bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum paraoxonase 1 activity in dogs: preanalytical and analytical factors and correlation with C‐reactive protein and alpha‐2‐globulin
Authors: Rossi Gabriele , Giordano Alessia , Pezzia Francesca , Kjelgaard‐Hansen Mads , Paltrinieri Saverio 
Published: August 2013

BackgroundSerum activity of paraoxonase (PON1) decreases during inflammation in many species. Little information is available on paraoxon‐based tests and the possible role ofPON1 in dogs.ObjectivesThe objectives of the study were to validate an automated paraoxon‐based assay to measurePON1 activity in canine serum, to determine its stability under different storage conditions, to determine a reference interval (RI) in healthy dogs, and to assess whetherPON1 is of comparable diagnostic value as C‐reactive protein (CRP) and α2‐globulins.MethodsIntra‐assay and inter‐assay imprecision, linearity under dilution (LUD), interference, and storage artifacts were evaluated. APON1RIwas determined for healthy dogs, andPON1 activity, sensitivity, and specificity were compared withCRPand α2‐globulins.ResultsIntra‐ and inter‐assayCVs were below 1.6% and 7.8%, respectively. TheLUDtest fitted the linear model.PON1 activity measurements were increased after addition of hemolysates and lipids, and after storage for 12 hours at room temperature, 72 hours at 4°C, and 6 months at −20°C.PON1 activity andCRPor α2‐globulins did not correlate well.PON1 activity decreased significantly only in dogs with very highCRPconcentrations. In contrast toCRPand α2‐globulins,PON1 activity was not significantly different between dogs with and without inflammation.ConclusionsThe automated paraoxon‐based method to assess serum caninePON1 activity was accurate and precise, but it was influenced by hemolysis, lipemia, and standard storage conditions. In this study, contrarily toCRPand α2‐globulins,PON1 activity did not provide diagnostic value as a negative acute phase protein in dogs.
Livestock Origin for a Human Pandemic Clone of Community-Associated Methicillin-Resistant Staphylococcus aureus
Authors: Spoor Laura E. , McAdam Paul R. , Weinert Lucy A. , Rambaut Andrew , Hasman Henrik , Aarestrup Frank M. , Kearns Angela M. , Larsen Anders R. , Skov Robert L. , Fitzgerald J. Ross 
Published: August 2013

ABSTRACT

The importance of livestock as a source of bacterial pathogens with the potential for epidemic spread in human populations is unclear. In recent years, there has been a global increase in community-associated methicillin-resistant
Staphylococcus aureus
(CA-MRSA) infections of healthy humans, but an understanding of the different evolutionary origins of CA-MRSA clones and the basis for their recent expansion is lacking. Here, using a high-resolution phylogenetic approach, we report the discovery of two emergent clones of human epidemic CA-MRSA which resulted from independent livestock-to-human host jumps by the major bovine
S. aureus
complex, CC97. Of note, one of the new clones was isolated from human infections on four continents, demonstrating its global dissemination since the host jump occurred over 40 years ago. The emergence of both human
S. aureus
clones coincided with the independent acquisition of mobile genetic elements encoding antimicrobial resistance and human-specific mediators of immune evasion, consistent with an important role for these genetic events in the capacity to survive and transmit among human populations. In conclusion, we provide evidence that livestock represent a reservoir for the emergence of new human-pathogenic
S. aureus
clones with the capacity for pandemic spread. These findings have major public health implications highlighting the importance of surveillance for early identification of emergent clones and improved transmission control measures at the human-livestock interface.

IMPORTANCE
Animals are the major source of new pathogens affecting humans. However, the potential for pathogenic bacteria that originally were found in animals to switch hosts and become widely established in human populations is not clear. Here, we report the discovery of emergent clones of methicillin-resistant
Staphylococcus aureus
(MRSA) that originated in livestock and switched to humans, followed by host-adaptive evolution and epidemic spread in global human populations. Our findings demonstrate that livestock can act as a reservoir for the emergence of new human bacterial clones with potential for pandemic spread, highlighting the potential role of surveillance and biosecurity measures in the agricultural setting for preventing the emergence of new human pathogens.
Genomic Insights to Control the Emergence of Vancomycin-Resistant Enterococci
Authors: Howden Benjamin P. , Holt Kathryn E. , Lam Margaret M. C. , Seemann Torsten , Ballard Susan , Coombs Geoffrey W. , Tong Steven Y. C. , Grayson M. Lindsay , Johnson Paul D. R. , Stinear Timothy P. 
Published: August 2013

