bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults
Authors: Berglund Johan , Vink Peter , Tavares Da Silva Fernanda , Lestrate Pascal , Boutriau Dominique 
Published: October 2013

ABSTRACT

We investigated a protein-based nontypeable
Haemophilus influenzae
(NTHi) and pneumococcal (HiP) vaccine containing pneumococcal histidine triad D (PhtD), detoxified pneumolysin (dPly), and NTHi protein D (PD) in adults. In a phase I study, 40 healthy 18- to 40-year-old subjects were randomized (2:2:1) to receive two HiP doses administered 60 days apart, with or without AS03 adjuvant (HiP-AS and HiP groups, respectively), or Engerix B (GlaxoSmithKline, Belgium) as a control. Safety, antibodies, and antigen-specific CD4
+
T-cell immune responses were assessed before and until 480 days after vaccination. No serious adverse events were reported, and no subject withdrew due to an adverse event. Local and systemic symptoms were reported more frequently in the HiP-AS group than in the other two groups. The frequency and intensity of local and systemic symptoms appeared to increase after the second dose of HiP-AS or HiP but not Engerix B. Antibody geometric mean concentrations (GMCs) for PhtD, dPly, and PD increased after each dose of HiP-AS or HiP, with higher GMCs being observed in the HiP-AS group (statistically significant for anti-PD after dose 1 and anti-Ply after dose 2). GMCs remained higher at day 420 than prior to vaccination in both the HiP-AS and HiP groups. Antigen-specific CD4
+
T cells increased after each dose but were unmeasurable by day 480. Two doses of an investigational PhtD-dPly-PD protein vaccine induced humoral immunity and antigen-specific CD4
+
T-cell responses after each dose, with generally higher responses when the vaccine was administered with AS03. HiP combined with AS03 appeared to be more reactogenic than the antigens alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT00814489.)
Assessment of an Oral Mycobacterium bovis BCG Vaccine and an Inactivated M. bovis Preparation for Wild Boar in Terms of Adverse Reactions, Vaccine Strain Survival, and Uptake by Nontarget Species
Authors: Beltrán-Beck Beatriz , Romero Beatriz , Sevilla Iker A. , Barasona Jose A. , Garrido Joseba M. , González-Barrio David , Díez-Delgado Iratxe , Minguijón Esmeralda , Casal Carmen , Vicente Joaquín , Gortázar Christian , Aranaz Alicia 
Published: October 2013

ABSTRACTWildlife vaccination is increasingly being considered as an option for tuberculosis control. We combined data from laboratory trials and an ongoing field trial to assess the risk of an oralMycobacterium bovisBCG vaccine and a prototype heat-inactivatedMycobacterium bovispreparation for Eurasian wild boar (Sus scrofa). We studied adverse reactions, BCG survival, BCG excretion, and bait uptake by nontarget species. No adverse reactions were observed after administration of BCG (n= 27) or inactivatedM. bovis(n= 21). BCG was not found at necropsy (175 to 300 days postvaccination [n= 27]). No BCG excretion was detected in fecal samples (n= 162) or in urine or nasal, oral, or fecal swab samples at 258 days postvaccination (n= 29). In the field, we found no evidence of loss of BCG viability in baits collected after 36 h (temperature range, 11°C to 41°C). Camera trapping showed that wild boar (39%) and birds (56%) were the most frequent visitors to bait stations (selective feeders). Wild boar activity patterns were nocturnal, while diurnal activities were recorded for all bird species. We found large proportions of chewed capsules (29%) (likely ingestion of the vaccine) and lost baits (39%) (presumably consumed), and the proportion of chewed capsules showed a positive correlation with the presence of wild boar. Both results suggest proper bait consumption (68%). These results indicate that BCG vaccination in wild boar is safe and that, while bait consumption by other species is possible, this can be minimized by using selective cages and strict timing of bait deployment.
Dengue Virus Subverts the Interferon Induction Pathway via NS2B/3 Protease-IκB Kinase ε Interaction
Authors: Angleró-Rodríguez Yesseinia I. , Pantoja Petraleigh , Sariol Carlos A. 
Published: October 2013

