bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pertussis Toxin Improves Immune Responses to a Combined Pneumococcal Antigen and Leads to Enhanced Protection against Streptococcus pneumoniae
Authors: Salcedo-Rivillas Carolina , Debrie Anne-Sophie , Miyaji Eliane Namie , Ferreira Jorge M. C. , Raw Isaías , Locht Camille , Ho Paulo L. , Mielcarek Nathalie , Oliveira Maria Leonor S. 
Published: May 2014

ABSTRACTPneumococcal surface protein A (PspA) is a candidate antigen for the composition of protein-based vaccines againstStreptococcus pneumoniae. While searching for efficient adjuvants for PspA-based vaccines, our group has described the potential of combining PspA with the whole-cell pertussis vaccine (wP). When given to mice through the nasal route, a formulation composed of PspA from clade 5 (PspA5) and wP (PspA5-wP) induced high levels of antibodies and protection against challenges with different pneumococcal strains. PspA5-wP also induced the secretion of interleukin 17 (IL-17) by splenocytes and the infiltration of leukocytes in the lungs after challenge. Here, we show that protection against a pneumococcal invasive challenge was completely abrogated in μMT−/−mice, which are deficient in the maturation of B cells, illustrating the importance of antibodies in the survival elicited by the PspA5-wP vaccine. Moreover, passive immunization showed that IgG purified from the sera of mice immunized with PspA5-wP conferred significant protection to naive mice, whereas the respective F(ab′)2did not. Additionally,in vivodepletion of complement abolished protection against the pneumococcal challenge. The combination of PspA5 with wild-type or mutantBordetella pertussisstrains or with purified components showed that the pertussis toxin (PT)-containing formulations induced the highest levels of antibodies and protection. This suggests that the adjuvant activity of wP in the PspA5 model is mediated at least in part by PT. The sera from mice immunized with such formulations displayed high IgG binding and induction of complement deposition on the pneumococcal surfacein vitro, which is consistent with thein vivoresults.
Mapping of Epitopes Recognized by Antibodies Induced by Immunization of Mice with PspA and PspC
Authors: Vadesilho Cintia F. M. , Ferreira Daniela M. , Gordon Stephen B. , Briles David E. , Moreno Adriana T. , Oliveira Maria Leonor S. , Ho Paulo L. , Miyaji Eliane N. 
Published: May 2014

ABSTRACTPneumococcal surface protein A (PspA) and pneumococcal surface protein C (PspC) are important candidates for an alternative vaccine against pneumococcal infections. Since these antigens show variability, the use of variants that do not afford broad protection may lead to the selection of vaccine escape bacteria. Epitopes capable of inducing antibodies with broad cross-reactivities should thus be the preferred antigens. In this work, experiments using peptide arrays show that most linear epitopes recognized by antibodies induced in mice against different PspAs were located at the initial 44 amino acids of the mature protein and that antibodies against these linear epitopes did not confer protection against a lethal challenge. Conversely, linear epitopes recognized by antibodies to PspC included the consensus sequences involved in the interaction with human factor H and secretory immunoglobulin A (sIgA). Since linear epitopes of PspA were not protective, larger overlapping fragments containing 100 amino acids of PspA of strain Rx1 were constructed (fragments 1 to 7, numbered from the N terminus) to permit the mapping of antibodies with conformational epitopes not represented in the peptide arrays. Antibodies from mice immunized with fragments 1, 2, 4, and 5 were capable of binding onto the surface of pneumococci and mediating protection against a lethal challenge. The fact that immunization of mice with 100-amino-acid fragments located at the more conserved N-terminal region of PspA (fragments 1 and 2) induced protection against a pneumococcal challenge indicates that the induction of antibodies against conformational epitopes present at this region may be important in strategies for inducing broad protection against pneumococci.
Prospective Cross-Sectional Evaluation of the Small Membrane Filtration Method for Diagnosis of Pulmonary Tuberculosis
Authors: Jones-López Edward , Manabe Yukari C. , Palaci Moises , Kayiza Carol , Armstrong Derek , Nakiyingi Lydia , Ssengooba Willy , Gaeddert Mary , Kubiak Rachel , Almeida Júnior Pedro , Alland David , Dietze Reynaldo , Joloba Moses , Ellner Jerrold J. , Dorman Susan E. 
Published: May 2014