ABSTRACT

Nosocomial outbreaks of vancomycin-resistant
Enterococcus faecium
(VREfm) are thought to occur by transmission of VREfm between patients, predicting that infection control interventions will limit cross-transmission. Despite implementation of such strategies, the incidence of VREfm infections continues to rise. We aimed to use genomics to better understand the epidemiology of
E. faecium
within a large hospital and investigate the reasons for failure of infection control strategies. Whole-genome sequencing was performed on 61
E. faecium
(36 VREfm) isolates, predominately from blood cultures collected at a single hospital between 1998 and 2009, and on five
vanB
-positive anaerobic commensal bacteria isolated from human feces. Phylogenomic analysis and precise mapping of the
vanB
gene, which contains the Tn
1549
transposon, showed that at least 18 of the 36 VREfm isolates had acquired the transposon via independent insertion events, indicating
de novo
generation of VREfm rather than cross-transmission. Furthermore, Tn
1549
sequences found in 15 of the 36 VREfm isolates were the same as the Tn
1549
sequence from one of the gut anaerobes. National and international comparator
E. faecium
isolates were phylogenetically interspersed with isolates from our hospital, suggesting that our findings might be globally representative. These data demonstrate that VREfm generation within a patient is common, presumably occurring in the human bowel during antibiotic therapy, and help explain our inability to reduce VREfm infections. A recommendation from our findings is that infection control practices should include screening patients for specific hospital clones of vancomycin-susceptible
E. faecium
rather than just VREfm.

IMPORTANCE
Enterococcus faecium
is an increasingly important human pathogen causing predominantly antibiotic-resistant infections in hospitalized patients. Large amounts of health care funding are spent trying to control antibiotic-resistant bacteria in hospitals globally, yet in many institutions around the world, vancomycin-resistant
E. faecium
(VREfm) infections continue to rise. The new findings from this study help explain the failures of our current approaches to controlling
vanB
VREfm in health care institutions. Given the importance of this bacterium as a cause of hospital-acquired infections and the difficulties faced by infection control units in trying to prevent colonization in their institutions, the novel findings from this study provide evidence that a new approach to controlling VREfm in hospitals is required. In particular, more attention should be given to understanding the epidemiology of hospital-adapted vancomycin-susceptible
E. faecium
, and patients at higher risk for
de novo
generation of VREfm need to be identified and optimally managed.
CspA from Borrelia burgdorferi Inhibits the Terminal Complement Pathway
Authors: Hallström Teresia , Siegel Corinna , Mörgelin Matthias , Kraiczy Peter , Skerka Christine , Zipfel Peter F. 
Published: August 2013

ABSTRACT

In order to survive and persist in an immunocompetent human host,
Borrelia burgdorferi
controls the human immune attack and blocks the damaging effects of the activated complement system. These Gram-negative spirochetes use CspA (CRASP-1) and four additional immune evasion proteins to bind combinations of human plasma regulators, including factor H, factor H-like protein 1 (FHL-1), complement factor H-related protein 1 (CFHR1), CFHR2, CFHR5, and plasminogen. As many microbial immune evasion proteins have multiple functions, we hypothesized that CspA has additional roles in complement or immune control. Here, we identify CspA as a terminal complement inhibitor. Borrelial CspA binds the human terminal complement components C7 and C9 and blocks assembly and membrane insertion of the terminal complement complex (TCC). CspA inhibits TCC assembly at the level of C7, as revealed by hemolytic assays, and inhibits polymerization of C9. CspA, when ectopically expressed on the surface of serum-sensitive
Borrelia garinii
, blocks TCC assembly on the level of C7 and induces serum resistance in the transformed bacteria. This CspA-mediated serum resistance and terminal complement pathway inhibition allow
B. burgdorferi
to survive in the hostile environment of human plasma.