ABSTRACTDengue is the world's most common mosquito-borne viral infection and a leading cause of morbidity throughout the tropics and subtropics. Viruses are known to evade the establishment of an antiviral state by regulating the activation of interferon regulatory factor 3 (IRF3), a critical transcription factor in the alpha/beta interferon induction pathway. Here, we show that dengue virus (DENV) circumvents the induction of the retinoic acid-inducible gene I-like receptor (RLR) pathway during infection by blocking serine 386 phosphorylation and nuclear translocation of IRF3. This effect is associated with the expression of nonstructural 2B/3 protein (NS2B/3) protease in human cells. Using interaction assays, we found that NS2B/3 interacts with the cellular IκB kinase ε (IKKε). Docking computational analysis revealed that in this interaction, NS2B/3 masks the kinase domain of IKKε and potentially affects its functionality. This observation is supported by the DENV-associated inhibition of the kinase activity of IKKε. Our data identify IKKε as a novel target of DENV NS2B/3 protease.
Use of Antigen-Specific Interleukin-2 To Differentiate between Cattle Vaccinated with Mycobacterium bovis BCG and Cattle Infected with M. bovis
Authors: Rhodes Shelley G. , McKinna Lucy C. , Steinbach Sabine , Dean Gilly S. , Villarreal-Ramos Bernardo , Whelan Adam O. , Pirson C. , Jones Gareth J. , Clifford Derek , Vordermeier H. Martin 
Published: October 2013

ABSTRACTWe describe here the application of a novel bovine interleukin-2 (IL-2) enzyme-linked immunosorbent assay (ELISA) for the measurement of antigen-specific IL-2 in cattle naturally infected withMycobacterium bovisand in cattle vaccinated withMycobacterium bovisBCG and then experimentally challenged with pathogenicM. bovis. Supernatants from whole-blood cultures stimulated with mycobacterial antigen (bovine purified protein derivative [PPDB] or the peptide cocktail ESAT6-CFP10) were assessed using a sandwich ELISA consisting of a new recombinant monoclonal fragment capture antibody and a commercially available polyclonal anti-bovine-IL-2. The production of IL-2 was compared to the production of gamma interferon (IFN-γ) in the same antigen-stimulated whole-blood supernatants. The data show that cattle infected withM. bovisproduced quantifiable levels of antigen-specific IL-2, while IL-2 levels in cattle vaccinated withM. bovisBCG did not. Furthermore, cattle vaccinated withM. bovisBCG and then challenged with pathogenicM. bovisdisplayed a more rapid induction of IL-2 but ultimately had lower levels of infection-induced IL-2 than did unvaccinated challenge control cattle. These data suggest that IL-2 responses are not detectable post-BCG vaccination and that these responses may require infection with virulentM. bovisto develop. This may be useful to differentiate infected cattle from uninfected or BCG-vaccinated cattle, although the overall sensitivity is relatively low, particularly in single intradermal comparative cervical tuberculin (SICCT)-negative infected animals. Furthermore, the strength of the IL-2 response may correlate with pathology, which poses interesting questions on the immunobiology of bovine tuberculosis in contrast to human tuberculosis, which is discussed.
Toxin-Producing Clostridium difficile Strains as Long-Term Gut Colonizers in Healthy Infants
Authors: Adlerberth Ingegerd , Huang Haihui , Lindberg Erika , Åberg Nils , Hesselmar Bill , Saalman Robert , Nord Carl Erik , Wold Agnes E. , Weintraub Andrej 
Published: October 2013

ABSTRACT

Clostridium difficile
is a colonizer of the human gut, and toxin-producing strains may cause diarrhea if the infectious burden is heavy. Infants are more frequently colonized than adults, but they rarely develop
C. difficile
disease. It is not known whether strains of
C. difficile
differ in the capacity to colonize and persist in the human gut microbiota. Here, we strain typed isolates of
C. difficile
that had colonized 42 healthy infants followed from birth to ≥12 months of age by using PCR ribotyping of the 16S-23S rRNA intergenic spacer region. The isolates were also characterized regarding carriage of the toxin genes
tcdA
,
tcdB
, and
cdtA/B
and the capacity to produce toxin B
in vitro
. Most strains (71%) were toxin producers, and 51% belonged to the 001 or 014 ribotypes, which often cause disease in adults. These ribotypes were significantly more likely than others to persist for ≥6 months in the infant micobiota, and they were isolated from 13/15 children carrying such long-term-colonizing strains. Ribotype 001 strains were often acquired in the first week of life and attained higher population counts than other
C. difficile
ribotypes in newborn infants' feces. Several toxin-negative ribotypes were identified, two of which (GI and GIII) were long-term colonizers, each found in one infant. Our results suggest that the toxin-producing
C. difficile
ribotypes 001 and 014 have special fitness in the infantile gut microbiota. Toxin-producing strains colonizing young children for long time periods may represent a reservoir for strains causing disease in adults.
Comparison of the Bruker Biotyper and Vitek MS Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Systems for Identification of Mycobacteria Using Simplified Protein Extraction Protocols
Authors: Mather Cheryl A. , Rivera Sheila F. , Butler-Wu Susan M. 
Published: October 2013

