bluuebunny/crossref_metadata_2025_split huggingface dataset:
Helicobacter pylori Activates Calpain via Toll-Like Receptor 2 To Disrupt Adherens Junctions in Human Gastric Epithelial Cells
Authors: O'Connor Pamela M. , Lapointe Tamia K. , Jackson Shannon , Beck Paul L. , Jones Nicola L. , Buret Andre G. 
Published: August 2011

ABSTRACT

Helicobacter pylori
is a risk factor for the development of gastritis, gastroduodenal ulcers, and gastric adenocarcinoma.
H. pylori
-induced disruption of epithelial adherens junctions (AJs) is thought to promote the development of severe disease; however, the mechanisms whereby
H. pylori
alters AJ structure remain incompletely understood. The present study demonstrates that
H. pylori
infection in human patients is associated with elevated serum levels of an 80-kDa E-cadherin ectodomain, whose presence is independent of the presence of serum antibodies against CagA.
In vitro
, a heat-labile
H. pylori
surface component activates the host protease calpain in human gastric MKN45 cells independently of the virulence factors CagA and VacA.
H. pylori
-induced calpain activation results in cleavage of E-cadherin to produce a 100-kDa truncated form and induce relocalization of E-cadherin and β-catenin. Stimulation of MKN45 cells with the toll-like receptor 2 (TLR2) ligand P3C activated calpain and disrupted E-cadherin and β-catenin in a pattern similar to that induced by
H. pylori
. Inhibition of TLR2 prevented
H. pylori
-induced calpain activation and AJ disassembly. Together, these findings identify a novel pathway whereby
H. pylori
activates calpain via TLR2 to disrupt gastric epithelial AJ structure.
The LuxS-Dependent Quorum-Sensing System Regulates Early Biofilm Formation by Streptococcus pneumoniae Strain D39
Authors: Vidal Jorge E. , Ludewick Herbert P. , Kunkel Rebekah M. , Zähner Dorothea , Klugman Keith P. 
Published: August 2011

ABSTRACT

Streptococcus pneumoniae
is the leading cause of death in children worldwide and forms highly organized biofilms in the nasopharynx, lungs, and middle ear mucosa. The
luxS
-controlled quorum-sensing (QS) system has recently been implicated in virulence and persistence in the nasopharynx, but its role in biofilms has not been studied. Here we show that this QS system plays a major role in the control of
S. pneumoniae
biofilm formation. Our results demonstrate that the
luxS
gene is contained by invasive isolates and normal-flora strains in a region that contains genes involved in division and cell wall biosynthesis. The
luxS
gene was maximally transcribed, as a monocistronic message, in the early mid-log phase of growth, and this coincides with the appearance of early biofilms. Demonstrating the role of the LuxS system in regulating
S. pneumoniae
biofilms, at 24 h postinoculation, two different D39Δ
luxS
mutants produced ∼80% less biofilm biomass than wild-type (WT) strain D39 did. Complementation of these strains with
luxS
, either in a plasmid or integrated as a single copy in the genome, restored their biofilm level to that of the WT. Moreover, a soluble factor secreted by WT strain D39 or purified AI-2 restored the biofilm phenotype of D39Δ
luxS
. Our results also demonstrate that during the early mid-log phase of growth, LuxS regulates the transcript levels of
lytA
, which encodes an autolysin previously implicated in biofilms, and also the transcript levels of
ply
, which encodes the pneumococcal pneumolysin. In conclusion, the
luxS
-controlled QS system is a key regulator of early biofilm formation by
S. pneumoniae
strain D39.
Identification of an ATPase, MsmK, Which Energizes Multiple Carbohydrate ABC Transporters in Streptococcus pneumoniae
Authors: Marion Carolyn , Aten Andrew E. , Woodiga Shireen A. , King Samantha J. 
Published: August 2011