IMPORTANCE
The present study defines a new mechanism by which the pathogenic bacterium
Borrelia burgdorferi
controls the terminal complement pathway of the human host to survive in human serum. The borrelial CspA binds to terminal pathway proteins C7 and C9 and inhibits the terminal complement pathway at the step of C7 and thereby inhibits terminal complement complex (TCC) assembly and membrane insertion. CspA blocks TCC assembly and insertion when expressed at the bacterial surface. CspA is the first TCC inhibitor cloned and functionally characterized from a Gram-negative bacterium. This identification of a bacterial TCC inhibitor of pathogen origin expands our knowledge of complement evasion of pathogenic bacteria and shows that pathogenic bacteria target the terminal pathway of complement. Thus, CspA as a central microbial virulence factor can represent an interesting biomarker and a target to develop new therapeutics and vaccines against borreliae.
Adherence to a Mediterranean diet is associated with a better health-related quality of life: a possible role of high dietary antioxidant content
Authors: Bonaccio Marialaura , Di Castelnuovo Augusto , Bonanni Americo , Costanzo Simona , De Lucia Francesca , Pounis George , Zito Francesco , Donati Maria Benedetta , de Gaetano Giovanni , Iacoviello Licia 
Published: August 2013

ObjectivesMediterranean diet (MD) is associated with a reduced risk of major chronic disease. Health-related quality of life (HRQL) is a valid predictor of mortality. The aim of this study is to investigate the association between MD and HRQL and to examine the possible role of dietary antioxidants, fibre content and/or fatty acid components.DesignCross-sectional study on a sample of Italian participants enrolled in the Moli-sani Project, a population-based cohort study. Food intake was recorded by the Italian European prospective investigation into cancer and nutrition study food frequency questionnaire. Adherence to MD was appraised by a Greek Mediterranean diet score (MDS), an Italian Mediterranean diet index (IMI) and by principal component analysis (PCA). HRQL was assessed by the 36-Item Short Form Health Survey.SettingMolise region, Italy.Participants16 937 participants of 24 325 Italian citizens (age≥35).Main outcomesDietary patterns and HRQL.ResultsMentalhealth was associated consistently and positively with MDS, IMI and an ‘Olive oil and vegetable’ pattern (PCA1), but negatively with an ‘Eggs and sweets’ pattern (PCA3).Physicalhealth was associated positively with MDS and PCA1, but negatively with a ‘Meat and pasta’ pattern. Subjects with the highest MD adherence had 42% (MDS), 34% (IMI) or 59% (PCA1) statistically significant multivariable odds of being in the uppermost level of mental health, as compared with subjects in the lowest category. The associations disappeared after further adjustment for either total food antioxidant content or dietary fibre, while they were not modified by the inclusion of either monounsaturated or polyunsaturated fatty acids. Individuals in the highest PCA1 or PCA3 had significantly higher odds of being in the top level of physical health.ConclusionsAdherence to an MD pattern is associated with better HRQL. The association is stronger with mental health than with physical health. Dietary total antioxidant and fibre content independently explain this relationship.
Gleason Grade Progression Is Uncommon
Authors: Penney Kathryn L. , Stampfer Meir J. , Jahn Jaquelyn L. , Sinnott Jennifer A. , Flavin Richard , Rider Jennifer R. , Finn Stephen , Giovannucci Edward , Sesso Howard D. , Loda Massimo , Mucci Lorelei A. , Fiorentino Michelangelo 
Published: August 2013

Abstract
Gleason grade is universally used for pathologic scoring of the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate-specific antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high-grade tumors. We studied 1,207 Physicians' Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer from 1982 to 2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982–1/1993), 19.9% stage ≥T3, to the latest (5/2000–12/2004), 3% stage T3, none T4. The proportion of Gleason score ≥8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between grade and stage varies by time period. As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest that grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance. Cancer Res; 73(16); 5163–8. ©2013 AACR.
Novel Clinically Relevant Genes in Gastrointestinal Stromal Tumors Identified by Exome Sequencing
Authors: Schoppmann Sebastian F. , Vinatzer Ursula , Popitsch Niko , Mittlböck Martina , Liebmann-Reindl Sandra , Jomrich Gerd , Streubel Berthold , Birner Peter 
Published: August 2013