ABSTRACT

Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) has recently been described as a fast and inexpensive method for the identification of mycobacteria. Although mycobacteria require extraction prior to MALDI-TOF MS analysis, previously published protocols have been relatively complex, involving significant hands-on time and materials not often found in the clinical laboratory. In this study, we tested two simplified protein extraction protocols developed at the University of Washington (UW) and by bioMérieux (BMX) for use with two different mass spectrometry platforms (the Bruker MALDI Biotyper and the bioMérieux Vitek MS, respectively). Both extraction protocols included vortexing with silica beads in the presence of ethanol. The commercial Bruker database was also augmented with an in-house database composed of 123 clinical
Mycobacterium
strains. A total of 198 clinical strains, representing 18
Mycobacterium
species, were correctly identified to the species level 94.9% of the time when extracted using the UW protocol and compared to the augmented database. The BMX protocol and Vitek MS system resulted in correct species-level identifications for 94.4% of these strains. In contrast, only 79.3% of the strains were identified to the species level by the nonaugmented Bruker database, although the use of a lower identification score threshold (≥1.7) increased the identification rate to 93.9%, with two misidentifications that were unlikely to be clinically relevant. The two simplified protein extraction protocols described in this study are easy to use for identifying commonly encountered
Mycobacterium
species.
First Report of Brain Abscess Caused by a Satelliting Phenotypic Variant of Helcococcus kunzii
Authors: Sridhar Siddharth , Chan Jasper F. W. , Yuen Kwok-Yung 
Published: October 2013

ABSTRACT

Helcococcus kunzii
was isolated from a brain abscess in a diabetic patient with cholesteatoma and demonstrated satellitism around
Staphylococcus aureus
in culture. This is the first reported case of severe central nervous system infection due to
H. kunzii
and the first description of a satelliting phenotypic variant of this organism.
Genotypic and Epidemiologic Trends of Norovirus Outbreaks in the United States, 2009 to 2013
Authors: Vega Everardo , Barclay Leslie , Gregoricus Nicole , Shirley S. Hannah , Lee David , Vinjé Jan 
Published: October 2013

ABSTRACT

Noroviruses are the leading cause of epidemic acute gastroenteritis in the United States. From September 2009 through August 2013, 3,960 norovirus outbreaks were reported to CaliciNet. Of the 2,895 outbreaks with a known transmission route, person-to-person and food-borne transmissions were reported for 2,425 (83.7%) and 465 (16.1%) of the outbreaks, respectively. A total of 2,475 outbreaks (62.5%) occurred in long-term care facilities (LTCF), 389 (9.8%) in restaurants, and 227 (5.7%) in schools. A total of 435 outbreaks (11%) were typed as genogroup I (GI) and 3,525 (89%) as GII noroviruses. GII.4 viruses caused 2,853 (72%) of all outbreaks, of which 94% typed as either GII.4 New Orleans or GII.4 Sydney. In addition, three non-GII.4 viruses, i.e., GII.12, GII.1, and GI.6, caused 528 (13%) of all outbreaks. Several non-GII.4 genotypes (GI.3, GI.6, GI.7, GII.3, GII.6, and GII.12) were significantly more associated with food-borne transmission (odds ratio, 1.9 to 7.1;
P
< 0.05). Patients in LTCF and people ≥65 years of age were at higher risk for GII.4 infections than those in other settings and with other genotypes (
P
< 0.05). Phylogeographic analysis identified three major dispersions from two geographic locations that were responsible for the GI.6 outbreaks from 2011 to 2013. In conclusion, our data demonstrate the cyclic emergence of new (non-GII.4) norovirus strains, and several genotypes are more often associated with food-borne outbreaks. These surveillance data can be used to improve viral food-borne surveillance and to help guide studies to develop and evaluate targeted prevention methods such as norovirus vaccines, antivirals, and environmental decontamination methods.
Seroprevalence of Human Malawi Polyomavirus
Authors: Nicol Jérôme T. J. , Leblond Valérie , Arnold Françoise , Guerra Giovanni , Mazzoni Elisa , Tognon Mauro , Coursaget Pierre , Touzé Antoine 
Published: October 2013