ABSTRACT

Streptococcus pneumoniae
is the leading cause of community-acquired pneumonia and results in over 1 million deaths each year worldwide. Asymptomatic colonization of the airway precedes disease, and acquisition of carbohydrates from the host environment is necessary for bacterial survival. We previously demonstrated that
S. pneumoniae
cleaves sialic acid from human glycoconjugates to be used as a carbohydrate source. The
satABC
genes are required for growth and import of sialic acid. The
satABC
genes are predicted to encode components of an ABC transporter but not the ATPases essential to energize transport. As this subunit is essential, an ATPase must be encoded elsewhere in the genome. We identified
msmK
as a candidate based on similarity to other known carbohydrate ATPases. Recombinant MsmK hydrolyzed ATP, revealing that MsmK is an ATPase. An
msmK
mutant was reduced in growth on and transport of sialic acid, demonstrating that MsmK is the ATPase energizing the sialic acid transporter. In addition to s
atABC
,
S. pneumoniae
contains five other loci that are predicted to encode CUT1 family carbohydrate ABC transporter components; each of these lacks a predicted ATPase. Data indicate that
msmK
is also required for growth on raffinose and maltotetraose, which are the substrates of two other characterized carbohydrate ABC transporters. Furthermore, an
msmK
mutant was reduced in airway colonization. Together, these data imply that
in vivo
, MsmK energizes multiple carbohydrate transporters in
S. pneumoniae
. This is the first demonstration of a shared ATPase in a pathogenic bacterium.
Host Cytosolic Phospholipase A
2
α Contributes to Group B Streptococcus Penetration of the Blood-Brain Barrier
Authors: Maruvada Ravi , Zhu Longkun , Pearce Donna , Sapirstein Adam , Kim Kwang Sik 
Published: August 2011

ABSTRACT

Group B
Streptococcus
(GBS) is the most common bacterium causing neonatal meningitis, and neonatal GBS meningitis continues to be an important cause of mortality and morbidity. Here we provide the first direct evidence that host cytosolic phospholipase A
2
α (cPLA
2
α) contributes to type III GBS invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier and penetration into the brain, the key step required for the development of GBS meningitis. This was shown by our demonstration that pharmacological inhibition and gene deletion of cPLA
2
α significantly decreased GBS invasion of the HBMEC monolayer and penetration into the brain. cPLA
2
α releases arachidonic acid from membrane phospholipids, and we showed that the contribution of cPLA
2
α to GBS invasion of HBMEC involved lipoxygenated metabolites of arachidonic acid, cysteinyl leukotrienes (LTs). In addition, type III GBS invasion of the HBMEC monolayer involves protein kinase Cα (PKCα), as shown by time-dependent PKCα activation in response to GBS as well as decreased GBS invasion in HBMEC expressing dominant-negative PKCα. PKCα activation in response to GBS, however, was abolished by inhibition of cPLA
2
α and cysteinyl LTs, suggesting that cPLA
2
α and cysteinyl LTs contribute to type III GBS invasion of the HBMEC monolayer via PKCα. These findings demonstrate that specific host factors involving cPLA
2
α and cysteinyl LTs contribute to type III GBS penetration of the blood-brain barrier and their contribution involves PKCα.
Course of Infection with the Emergent Pathogen Brucella microti in Immunocompromised Mice
Authors: Jiménez de Bagüés María P. , de Martino Alba , Quintana Juan F. , Alcaraz Ana , Pardo Julián 
Published: August 2011

ABSTRACT

A new
Brucella
species,
Brucella microti
, has been isolated from wild rodents and found to be pathogenic in mice. The biological relevance of this new mouse pathogen is clear, as it allows us to study
Brucella
infection in a species-specific model. The course of infection in wild-type (wt) and immunodeficient mice that lack B (Jh), T and B (SCID), or T, B, and NK (SCID.Beige) cells was analyzed over 3 weeks. wt mice completely cleared bacteria from the liver and spleen after that time. However, SCID mice showed a much higher bacterial load in the spleen and liver than wt and Jh mice after 1 week and maintained the same level during the next 2 weeks. All mice tested survived for the 3 weeks. In contrast, the bacterial levels in mice that lacked NK cell activity progressively increased and these mice succumbed to infection after 16 to 18 days. Histopathology analysis of infected mice showed extensive areas of necrotic tissue and thrombosis in liver after 1 week in all infected SCID.Beige mice but were not seen in either SCID or wt animals. These processes were dramatically increased after 21 days, corresponding with the death of SCID.Beige animals. Our results indicate that T and/or B cells are required for the control of infection with the mouse pathogen
Brucella microti
in liver and spleen but that NK cells are crucial for survival in the absence of B and T cells. In addition, they suggest that controlled granuloma formation is critical to clear this type of infection in wt mice.
Filifactor alocis Has Virulence Attributes That Can Enhance Its Persistence under Oxidative Stress Conditions and Mediate Invasion of Epithelial Cells by Porphyromonas gingivalis
Authors: Aruni A. Wilson , Roy Francis , Fletcher H. M. 
Published: August 2011

