bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trypanosoma cruzitrans-Sialidase Prevents Elicitation of Th1 Cell Response via Interleukin 10 and Downregulates Th1 Effector Cells
Authors: Ruiz Díaz Pablo , Mucci Juan , Meira María Ana , Bogliotti Yanina , Musikant Daniel , Leguizamón María Susana , Campetella Oscar 
Published: March 2015

ABSTRACTThetrans-sialidases (TSs) fromTrypanosoma cruzi, the agent of Chagas disease, are virulence factors shed to the bloodstream that induce strong alterations in the immune system. Here, we report that both enzymatically active TS (aTS) and its lectinlike isoform (iTS) disturb CD4 T cell physiology, inducing downregulation of Th1 cell functionality andin vivocell expansion. By using ovalbumin-specific DO11.10 cells as tracers of clones developing the Th1 phenotype, we found that the infection induced significant amounts of gamma interferon (IFN-γ) but low levels of interleukin 2 (IL-2) and increased IL-4 productionin vivo, in agreement with a mixed T helper response. The production of cytokines associated with the Th2 phenotype was prevented by passive transfer of anti-TS neutralizing antibodies. TSs also reduced the T cell receptor signaling as assayed by Zap-70 phosphorylation. TSs also reduced IL-2 and IFN-γ secretion, with a concomitant increase in IL-4 production and then an unbalancing of the CD4 T cell response toward the Th2 phenotype. This effect was prevented by using anti-IL-10 neutralizing antibodies or IL-10−/−antigen-presenting cells, supporting the subversion of this regulatory pathway. In support, TSs stimulated IL-10 secretion by antigen-presenting cells during their interaction with CD4 T cells. When polarized cells were stimulated in the presence of TSs, the secretion of IL-2 and IFN-γ was strongly downregulated in Th1 cells, while IL-2 production was upregulated in Th2 cells. Although the Th1 response is associated with host survival, it may simultaneously induce extensive damage to infected tissues. Thus, by delaying the elicitation of the Th1 response and limiting its effector properties, TSs restrain the cell response, supportingT. cruzicolonization and persistence while favoring host survival.
Superantigenic Yersinia pseudotuberculosis Induces the Expression of Granzymes and Perforin by CD4+T Cells
Authors: Goubard Agathe , Loïez Caroline , Abe Jun , Fichel Caroline , Herwegh Stéphanie , Faveeuw Christelle , Porte Rémi , Cayet Delphine , Sebbane Florent , Penet Sylvie , Foligné Benoit , Desreumaux Pierre , Saito Hirohisa , Sirard Jean-Claude , Simonet Michel , Carnoy Christophe 
Published: March 2015

ABSTRACTBacterial superantigens (SAgs) are immunostimulatory toxins that induce acute diseases mainly through the massive release of inflammatory cytokines.Yersinia pseudotuberculosisis the only Gram-negative bacterium known to produce a SAg (Y. pseudotuberculosis-derived mitogen [YPM]). This SAg binds major histocompatibility complex class II molecules on antigen-presenting cells and T cell receptors (TcR) bearing the variable region Vβ3, Vβ9, Vβ13.1, or Vβ13.2 (in humans) and Vβ7 or Vβ8 (in mice). We have previously shown that YPM exacerbates the virulence ofY. pseudotuberculosisin mice. With a view to understanding the mechanism of YPM's toxicity, we compared the immune response in BALB/c mice infected with a YPM-producingY. pseudotuberculosisor the corresponding isogenic, SAg-deficient mutant. Five days after infection, we observed strong CD4+Vβ7+T cell expansion and marked interleukin-4 (IL-4) production in mice inoculated with SAg-producingY. pseudotuberculosis. These phenomena were correlated with the activation ofypmgene transcription in liver and spleen. A transcriptomic analysis revealed that the presence of YPM also increased expression of granzyme and perforin genes in the host's liver and spleen. This expression was attributed to a CD4+T cell subset, rather than to natural killer T (NKT) cells that display a TcR with a Vβ region that is potentially recognized by YPM. Increased production of cytotoxic molecules was correlated with hepatotoxicity, as demonstrated by an increase in plasma alanine aminotransferase activity. Our results demonstrate that YPM activates a potentially hepatotoxic CD4+T cell population.
High-Throughput, Signature-Tagged Mutagenic Approach To Identify Novel Virulence Factors of Yersinia pestis CO92 in a Mouse Model of Infection
Authors: Ponnusamy Duraisamy , Fitts Eric C. , Sha Jian , Erova Tatiana E. , Kozlova Elena V. , Kirtley Michelle L. , Tiner Bethany L. , Andersson Jourdan A. , Chopra Ashok K. 
Published: March 2015