AbstractPurpose: Chromosomal gains and losses resulting in altered gene dosage are known to be recurrent in gastrointestinal stromal tumors (GIST). The aim of our study was the identification of clinical relevant genes in these candidate regions.Material and Methods: A cohort of 174 GIST was investigated using DNA array (n = 29), FISH (n = 125), exome sequencing (n = 13), and immunohistochemistry (n = 145).Results: Array analysis revealed recurrent copy number variations (CNVs) of chromosomal arms 1p, 1q, 3p, 4q, 5q, 7p, 11q, 12p, 13q, 14q, 15q, and 22q. FISH studies of these CNVs showed that relative loss of 1p was associated with shorter disease-free survival (DFS). Analysis of exome sequencing concentrating on target regions showing recurrent CNVs revealed a median number of 3,404 (range 1,641–13,602) variants (SNPs, insertions, deletions) in each tumor minus paired blood sample; variants in at least three samples were observed in 37 genes. After further analysis, target genes were reduced to 10 in addition to KIT and PDGFRA. Immunohistochemical investigation showed that expression of SYNE2 and DIAPH1 was associated with shorter DFS, expression of RAD54L2 with shorter and expression of KIT with longer overall survival.Conclusion: Using a novel approach combining DNA arrays, exome sequencing, and immunohistochemistry, we were able to identify 10 target genes in GIST, of which three showed hithero unknown clinical relevance. Because the identified target genes SYNE2, MAPK8IP2, and DIAPH1 have been shown to be involved in MAP kinase signaling, our data further indicate the important role of this pathway in GIST. Clin Cancer Res; 19(19); 5329–39. ©2013 AACR.
Pharmacologic Inhibition of Jak2–Stat5 Signaling By Jak2 Inhibitor AZD1480 Potently Suppresses Growth of Both Primary and Castrate-Resistant Prostate Cancer
Authors: Gu Lei , Liao Zhiyong , Hoang David T. , Dagvadorj Ayush , Gupta Shilpa , Blackmon Shauna , Ellsworth Elyse , Talati Pooja , Leiby Benjamin , Zinda Michael , Lallas Costas D. , Trabulsi Edouard J. , McCue Peter , Gomella Leonard , Huszar Dennis , Nevalainen Marja T. 
Published: August 2013

Abstract
Purpose: Progression of prostate cancer to the lethal castrate-resistant stage coincides with loss of responsiveness to androgen deprivation and requires development of novel therapies. We previously provided proof-of-concept that Stat5a/b is a therapeutic target protein for prostate cancer. Here, we show that pharmacologic targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks castrate-resistant growth of prostate cancer.
Experimental Design: Efficacy of AZD1480 in disrupting Jak2–Stat5a/b signaling and decreasing prostate cancer cell viability was evaluated in prostate cancer cells. A unique prostate cancer xenograft mouse model (CWR22Pc), which mimics prostate cancer clinical progression in patients, was used to assess in vivo responsiveness of primary and castrate-resistant prostate cancer (CRPC) to AZD1480. Patient-derived clinical prostate cancers, grown ex vivo in organ explant cultures, were tested for responsiveness to AZD1480.
Results: AZD1480 robustly inhibited Stat5a/b phosphorylation, dimerization, nuclear translocation, DNA binding, and transcriptional activity in prostate cancer cells. AZD1480 reduced prostate cancer cell viability sustained by Jak2–Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacologic targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent castrate-resistant CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice versus vehicle or docetaxel-treated mice. Finally, nine of 12 clinical prostate cancers responded to AZD1480 by extensive apoptotic epithelial cell loss, concurrent with reduced levels of nuclear Stat5a/b.
Conclusions: We report the first evidence for efficacy of pharmacologic targeting of Stat5a/b as a strategy to inhibit castrate-resistant growth of prostate cancer, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced prostate cancer. Clin Cancer Res; 19(20); 5658–74. ©2013 AACR.
Examination of Whole Blood DNA Methylation as a Potential Risk Marker for Gastric Cancer
Authors: Tahara Tomomitsu , Maegawa Shinji , Chung Woonbok , Garriga Judith , Jelinek Jaroslav , Estécio Marcos R.H. , Shibata Tomoyuki , Hirata Ichiro , Arisawa Tomiyasu , Issa Jean-Pierre J. 
Published: August 2013