ABSTRACT

Smear microscopy has suboptimal sensitivity, and there is a need to improve its performance since it is commonly used to diagnose tuberculosis (TB). We prospectively evaluated the diagnostic accuracy of the
s
mall
m
embrane
f
iltration (SMF) method, an approach that uses a vacuum manifold and is designed to concentrate bacilli onto a filter that can be examined microscopically. We enrolled hospitalized adults suspected to have pulmonary TB in Kampala, Uganda. We obtained a clinical history and three spontaneously expectorated sputum specimens for smear microscopy (direct, concentrated, and SMF), MGIT (mycobacterial growth indicator tube) 960 and Lowenstein-Jensen (LJ) cultures, and Xpert MTB/RIF testing. We performed per-specimen (primary) and per-patient analyses. From October 2012 to June 2013, we enrolled 212 patients (579 sputum specimens). The participants were mostly female (63.2%), and 81.6% were HIV infected; their median CD4 cell count was 47 cells/μl. Overall, 19.0%, 20.4%, 27.1%, 25.2%, and 25.9% of specimens tested positive by direct smear, concentrated smear, MGIT culture, LJ culture, and Xpert test, respectively. In the per-specimen analysis, the sensitivity of the SMF method (48.5%; 95% confidence interval [CI], 37.4 to 59.6) was lower than those of direct smear (60.9%; 51.4 to 70.5 [
P
= 0.0001]) and concentrated smear (63.3%; 53.6 to 73.1 [
P
< 0.0001]). Subgroup analyses showed that SMF performed poorly in specimens having a low volume or low bacterial load. The SMF method performed poorly compared to standard smear techniques and was sensitive to sample preparation techniques. The optimal laboratory SMF protocol may require striking a fine balance between sample dilution and filtration failure rate.
African Green Monkeys Recapitulate the Clinical Experience with Replication of Live Attenuated Pandemic Influenza Virus Vaccine Candidates
Authors: Matsuoka Yumiko , Suguitan Amorsolo , Orandle Marlene , Paskel Myeisha , Boonnak Kobporn , Gardner Donald J. , Feldmann Friederike , Feldmann Heinz , Marino Michael , Jin Hong , Kemble George , Subbarao Kanta 
Published: May 2014

ABSTRACT

Live attenuated cold-adapted (
ca
) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (
wt
) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication of
wt
and
ca
viruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the
wt
viruses replicated efficiently, while replication of the
ca
vaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2
ca
vaccines. Protection from
wt
virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication of
ca
vaccine candidates.

IMPORTANCE
Ferrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we observed significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a nonhuman primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza virus vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans and that AGMs can be useful for evaluation of the protective efficacy of pLAIV.
Herpes Simplex Virus 1 Protein Kinase US3 Hyperphosphorylates p65/RelA and Dampens NF-κB Activation
Authors: Wang Kezhen , Ni Liwen , Wang Shuai , Zheng Chunfu 
Published: May 2014

ABSTRACT
Nuclear factor κB (NF-κB) plays important roles in innate immune responses by regulating the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation, and survival. To survive in the host cells, viruses have evolved multiple strategies to evade and subvert the host immune response. Herpes simplex virus 1 (HSV-1) bears a large DNA genome, with the capacity to encode many different viral proteins to counteract the host immune responses. In the present study, we demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-κB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 was also shown to hyperphosphorylate p65 at serine 75 and block its nuclear translocation. Two US3 mutants, K220M and D305A, still interacted with p65; however, they could not hyperphosphorylate p65, indicating that the kinase activity of US3 was indispensable for the function. The attenuation of NF-κB activation by HSV-1 US3 protein kinase may represent a critical adaptation to enable virus persistence within the host.

IMPORTANCE
This study demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-κB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 hyperphosphorylated p65 at serine 75 to inhibit NF-κB activation. The kinase activity of US3 was indispensable for its hyperphosphorylation of p65 and abrogation of the nuclear translocation of p65. The present study elaborated a novel mechanism of HSV-1 US3 to evade the host innate immunity.
Within-Host Evolution of Pseudomonas aeruginosa Reveals Adaptation toward Iron Acquisition from Hemoglobin
Authors: Marvig Rasmus Lykke , Damkiær Søren , Khademi S. M. Hossein , Markussen Trine M. , Molin Søren , Jelsbak Lars 
Published: May 2014