ABSTRACT

Filifactor alocis
, a Gram-positive anaerobic rod, is one of the most abundant bacteria identified in the periodontal pockets of periodontitis patients. There is a gap in our understanding of its pathogenicity and ability to interact with other periodontal pathogens. To evaluate the virulence potential of
F. alocis
and its ability to interact with
Porphyromonas gingivalis
W83, several clinical isolates of
F. alocis
were characterized.
F. alocis
showed nongingipain protease and sialidase activities.
In silico
analysis revealed the molecular relatedness of several virulence factors from
F. alocis
and
P. gingivalis
. In contrast to
P. gingivalis
,
F. alocis
was relatively resistant to oxidative stress and its growth was stimulated under those conditions. Biofilm formation was significantly increased in coculture. There was an increase in adherence and invasion of epithelial cells in coculture compared with
P. gingivalis
or
F. alocis
monocultures. In those epithelial cells, endocytic vesicle-mediated internalization was observed only during coculture. The
F. alocis
clinical isolate had an increased invasive capacity in coculture with
P. gingivalis
compared to the ATCC 35896 strain. In addition, there was variation in the proteomes of the clinical isolates compared to the ATCC 35896 strain. Hypothetical proteins and those known to be important virulence factors in other bacteria were identified. These results indicate that
F. alocis
has virulence properties that may enhance its ability to survive and persist in the periodontal pocket and may play an important role in infection-induced periodontal disease.
Targeting the Microtubular Network as a New Antimyeloma Strategy
Authors: Feng Rentian , Li Shirong , Lu Caisheng , Andreas Carrie , Stolz Donna B. , Mapara Markus Y. , Lentzsch Suzanne 
Published: August 2011

Abstract
We identified nocodazole as a potent antimyeloma drug from a drug screening library provided by the Multiple Myeloma Research Foundation. Nocodazole is a benzimidazole that was originally categorized as a broad-spectrum anthelmintic drug with antineoplastic properties. We found that nocodazole inhibited growth and induced apoptosis of primary and multiresistant multiple myeloma cells cultured alone and in the presence of bone marrow stromal cells. Nocodazole caused cell-cycle prophase and prometaphase arrest accompanied by microtubular network disarray. Signaling studies indicated that increased expression of Bim protein and reduced X-linked inhibitor of apoptosis protein and Mcl-1L levels were involved in nocodazole-induced apoptosis. Further investigation showed Bcl-2 phosphorylation as a critical mediator of cell death, triggered by the activation of c-jun-NH2 kinase (JNK) instead of p38 kinase or extracellular signal–regulated kinases. Treatment with JNK inhibitor decreased Bcl-2 phosphorylation and subsequently reduced nocodazole-induced cell death. Nocodazole combined with dexamethasone significantly inhibited myeloma tumor growth and prolonged survival in a human xenograft mouse model. Our studies show that nocodazole has potent antimyeloma activity and that targeting the microtubular network might be a promising new treatment approach for multiple myeloma. Mol Cancer Ther; 10(10); 1886–96. ©2011 AACR.
Macrophage-Dependent Cleavage of the Laminin Receptor α6β1 in Prostate Cancer
Authors: Sroka Isis C. , Sandoval Cynthia P. , Chopra Harsharon , Gard Jaime M. C. , Pawar Sangita C. , Cress Anne E. 
Published: August 2011

AbstractThe laminin-binding integrin α6β1 plays a major role in determining the aggressive phenotype of tumor cells during metastasis. Our previous work has shown that cleavage of the α6β1 integrin to produce the structural variant α6pβ1 on tumor cell surfaces is mediated by the serine protease urokinase plasminogen activator (uPA). Cleavage of α6β1 increases tumor cell motility, invasion, and prostate cancer metastasis, and blockage of uPA inhibits α6pβ1 production. In human tumors, uPA and uPAR are expressed in tumor cells and tumor-associated macrophages (TAM). TAMs localize to solid tumors and contribute to increased tumor growth and the metastatic phenotype. In this study, we utilized a coculture system of PC-3 prostate tumor cells and macrophages [12-O-tetradecanoylphorbol-13-acetate (TPA)-differentiated human leukemia HL-60 cells] to investigate the hypothesis that macrophages stimulate the production of the prometastatic variant α6pβ1 on human prostate cancer cells via the uPA/uPAR axis. Our results indicate that adherent macrophages cocultured with PC-3 cells increased PC-3 uPAR mRNA, uPAR cell surface protein expression and α6 integrin cleavage. The stimulation does not require macrophage/tumor cell contact because macrophage conditioned medium is sufficient for increased uPAR transcription and α6 cleavage–dependent PC-3 cell invasion. The increased cleavage was dependent on uPAR because production was blocked by silencing RNA–targeting uPAR. These results indicate that macrophages can stimulate uPA/uPAR production in tumor cells which results in α6 integrin cleavage. These data suggest that TAMs promote prometastatic integrin-dependent pericellular proteolysis. Mol Cancer Res; 9(10); 1319–28. ©2011 AACR.
Arteriogenic Therapy by Intramyocardial Sustained Delivery of a Novel Growth Factor Combination Prevents Chronic Heart Failure
Authors: Banquet Sébastien , Gomez Elodie , Nicol Lionel , Edwards-Lévy Florence , Henry Jean-Paul , Cao Renhai , Schapman Damien , Dautreaux Brigitte , Lallemand Francoise , Bauer Fabrice , Cao Yihai , Thuillez Christian , Mulder Paul , Richard Vincent , Brakenhielm Ebba 
Published: August 2011