Abstract
Whole blood DNA methylation analysis has been proposed to be a risk marker for cancer that can be used to target patients for preventive interventions. To test this, we examined whole blood DNA methylation of 16 CpG island promoters and LINE1 repetitive element in patients with gastric cancer and control subjects. Bisulfite pyrosequencing was used to quantify the methylation of 14 CpG island promoters (MINT25, RORA, GDNF, CDH1, RARAB2, ER, CDH13, MYOD1, SFRP1, P2RX7, SLC16A12, IGF2, DPYS, and N33) and LINE1 from 72 patients with gastric cancer, 67 control, and 52 healthy young individuals. Quantitative methylation-specific real-time PCR was also conducted for 3 CpG island promoters (MINT25, MYO3A, and SOX11). Among all sites tested, only a marginal increase in the methylation of the SFRP1 promoter was observed in the blood of patients with gastric cancer when compared with the control group (11.3 % vs 10.5%; age-adjusted P value: P = 0.009), and this association was also seen in a validation set of 91 patients with gastric cancer (11.5% vs 10.5%; age-adjusted P value: P = 0.001). The methylation of 9 sites (GDNF, CDH1, RARAB2, CDH13, MYOD1, SFRP1, SLC16A12, DPYS, N33, and LINE1) and their mean Z score was correlated with higher age (R = 0.41, P &lt; 0.0001) and marginally with telomere shortening (R = −0.18, P = 0.01) but not with gastric cancer risk (other than SFRP1 methylation). Variability in whole blood DNA methylation of cancer markers is primarily associated with aging, reflecting turnover of white blood cells, and has no direct link to gastric cancer predisposition. SFRP1 methylation in whole blood may be associated with gastric cancer risk. Cancer Prev Res; 6(10); 1093–100. ©2013 AACR.
Adoption of Transradial Percutaneous Coronary Intervention and Outcomes According to Center Radial Volume in the Veterans Affairs Healthcare System
Authors: Gutierrez Antonio , Tsai Thomas T. , Stanislawski Maggie A. , Vidovich Mladen , Bryson Christopher L. , Bhatt Deepak L. , Grunwald Gary K. , Rumsfeld John , Rao Sunil V. 
Published: August 2013

Background—
Studies examining the association between radial approach and post–percutaneous coronary intervention (PCI) bleeding and mortality have reached conflicting conclusions. There are no current data about the use and outcomes of transradial PCI (r-PCI) in the Veterans Affairs system.

Methods and Results—

Consecutive veterans (n=24 143 patients) undergoing PCI in the Veterans Affairs between 2007 and 2010 were examined. On the basis of propensity to undergo r-PCI, 3 cohorts matched with veterans undergoing transfemoral access were constructed among sites performing ≥1 r-PCI, ≥50 r-PCI (high volume), and <50 r-PCI (low volume). Cox proportional hazard models were used to determine the association between PCI access site, blood transfusion, and mortality. The prevalence of r-PCI increased over time (2007=2.1%; 2010=8.8%). Overall, there was no difference in procedure success between matched groups (r-PCI 97.3% versus transfemoral PCI 96.6%;
P
=0.182), or in the risk of postprocedure transfusion or mortality. Among matched patients treated at high r-PCI volume sites, radial access was associated with a decreased risk of post-PCI blood transfusion (hazard ratio, 0.4; 95% confidence interval, 0.3–0.7;
P
<0.001), and no significant difference in the risk of mortality (hazard ratio, 0.7; 95% confidence interval, 0.4–1.3;
P
=0.279).

Conclusions—
Within the Veterans Affairs, the use of r-PCI increased over time. r-PCI may be associated with a significant decreased risk of post-PCI blood transfusion among higher volume r-PCI sites. These data demonstrate that potential benefits of r-PCI in terms of reduced post-PCI blood transfusions may be more pronounced at sites that routinely use radial access.