ABSTRACT

Pseudomonas aeruginosa
airway infections are a major cause of mortality and morbidity of cystic fibrosis (CF) patients. In order to persist,
P. aeruginosa
depends on acquiring iron from its host, and multiple different iron acquisition systems may be active during infection. This includes the pyoverdine siderophore and the
Pseudomonas
heme utilization (
phu
) system. While the regulation and mechanisms of several iron-scavenging systems are well described, it is not clear whether such systems are targets for selection during adaptation of
P. aeruginosa
to the host environment. Here we investigated the within-host evolution of the transmissible
P. aeruginosa
DK2 lineage. We found positive selection for promoter mutations leading to increased expression of the
phu
system. By mimicking conditions of the CF airways
in vitro
, we experimentally demonstrate that increased expression of
phuR
confers a growth advantage in the presence of hemoglobin, thus suggesting that
P. aeruginosa
evolves toward iron acquisition from hemoglobin. To rule out that this adaptive trait is specific to the DK2 lineage, we inspected the genomes of additional
P. aeruginosa
lineages isolated from CF airways and found similar adaptive evolution in two distinct lineages (DK1 and PA clone C). Furthermore, in all three lineages,
phuR
promoter mutations coincided with the loss of pyoverdine production, suggesting that within-host adaptation toward heme utilization is triggered by the loss of pyoverdine production. Targeting heme utilization might therefore be a promising strategy for the treatment of
P. aeruginosa
infections in CF patients.

IMPORTANCE
Most bacterial pathogens depend on scavenging iron within their hosts, which makes the battle for iron between pathogens and hosts a hallmark of infection. Accordingly, the ability of the opportunistic pathogen
Pseudomonas aeruginosa
to cause chronic infections in cystic fibrosis (CF) patients also depends on iron-scavenging systems. While the regulation and mechanisms of several such iron-scavenging systems have been well described, not much is known about how the within-host selection pressures act on the pathogens’ ability to acquire iron. Here, we investigated the within-host evolution of
P. aeruginosa
, and we found evidence that
P. aeruginosa
during long-term infections evolves toward iron acquisition from hemoglobin. This adaptive strategy might be due to a selective loss of other iron-scavenging mechanisms and/or an increase in the availability of hemoglobin at the site of infection. This information is relevant to the design of novel CF therapeutics and the development of models of chronic CF infections.
Simulation-based training improves ITU staff knowledge in the management of head injuries.
Authors: Smith Matthew , jankowski stefan 
Published: May 2014

AbstractTraumatic brain injury (TBI) in the polytrauma situation is a phenomenon often seen at UK hospitals. Without immediate access to dedicated neurocritical care facilities, the potential for under-treatment of the underlying brain injury and serious neurological sequalae is high, especially if staff on the general intensive care units on which these patients are treated lack confidence in this area of practice, a reality confirmed by our baseline study.We found that by engaging staff by implementing a regular simulation-based team training programme, we were able to boost the skills, knowledge, and ultimately confidence levels in treating TBI amongst these groups of staff. "Buy-in" by those concerned was high, and we found that self-reported scores for the attributes described above were improved considerably and consistently by our intervention. This quality improvement project has been rolled out through several iterations to become sustainable, has significant cost-saving potential, and will hopefully lead to proven improved clinical outcomes for this group of patients.
ANALYSIS OF MULTI-STAGE AND MULTI-RATE IIR SC DECIMATORS USING ISCMRATE
Authors: CHEONG NGAI 
Published: May 2014

This paper describes an analysis of multi-stage and multi-rate IIR switched capacitor (SC) decimators using an interactive switched capacitor multi-rate compiler (ISCMRATE). Motivated by the experimental observations, the purpose of this paper is to explore a portion of characteristics for the multi-stage IIR SC decimators, with their implications in the context of a complete IIR SC filter. To overcome the limitations of conventional multi-stage IIR SC decimators, a novel solution has been introduced for the implementation of a multi-stage IIR SC circuit. Based on the statistical approach of the compiler, we provide the comparative analysis for different IIR SC decimators, including total capacitor area, capacitance spread and arbitrary anti-aliasing amplitude responses with a decimating factor in single and multi-stage building blocks. Examples are given to illustrate the practical feasibility of this compiler.
Association ofHelicobacter pyloriInfection with Glycemic Control in Patients with Diabetes: A Meta-Analysis
Authors: Horikawa Chika , Kodama Satoru , Fujihara Kazuya , Yachi Yoko , Tanaka Shiro , Suzuki Akiko , Hanyu Osamu , Shimano Hitoshi , Sone Hirohito 
Published: May 2014

