “Progress in Pharmacodynamic Endpoints.”
Clin Cancer Res; 20(10); 2569–77. ©2014 AACR.
Pharmacodynamic Biomarkers: Falling Short of the Mark?
Authors: Gainor Justin F. , Longo Dan L. , Chabner Bruce A. 
Published: May 2014

Abstract
In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treated—typically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non–small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail.
See all articles in this CCR Focus section, “Progress in Pharmacodynamic Endpoints.”
Clin Cancer Res; 20(10); 2587–94. ©2014 AACR.
Implementation of Validated Pharmacodynamic Assays in Multiple Laboratories: Challenges, Successes, and Limitations
Authors: Kinders Robert , Ferry-Galow Kate , Wang Lihua , Srivastava Apurva K. , Ji Jiuping (Jay) , Parchment Ralph E. 
Published: May 2014

AbstractThere is a “life cycle” of pharmacodynamic (PD) biomarker assays that guides the development and clinical implementation in our laboratories. The well-recognized elements of analytical assay validation and demonstration of fitness-for-purpose of the biomarker, specimen collection, handling, and assay methods are only a part of the required activities. Assay transfer across laboratories and testing on actual human clinical specimens are vital for understanding assay performance and robustness. In our experience, this patient specimen-centered approach has required assay method modifications, some unexpected, but which were critical to successful implementation in clinical trials. In addition, dispersing assays throughout the National Cancer Institute's clinical trials network has required the development of calibrator and control materials as well as formal training courses for smooth implementation. One measure of success of this approach has been that a number of the assays developed at NCI's Frederick National Laboratory have ultimately reached the stage of commercialization, enabling wide accessibility of the PD biomarker assays by the research community.See all articles in this CCR Focus section, “Progress in Pharmacodynamic Endpoints.”Clin Cancer Res; 20(10); 2578–86. ©2014 AACR.
Variability of Regional TOA Flux Diurnal Cycle Composites at the Monthly Time Scale
Authors: Taylor Patrick C. 
Published: May 2014

Abstract
Diurnal variability is a fundamental component of Earth’s climate system. Clouds, temperature, and precipitation exhibit robust responses to the daily cycle of solar insolation. Recent work indicates significant variability in the top-of-the-atmosphere (TOA) flux diurnal cycle in the tropics associated with monthly changes in the cloud diurnal cycle evolution. It has been proposed that the observed month-to-month variations in the TOA flux diurnal cycle are caused by anomalies in the atmospheric dynamic and thermodynamic state. This hypothesis is tested using a regression analysis to quantify the relationship between diurnal cycle shape and the atmospheric dynamic and thermodynamic state. TOA radiative fluxes are obtained from Clouds and the Earth’s Radiant Energy System (CERES) Edition 3 data and the atmospheric dynamic and thermodynamic state is taken from the European Centre for Medium-Range Weather Forecasts (ECMWF) Interim Re-Analysis. Four regions representing traditional diurnal cycle regimes are used in this analysis: North Africa (land nonconvective), central South America (land convective), Peru marine stratocumulus (ocean nonconvective), and Indian Ocean (ocean convective). The results show a statistically significant diurnal cycle shape change and cloud response related to monthly atmospheric state anomalies. Using the single-variable regression relationships to predict monthly diurnal cycle variability shows improvements of 1%–18% over assuming a climatological diurnal cycle shape; the most significant gains are found in North Africa. The proposed hypothesis, therefore, contributes to diurnal cycle variability explaining at least 10%–20% of the total monthly-mean diurnal cycle variability.
Interdecadal Variations in ENSO Influences on Northwest Pacific–East Asian Early Summertime Climate Simulated in CMIP5 Models
Authors: Hu Kaiming , Huang Gang , Zheng Xiao-Tong , Xie Shang-Ping , Qu Xia , Du Yan , Liu Lin 
Published: May 2014

Abstract
The present study investigates interdecadal modulations of the El Niño–Southern Oscillation (ENSO) influence on the climate of the northwest Pacific (NWP) and East Asia (EA) in early boreal summer following a winter ENSO event, based on 19 simulations from phase 5 of the Coupled Model Intercomparison Project (CMIP5). In the historical run, 8 out of 19 models capture a realistic relationship between ENSO and NWP early summer climate—an anomalous anticyclone develops over the NWP following a winter El Niño event—and the interdecadal modulations of this correlation. During periods when the association between ENSO and NWP early summer climate is strong, ENSO variance and ENSO-induced anomalies of summer sea surface temperature (SST) and tropospheric temperature over the tropical Indian Ocean (TIO) all strengthen relative to periods when the association is weak.
In future projections with representative concentration pathways 4.5 and 8.5, the response of TIO SST, tropospheric temperature, and NWP anomalous anticyclone to ENSO all strengthen regardless of ENSO amplitude change. In a warmer climate, low-level specific humidity response to interannual SST variability strengthens following the Clausius–Clapeyron equation. The resultant intensification of tropospheric temperature response to interannual TIO warming is suggested as the mechanism for the strengthened ENSO effect on NWP–EA summer climate.
Modulation of Daily Precipitation over East Africa by the Madden–Julian Oscillation*
Authors: Berhane Fisseha , Zaitchik Benjamin 
Published: May 2014

Abstract
Spatiotemporal variability in East African precipitation affects the livelihood of tens of millions of people. From the perspective of floods, flash droughts, and agriculture, variability on intraseasonal time scales is a critical component of total variability. The principal objective of this study is to explore subseasonal impacts of the Madden–Julian oscillation (MJO) on tropospheric circulations affecting East Africa (EA) during the long (March–May) and short (October–December) rains and associated variability in precipitation. Analyses are performed for 1979–2012 for dynamics and 1998–2012 for precipitation. Consistent with previous studies, significant MJO influence is found on wet and dry spells during the long and short rains. This influence, however, is found to vary within each season. Specifically, indices of MJO convection at 70°–80°E and 120°W are strongly associated with precipitation variability across much of EA in the early (March) and late (May) long rainy season and in the middle and late (November–December) short rainy season. In the early short rains (October) a different pattern emerges, in which MJO strength at 120°E (10°W) is associated with dry (wet) spells in coastal EA but not the interior. In April the MJO influence on precipitation is obscured but can be diagnosed in lead time associations. This diversity of influences reflects a diversity of mechanisms of MJO influence, including dynamic and thermodynamic mechanisms tied to large-scale atmospheric circulations and localized dynamics associated with MJO modulation of the Somali low-level jet. These differences are relevant to problems of subseasonal weather forecasts and climate projections for EA.