ABSTRACT

The identification of new virulence factors in
Yersinia pestis
and understanding their molecular mechanisms during an infection process are necessary in designing a better vaccine or to formulate an appropriate therapeutic intervention. By using a high-throughput, signature-tagged mutagenic approach, we created 5,088 mutants of
Y. pestis
strain CO92 and screened them in a mouse model of pneumonic plague at a dose equivalent to 5 50% lethal doses (LD
50
) of wild-type (WT) CO92. From this screen, we obtained 118 clones showing impairment in disseminating to the spleen, based on hybridization of input versus output DNA from mutant pools with 53 unique signature tags. In the subsequent screen, 20/118 mutants exhibited attenuation at 8 LD
50
when tested in a mouse model of bubonic plague, with infection by 10/20 of the aforementioned mutants resulting in 40% or higher survival rates at an infectious dose of 40 LD
50
. Upon sequencing, six of the attenuated mutants were found to carry interruptions in genes encoding hypothetical proteins or proteins with putative functions. Mutants with in-frame deletion mutations of two of the genes identified from the screen, namely,
rbsA
, which codes for a putative sugar transport system ATP-binding protein, and
vasK
, a component of the type VI secretion system, were also found to exhibit some attenuation at 11 or 12 LD
50
in a mouse model of pneumonic plague. Likewise, among the remaining 18 signature-tagged mutants, 9 were also attenuated (40 to 100%) at 12 LD
50
in a pneumonic plague mouse model. Previously, we found that deleting genes encoding Braun lipoprotein (Lpp) and acyltransferase (MsbB), the latter of which modifies lipopolysaccharide function, reduced the virulence of
Y. pestis
CO92 in mouse models of bubonic and pneumonic plague. Deletion of
rbsA
and
vasK
genes from either the Δ
lpp
single or the Δ
lpp
Δ
msbB
double mutant augmented the attenuation to provide 90 to 100% survivability to mice in a pneumonic plague model at 20 to 50 LD
50
. The mice infected with the Δ
lpp
Δ
msbB
Δ
rbsA
triple mutant at 50 LD
50
were 90% protected upon subsequent challenge with 12 LD
50
of WT CO92, suggesting that this mutant or others carrying combinational deletions of genes identified through our screen could potentially be further tested and developed into a live attenuated plague vaccine(s).
Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection
Authors: Hoang Truc , Agger Else Marie , Cassidy Joseph P. , Christensen Jan P. , Andersen Peter 
Published: March 2015

ABSTRACT

Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse of
Mycobacterium tuberculosis
, as well as increased pathology, in both
Mycobacterium bovis
BCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ
+
TNF-α
+
and IFN-γ
+
cells). PEM during
M. tuberculosis
infection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine against
M. tuberculosis
infection.
hfq
Plays Important Roles in Virulence and Stress Adaptation in Cronobacter sakazakii ATCC 29544
Authors: Kim Seongok , Hwang Hyelyeon , Kim Kwang-Pyo , Yoon Hyunjin , Kang Dong-Hyun , Ryu Sangryeol 
Published: March 2015