Background—
Therapeutic angiogenesis is a promising approach for the treatment of cardiovascular diseases, including myocardial infarction and chronic heart failure. We aimed to improve proangiogenic therapies by identifying novel arteriogenic growth factor combinations, developing injectable delivery systems for spatiotemporally controlled growth factor release, and evaluating functional consequences of targeted intramyocardial growth factor delivery in chronic heart failure.

Methods and Results—
First, we observed that fibroblast growth factor and hepatocyte growth factor synergistically stimulate vascular cell migration and proliferation in vitro. Using 2 in vivo angiogenesis assays (n=5 mice per group), we found that the growth factor combination results in a more potent and durable angiogenic response than either growth factor used alone. Furthermore, we determined that the molecular mechanisms involve potentiation of Akt and mitogen-activated protein kinase signal transduction pathways, as well as upregulation of angiogenic growth factor receptors. Next, we developed crosslinked albumin-alginate microcapsules that sequentially release fibroblast growth factor-2 and hepatocyte growth factor. Finally, in a rat model of chronic heart failure induced by coronary ligation (n=14 to 15 rats per group), we found that intramyocardial slow release of fibroblast growth factor-2 with hepatocyte growth factor potently stimulates angiogenesis and arteriogenesis and prevents cardiac hypertrophy and fibrosis, as determined by immunohistochemistry, leading to improved cardiac perfusion after 3 months, as shown by magnetic resonance imaging. These multiple beneficial effects resulted in reduced adverse cardiac remodeling and improved left ventricular function, as revealed by echocardiography.

Conclusion—
Our data showing the selective advantage of using fibroblast growth factor-2 together with hepatocyte growth factor suggest that this growth factor combination may constitute an efficient novel treatment for chronic heart failure.
Aortic Valve Replacement in the Elderly
Authors: Ashikhmina Elena A. , Schaff Hartzell V. , Dearani Joseph A. , Sundt Thoralf M. , Suri Rakesh M. , Park Soon J. , Burkhart Harold M. , Li Zhuo , Daly Richard C. 
Published: August 2011

Background—
Few data exist on long-term outcomes of elderly patients after aortic valve replacement. We evaluated latest follow-up information for patients ≥70 years of age after aortic valve replacement.

Methods and Results—

Late overall survival of 2890 consecutive patients ≥70 years of age who underwent aortic valve replacement between January 1993 and December 2007 was reviewed retrospectively, analyzed, and stratified by preoperative and intraoperative variables. Observed 5-, 10-, and 15-year late postoperative survival was lower than generally expected (68%, 34%, and 8% versus 70%, 42%, and 20%, respectively;
P
<0.001). Independent predictors of late death included older age, renal failure, diabetes mellitus, stroke, myocardial infarction, immunosuppression, prior coronary artery bypass grafting, implanted pacemaker, lower ejection fraction, hypertension, and New York Heart Association class III or IV. After stratification by age–comorbidity risk score, 10-year survival for the lowest-risk group (n=946 [33%]) was similar to expected survival (55% versus 55%;
P
=0.50), but for the highest-risk group (n=564 [20%]), survival was significantly lower than expected (9% versus 26%;
P
<0.001). For 229 pairs of propensity-matched patients with mechanical or biological prostheses, survival was not significantly different (67%, 40%, and 19% versus 71%, 45%, and 7% at 5, 10, and 15 years, respectively;
P
=0.81). Structural deterioration of bioprostheses occurred in 64 patients (2.4%).