ABSTRACT
The seroprevalence of the recently discovered human Malawi polyomavirus (MWPyV) was determined by virus-like particle-based enzyme-linked immunosorbent assay (ELISA) in age-stratified Italian subjects. The findings indicated that MWPyV infection occurs early in life, and seroprevalence was shown to reach 42% in adulthood.
Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues
Authors: Sun Yingjie , Yu Shengqing , Ding Na , Meng Chunchun , Meng Songshu , Zhang Shilei , Zhan Yuan , Qiu Xusheng , Tan Lei , Chen Hongjun , Song Cuiping , Ding Chan 
Published: October 2013

ABSTRACT

Newcastle disease virus (NDV) is an important avian pathogen. We previously reported that NDV triggers autophagy in U251 glioma cells, resulting in enhanced virus replication. In this study, we investigated whether NDV triggers autophagy in chicken cells and tissues to enhance virus replication. We demonstrated that NDV infection induced steady-state autophagy in chicken-derived DF-1 cells and in primary chicken embryo fibroblast (CEF) cells, evident through increased double- or single-membrane vesicles, the accumulation of green fluorescent protein (GFP)-LC3 dots, and the conversion of LC3-I to LC3-II. In addition, we measured autophagic flux by monitoring p62/SQSTM1 degradation, LC3-II turnover, and GFP-LC3 lysosomal delivery and proteolysis, to confirm that NDV infection induced the complete autophagic process. Inhibition of autophagy by pharmacological inhibitors and RNA interference reduced virus replication, indicating an important role for autophagy in NDV infection. Furthermore, we conducted
in vivo
experiments and observed the conversion of LC3-I to LC3-II in heart, liver, spleen, lung, and kidney of NDV-infected chickens. Regulation of the induction of autophagy with wortmannin, chloroquine, or starvation treatment affects NDV production and pathogenesis in tissues of both lung and intestine; however, treatment with rapamycin, an autophagy inducer of mammalian cells, showed no detectable changes in chicken cells and tissues. Moreover, administration of the autophagy inhibitor wortmannin increased the survival rate of NDV-infected chickens. Our studies provide strong evidence that NDV infection induces autophagy which benefits NDV replication in chicken cells and tissues.
Hepatocyte Nuclear Factor 4α and Downstream Secreted Phospholipase A
2
GXIIB Regulate Production of Infectious Hepatitis C Virus
Authors: Li Xinlei , Jiang Hanfang , Qu Linbing , Yao Wenxia , Cai Hua , Chen Ling , Peng Tao 
Published: October 2013

ABSTRACT

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans. The life cycle of HCV is closely associated with the metabolism of lipids, especially very-low-density lipoprotein (VLDL) in hepatocytes. Hepatocyte nuclear factor 4α (HNF4α), the most abundant transcription factor in the liver, regulates the VLDL secretory pathway. However, the effects of HNF4α on the HCV life cycle are unclear. In this study, we investigated the regulatory effects of HNF4α on HCV assembly and secretion. HCV in HNF4α-deficient hepatocytes showed reduced assembly and secretion but unchanged entry and RNA replication. Bezafibrate, a chemical inhibitor of HNF4α, suppressed HCV assembly and secretion. HNF4α downregulation resulted in rearrangement of cytosolic lipid droplets (LDs), as evidenced by the aggregation of large LDs and distorted cytosolic distribution. Phospholipase A
2
GXIIB (PLA
2
GXIIB), an HNF4α-regulated factor involved in VLDL secretion, was found to be crucial in HCV secretion. PLA
2
GXIIB expression was upregulated in hepatocytes harboring HCV subgenomic replicons or in HCV-infected hepatocytes. This upregulation was transcriptionally controlled in an HNF4α-dependent manner after HCV infection. Furthermore, PLA
2
GXIIB combined with microsomal triglyceride transfer protein was found to be responsible for the regulation of HNF4α-induced HCV infectivity. These results suggest that HNF4α and its downstream PLA
2
GXIIB are important factors affecting the late stage of the HCV life cycle and may serve as potential drug targets for the treatment of HCV infection.
B Lymphocytes from Patients with a Hypomorphic Mutation inSTAT3Resist Epstein-Barr Virus-Driven Cell Proliferation
Authors: Koganti Siva , de la Paz Amanda , Freeman Alexandra F. , Bhaduri-McIntosh Sumita 
Published: October 2013