ABSTRACT

Cronobacter
spp. are opportunistic pathogens that cause neonatal meningitis and sepsis with high mortality in neonates. Despite the peril associated with
Cronobacter
infection, the mechanisms of pathogenesis are still being unraveled. Hfq, which is known as an RNA chaperone, participates in the interaction with bacterial small RNAs (sRNAs) to regulate posttranscriptionally the expression of various genes. Recent studies have demonstrated that Hfq contributes to the pathogenesis of numerous species of bacteria, and its roles are varied between bacterial species. Here, we tried to elucidate the role of Hfq in
C. sakazakii
virulence. In the absence of
hfq
,
C. sakazakii
was highly attenuated in dissemination
in vivo
, showed defects in invasion (3-fold) into animal cells and survival (10
3
-fold) within host cells, and exhibited low resistance to hydrogen peroxide (10
2
-fold). Remarkably, the loss of
hfq
led to hypermotility on soft agar, which is contrary to what has been observed in other pathogenic bacteria. The hyperflagellated bacteria were likely to be attributable to the increased transcription of genes associated with flagellar biosynthesis in a strain lacking
hfq
. Together, these data strongly suggest that
hfq
plays important roles in the virulence of
C. sakazakii
by participating in the regulation of multiple genes.
Cricket fast bowling workload patterns as risk factors for tendon, muscle, bone and joint injuries
Authors: Orchard John W , Blanch Peter , Paoloni Justin , Kountouris Alex , Sims Kevin , Orchard Jessica J , Brukner Peter 
Published: March 2015

ObjectiveTo assess workload-related risk factors for injuries to particular tissue types in cricket fast bowlers.Design235 fast bowlers who bowled in 14600 player innings over a period of 15 years were followed in a prospective cohort risk factor study to compare overs bowled in each match (including preceding workload patterns) and injury risk in the 3–4 weeks subsequent to the match. Injuries were categorised according to the affected tissue type as either: bone stress, tendon injuries, muscle strain or joint injuries. Workload risk factors were examined using binomial logistic regression multivariate analysis, with a forward stepwise procedure requiring a significance of <0.05.ResultsHigh acute match workload and high previous season workload were risk factors for tendon injuries, but high medium term (3-month workload) was protective. For bone stress injuries, high medium term workload and low career workload were risk factors. For joint injuries, high previous season and career workload were risk factors. There was little relationship between muscle injury and workload although high previous season workload was slightly protective.ConclusionsThe level of injury risk for some tissue types varies in response to preceding fast bowling workload, with tendon injuries most affected by workload patterns. Workload planning may need to be individualised, depending on individual susceptibility to various injury types. This study supports the theory that tendons are at lowest risk with consistent workloads and susceptible to injury with sudden upgrades in workload. Gradual upgrades are recommended, particularly at the start of a bowler's career to reduce the risk of bone stress injury.
Protocol for the PREHAB study—Pre-operative Rehabilitation for reduction of Hospitalization After coronary Bypass and valvular surgery: a randomised controlled trial
Authors: Stammers Andrew N , Kehler D Scott , Afilalo Jonathan , Avery Lorraine J , Bagshaw Sean M , Grocott Hilary P , Légaré Jean-Francois , Logsetty Sarvesh , Metge Colleen , Nguyen Thang , Rockwood Kenneth , Sareen Jitender , Sawatzky Jo-Ann , Tangri Navdeep , Giacomantonio Nicholas , Hassan Ansar , Duhamel Todd A , Arora Rakesh C 
Published: March 2015

IntroductionFrailty is a geriatric syndrome characterised by reductions in muscle mass, strength, endurance and activity level. The frailty syndrome, prevalent in 25–50% of patients undergoing cardiac surgery, is associated with increased rates of mortality and major morbidity as well as function decline postoperatively. This trial will compare a preoperative, interdisciplinary exercise and health promotion intervention to current standard of care (StanC) for elective coronary artery bypass and valvular surgery patients for the purpose of determining if the intervention improves 3-month and 12-month clinical outcomes among a population of frail patients waiting for elective cardiac surgery.Methods and analysisThis is a multicentre, randomised, open end point, controlled trial using assessor blinding and intent-to-treat analysis. Two-hundred and forty-four elective cardiac surgical patients will be recruited and randomised to receive either StanC or StanC plus an 8-week exercise and education intervention at a certified medical fitness facility. Patients will attend two weekly sessions and aerobic exercise will be prescribed at 40–60% of heart rate reserve. Data collection will occur at baseline, 1–2 weeks preoperatively, and at 3 and 12 months postoperatively. The primary outcome of the trial will be the proportion of patients requiring a hospital length of stay greater than 7 days.Potential impact of studyThe healthcare team is faced with an increasingly complex older adult patient population. As such, this trial aims to provide novel evidence supporting a health intervention to ensure that frail, older adult patients thrive after undergoing cardiac surgery.Ethics and disseminationTrial results will be published in peer-reviewed journals, and presented at national and international scientific meetings. The University of Manitoba Health Research Ethics Board has approved the study protocol V.1.3, dated 11 August 2014 (H2014:208).Trial registration numberThe trial has been registered on ClinicalTrials.gov, a registry and results database of privately and publicly funded clinical studies (NCT02219815).
Female perineal injuries in children and adolescents presenting to a paediatric emergency department
Authors: Roland Damian , Lewis Gareth , Rowlands Rachel , Davidson Emmanuel , Davies Ffion 
Published: March 2015