Objective. To assess the association betweenHelicobacter pylori(HP) infection and glycemic control in patients with diabetes through a meta-analytic approach.Research Design and Methods. Electronic literature searches were conducted for cross-sectional studies that examined the hemoglobin A1c (A1C) level by whether patients with diabetes were or were not carriers of HP. Mean differences in A1C between groups with and without HP infection were pooled with a random-effects model.Results. Thirteen eligible studies were included in this meta-analysis. Overall, the HP carriers did not have significantly higher A1C levels compared with HP noncarriers (mean difference (95% CI), 0.19% (−0.18 to 0.46),P = 0.16). When the analysis was limited to studies targeting patients with type 1 diabetes, there was also no significant difference in A1C (0.69% (−0.31 to 1.68),P = 0.18).Conclusions. There was insufficient evidence that HP infection worsened glycemic control in patients with diabetes.
Ly49 Family Receptors Are Required for Cancer Immunosurveillance Mediated by Natural Killer Cells
Authors: Tu Megan M. , Mahmoud Ahmad Bakur , Wight Andrew , Mottashed Amelia , Bélanger Simon , Rahim Mir Munir A. , Abou-Samra Elias , Makrigiannis Andrew P. 
Published: May 2014

AbstractAccording to the missing-self hypothesis, natural killer (NK) cells survey for target cells that lack MHC-I molecules. The Ly49 receptor family recognizes loss of MHC-I and is critical for educating NK cells, conferring the ability to eliminate transformed or infected cells. In this study, we evaluated their requirement in innate immune surveillance of cancer cells using genetically manipulated mice with attenuated expression of Ly49 receptors (NKCKD) in several models of carcinoma and metastasis. We found that NKCKD mice exhibited uncontrolled tumor growth and metastases. Expression of two MHC-I alleles, H-2Kb and H-2Db, was decreased in tumors from NKCKD mice in support of the likelihood of NK-mediated tumor immunoediting. These tumor cells exhibited directed alterations to their cell surface expression in response to the genetically altered immune environment to evade host recognition. Immunoediting in NKCKD mice was restricted to MHC-I molecules, which are ligands for Ly49 receptors, while expression of Rae-1 and Mult1, ligands for another NK cell receptor, NKG2D, were unaffected. Restoring NK cell education in NKCKD mice with a transgene for the inhibitory self-MHC-I receptor Ly49I restored suppression of cancer onset and growth. Interestingly, immune surveillance mediated by activating Ly49 receptors remained intact in NKCKD mice, as demonstrated by the ability to stimulate the NKG2D receptor with tumor cells or splenocytes expressing Rae-1. Together, our results genetically establish the integral role of Ly49 in NK cell-mediated control of carcinogenesis through MHC-I–dependent missing-self recognition. Cancer Res; 74(14); 3684–94. ©2014 AACR.
Loss of Cdk2 and Cyclin A2 Impairs Cell Proliferation and Tumorigenesis
Authors: Gopinathan Lakshmi , Tan Shawn Lu Wen , Padmakumar V. C. , Coppola Vincenzo , Tessarollo Lino , Kaldis Philipp 
Published: May 2014

Abstract
Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2–deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogene-transformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy. Cancer Res; 74(14); 3870–9. ©2014 AACR.
Reducing Prostate Cancer Racial Disparity: Evidence for Aggressive Early Prostate Cancer PSA Testing of African American Men
Authors: Powell Isaac J. , Vigneau Fawn D. , Bock Cathryn H. , Ruterbusch Julie , Heilbrun Lance K. 
Published: May 2014

Abstract
Background: There is continuing controversy about prostate cancer testing and the recent American Urological Association guidelines. We hypothesize that the reduction and elimination of racial survival disparity among African American men (AAM; high-risk group) compared with European American men (EAM; intermediate-risk group) during the PSA testing era compared with the pre-PSA era strongly supports the use of PSA testing in AAM.
Methods: We used Surveillance, Epidemiology, and End Results (SEER) data to investigate relative survival disparities between AAM and EAM. To evaluate pre-PSA testing era, we selected malignant first primary prostate cancer in AAM and EAM, all stages, diagnosed during 1973–1994. To evaluate relative survival disparities in the current PSA testing era, we selected malignant first primary local, regional, and distant stage prostate cancers diagnosed during 1998–2005 to calculate 5-year relative survival rates.
Results: Age-adjusted 5-year relative survival of prostate cancer diagnosed during 1973–1994 in the national SEER data revealed significantly shorter survival for AAM compared with EAM (P &lt; 0.0001). The SEER-based survival analysis from 1995 to 2005 indicated no statistical difference in relative survival rates between AAM and EAM by year of diagnosis of local, regional, or distant stage prostate cancer.
Conclusion: We conclude that the elimination of prostate cancer racial disparity of local, regional, and metastatic prostate cancer relative survival in the current PSA testing era compared with pre-PSA era as an endpoint to test PSA efficacy as a marker for prostate cancer diagnosis is evidence for aggressive testing of AAM.
Impact: Evidence for screening AAM. Cancer Epidemiol Biomarkers Prev; 23(8); 1505–11. ©2014 AACR.