ABSTRACTEpstein-Barr virus (EBV) oncogenes exert potent B cell proliferative effects. EBV infection gives rise to B cell lines that readily proliferate in culture. This ability of EBV represents a powerful tool to study cell proliferation. In efforts to delineate the contribution of signal transducer and activator of transcription 3 (STAT3) toward EBV-driven cell proliferation, we have discovered that B cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES) resist such EBV oncogene-driven outgrowth of cells. Patients with AD-HIES have a dominant negative mutation in theirSTAT3gene which renders most of the protein nonfunctional. Exposure of healthy subject-derived B cells to EBV resulted in early activation of STAT3, rapidly followed by increased expression of its mRNA and protein. STAT3 upregulation preceded the expression of EBNA2, temporally one of the first viral oncogenes to be expressed. We found that STAT3 was necessary for subsequent survival and for proliferation of EBV-infected cells past the S phase of the cell cycle. Consequently, B cells from AD-HIES patients were prone to dying and accumulated in the S phase, thereby accounting for impaired cell outgrowth. Of importance, we have now identified a cohort of patients with a primary immunodeficiency disorder whose B cells oppose EBV-driven proliferative signals. These findings simultaneously reveal how EBV manipulates host STAT3 even before expression of viral oncogenes to facilitate cell survival and proliferation, processes fundamental to EBV lymphomagenesis.
Exposure to Mimivirus Collagen Promotes Arthritis
Authors: Shah Nikunj , Hülsmeier Andreas J. , Hochhold Nina , Neidhart Michel , Gay Steffen , Hennet Thierry 
Published: October 2013

ABSTRACT

Collagens, the most abundant proteins in animals, also occur in some recently described nucleocytoplasmic large DNA viruses such as
Mimiviridae
, which replicate in amoebae. To clarify the impact of viral collagens on the immune response of animals exposed to
Mimiviridae
, we have investigated the localization of collagens in
Acanthamoeba polyphaga
mimivirus particles and the response of mice to immunization with mimivirus particles. Using protein biotinylation, we have first shown that viral collagen encoded by open reading frame L71 is present at the surface of mimivirus particles. Exposure to mimivirus collagens elicited the production of anti-collagen antibodies in DBA/1 mice immunized intradermally with mimivirus protein extracts. This antibody response also targeted mouse collagen type II and was accompanied by T-cell reactivity to collagen and joint inflammation, as observed in collagen-induced arthritis following immunization of mice with bovine collagen type II. The broad distribution of nucleocytoplasmic large DNA viruses in the environment suggests that humans are constantly exposed to such large virus particles. A survey of blood sera from healthy human subjects and from rheumatoid arthritis patients indeed demonstrated that 30% of healthy-subject and 36% of rheumatoid arthritis sera recognized the major mimivirus capsid protein L425. Moreover, whereas 6% of healthy-subject sera recognized the mimivirus collagen protein L71, 22% of rheumatoid arthritis sera were positive for mimivirus L71. Accordingly, our study shows that environmental exposure to mimivirus represents a risk factor in triggering autoimmunity to collagens.
Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer
Authors: Proia David A. , Zhang Chaohua , Sequeira Manuel , Jimenez John-Paul , He Suqin , Spector Neil , Shapiro Geoffrey I. , Tolaney Sara , Nagai Masazumi , Acquaviva Jaime , Smith Donald L. , Sang Jim , Bates Richard C. , El-Hariry Iman 
Published: October 2013

AbstractPurpose: Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy.Experimental Design: The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment.Results: Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin–cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy.Conclusion: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC. Clin Cancer Res; 20(2); 413–24. ©2013 AACR.