This retrospective case series determined documentation quality and likelihood of safeguarding issues in girls aged 0–15 years with perineal and genital injuries presenting to a paediatric emergency department (ED). During the period between 2002 and 2010, cases were identified and clinical information was recorded. Cases were cross-referenced against the hospital's safeguarding unit's records up to 2011. In total, 181 case notes were available for review with 76.2% of patients discharged home from the ED. Fewer than 50% of case notes contained clear anatomical description of the injuries. In 51 (28.2%) cases, child safeguarding issues were considered, with specific referrals made to safeguarding services in 20 of these (11.0%). Only one case involved subsequent child safeguarding proceedings. Clear documentation of injury patterns by medical staff was poor, but medical and nursing staff should not be anxious about dealing with this cohort of patients as they are no different from other incidental injuries needing diligent levels of child safeguarding awareness.
Lactate level, aetiology and mortality of adult patients in an emergency department: a cohort study
Authors: Pedersen Mathilde , Brandt Vibeke Schnack , Holler Jon Gitz , Lassen Annmarie Touborg 
Published: March 2015

BackgroundIncreased lactate is associated with high mortality among patients with suspected infection or trauma in the emergency department (ED), but the association with patients with other aetiologies is less well described. The aim of this study was to describe the relation between lactate, aetiology and 7-day mortality in adult ED patients.MethodsA retrospective cohort study of all adult patients who had a lactate measured within 4 h after arrival to the ED at Odense University Hospital between June 2012 and May 2013. The categorisation of suspected aetiology was based on discharge diagnoses.Results5360 patients were included; 51.7% were men, and the median age was 67 years (IQR 50–79). 77.2% had low lactate (0–1.9 mmol/L), 16.2% intermediate lactate (2–3.9 mmol/L), and 6.6% high lactate (≥4 mmol/L). 7-day mortality was 2.9% (95% CI 2.4% to 3.5%) for patients with low lactate, 7.8% (95% CI 6.1% to 9.8%) for patients with intermediate lactate, and 23.9% (95% CI 19.6% to 28.8%) for patients with high lactate. The association between lactate level and mortality varied across different diagnostic groups. Based on Area Under the Curve in receiver operating characteristic analysis, lactate level showed to be useful in patients with infection (0.78, 95% CI 0.73 to 0.84), trauma (0.78, 95% CI 0.65 to 0.92), cardiac diseases (0.83, 95% CI 0.75 to 0.91) and gastrointestinal diseases (0.83, 95% CI 0.68 to 0.98). Lactate level was not useful in neurological (0.58, 95% CI 0.50 to 0.67) and respiratory disease (0.64, 95% CI 0.55 to 0.74), and of uncertain value in the remaining diagnostic groups.ConclusionsAmong adult ED patients, the prognostic value of lactate varies between diagnostic groups.
Age and sex-dependent trends in pulmonary embolism testing and derivation of a clinical decision rule for young patients
Authors: Mongan John , Kline Jeffrey , Smith-Bindman Rebecca 
Published: March 2015

ImportanceDespite low prevalence of pulmonary embolism (PE) in young adults, they are frequently imaged for PE, which involves radiation exposure and substantial financial cost.ObjectiveDetermine the use and positive proportions for PE imaging by age, differences in clinical presentation of PE by age and the projected impact of an age-targeted decision rule.DesignAnalysis of two national population-based datasets: the 2009 Nationwide Emergency Department Sample, a 20% sample of US emergency departments (EDs) and the 2003–2006 Pulmonary Embolism Rule-out Criteria (PERC) dataset, a multisite cohort of ED patients with suspected PE from 12 US EDs.ResultsPrevalence of PE was 10 times lower in young patients (18–35 years) than in older patients (>65 years) (0.06% vs 0.60%, p<0.001), but young patients were imaged for PE almost as frequently as older patients (2.3% vs 3.2%). This resulted in a lower proportion of positive examinations in young adults than older adults (2.3% vs 17.4%, p<0.001 in women; 4.0% vs 21.4%, p<0.001 in men). Clinical predictors of PE varied by age. Tachycardia was a significant predictor of PE in older patients (OR: 1.2–1.9, p<0.001), but not young patients. Fever was a significant predictor only in young patients (OR: 1.4–7.2, p<0.01). A modification of the previously described PERC rule to include age-specific risk factors could reduce PE imaging by 51% in young patients, with a missed PE rate of 0.6% in those excluded from imaging.Conclusions and relevanceYoung patients are frequently imaged for PE and have lower positive imaging rates than older patients. After further validation, application of our proposed rule for excluding young patients from PE imaging could reduce imaging, increase the positive rate of imaging and result in a low rate of missed PE among those excluded from imaging.
FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer
Authors: Khozin Sean , Blumenthal Gideon M. , Zhang Lijun , Tang Shenghui , Brower Margaret , Fox Emily , Helms Whitney , Leong Ruby , Song Pengfei , Pan Yuzhuo , Liu Qi , Zhao Ping , Zhao Hong , Lu Donghao , Tang Zhe , Al Hakim Ali , Boyd Karen , Keegan Patricia , Justice Robert , Pazdur Richard 
Published: March 2015

Abstract
On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)–positive, metastatic non–small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36–52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit–risk analysis was considered favorable because of the clinically meaningful ORR and DOR. Clin Cancer Res; 21(11); 2436–9. ©2015 AACR.
A Protein Interaction between β-Catenin and Dnmt1 Regulates Wnt Signaling and DNA Methylation in Colorectal Cancer Cells
Authors: Song Jing , Du Zhanwen , Ravasz Mate , Dong Bohan , Wang Zhenghe , Ewing Rob M. 
Published: March 2015

Abstract
Aberrant activation of the Wnt signaling pathway is an important step in the initiation and progression of tumor development in diverse cancers. The central effector of canonical Wnt signaling, β-catenin (CTNNB1), is a multifunctional protein, and has been extensively studied with respect to its roles in cell–cell adhesion and in regulation of Wnt-driven transcription. Here, a novel mass spectrometry–based proteomics technique in colorectal cancer cells expressing stabilized β-catenin, was used to identify a protein–protein interaction between β-catenin and DNA methyltransferase I (Dnmt1) protein, the primary regulator of DNA methylation patterns in mammalian cells. Dnmt1 and β-catenin strongly colocalized in the nuclei of colorectal cancer cells, and the interaction is mediated by the central domain of the Dnmt1 protein. Dnmt1 protein abundance is dependent upon the levels of β-catenin, and is increased in cells expressing stabilized mutant β-catenin. Conversely, the Dnmt1 regulates the levels of nuclear β-catenin and β-catenin/TCF–driven transcription. In addition, lysine-specific demethylase 1 (LSD1/KDM1A), a regulator of DNMT1 stability, was identified as a component of the Dnmt1–β-catenin protein complex and perturbation of the Dnmt1–β-catenin interaction altered DNA methylation. In summary, a functional protein–protein interaction was identified between two critically important oncoproteins, in turn revealing a link between Wnt signaling and downstream nuclear functions mediated by Dnmt1.
Implications: Two critical oncoproteins, Dnmt1 and β-catenin, mutually regulate one each other's levels and activities in colorectal cancer cells. Mol Cancer Res; 13(6); 969–81. ©2015 AACR.