Conclusions—
Survival of elderly patients after aortic valve replacement is influenced by age and preoperative comorbidities; 33% at lowest risk had overall survival similar to that of an age- and sex-matched general population. There was no sufficient evidence that valve type affected survival. Structural deterioration of aortic bioprostheses was rare.
Uncontrolled and Apparent Treatment Resistant Hypertension in the United States, 1988 to 2008
Authors: Egan Brent M. , Zhao Yumin , Axon R. Neal , Brzezinski Walter A. , Ferdinand Keith C. 
Published: August 2011

Background—
Despite progress, many hypertensive patients remain uncontrolled. Defining characteristics of uncontrolled hypertensives may facilitate efforts to improve blood pressure control.

Methods and Results—

Subjects included 13 375 hypertensive adults from National Health and Nutrition Examination Surveys (NHANESs) subdivided into 1988 to 1994, 1999 to 2004, and 2005 to 2008. Uncontrolled hypertension was defined as blood pressure ≥140/≥90 mm Hg and apparent treatment-resistant hypertension (aTRH) when subjects reported taking ≥3 antihypertensive medications. Framingham 10-year coronary risk was calculated. Multivariable logistic regression was used to identify clinical characteristics associated with untreated, treated uncontrolled on 1 to 2 blood pressure medications, and aTRH across all 3 survey periods. More than half of uncontrolled hypertensives were untreated across surveys, including 52.2% in 2005 to 2008. Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits (0 to 1 per year), body mass index <25 kg/m
2
, absence of chronic kidney disease, and Framingham 10-year coronary risk <10% (
P
<0.01). Most treated uncontrolled patients reported taking 1 to 2 blood pressure medications, a proxy for therapeutic inertia. This group was older, had higher Framingham 10-year coronary risk than patients controlled on 1 to 2 medications (
P
<0.01), and comprised 34.4% of all uncontrolled and 72.0% of treated uncontrolled patients in 2005 to 2008. We found that aTRH increased from 15.9% (1998–2004) to 28.0% (2005–2008) of treated patients (
P
<0.001). Clinical characteristics associated with aTRH included ≥4 visits per year, obesity, chronic kidney disease, and Framingham 10-year coronary risk >20% (
P
<0.01).

Conclusion—
Untreated, undertreated, and aTRH patients have consistent characteristics that could inform strategies to improve blood pressure control by decreasing untreated hypertension, reducing therapeutic inertia in undertreated patients, and enhancing therapeutic efficiency in aTRH.
Differential Clinical Responses to Everolimus-Eluting and Paclitaxel-Eluting Coronary Stents in Patients With and Without Diabetes Mellitus
Authors: Stone Gregg. W. , Kedhi Elvin , Kereiakes Dean J. , Parise Helen , Fahy Martin , Serruys Patrick W. , Smits Pieter C. 
Published: August 2011

Background—
Some (but not all) prior trials have reported differential outcomes after percutaneous coronary intervention with paclitaxel-eluting stents versus stents eluting rapamycin analogs according to the presence of diabetes mellitus. These studies lacked sufficient power to examine individual safety and efficacy end points.

Methods and Results—

To determine whether an interaction exists between the presence of diabetes mellitus and treatment with everolimus-eluting stents compared with paclitaxel-eluting stents, we pooled the databases from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SPIRIT) II, SPIRIT III, SPIRIT IV, and A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice (COMPARE) trials in which percutaneous coronary intervention was performed in 6780 patients, 1869 (27.6%) of whom had diabetes mellitus. Patients without diabetes mellitus treated with everolimus-eluting stents compared with paclitaxel-eluting stents had significantly reduced 2-year rates of mortality (1.9% versus 3.1%;
P
=0.01), myocardial infarction (2.5% versus 5.8%;
P
<0.0001), stent thrombosis (0.3% versus 2.4%;
P
<0.0001), and ischemia-driven target lesion revascularization (3.6% versus 6.9%;
P
<0.0001). In contrast, among patients with diabetes mellitus, there were no significant differences between the 2 stent types in any measured safety or efficacy parameter. Significant interactions were present between diabetic status and stent type for the 2-year end points of myocardial infarction (
P
=0.01), stent thrombosis (
P
=0.0006), and target lesion revascularization (
P
=0.02).

Conclusions—
We have identified a substantial interaction between diabetes mellitus and stent type on clinical outcomes after percutaneous coronary intervention. In patients without diabetes mellitus, everolimus-eluting stents compared with paclitaxel-eluting stents resulted in substantial 2-year reductions in death, myocardial infarction, stent thrombosis, and target lesion revascularization, whereas no significant differences in safety or efficacy outcomes were present in diabetic patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00180310 (SPIRIT II), NCT00180479 (SPIRIT III), NCT00307047 (SPIRIT IV), and NCT01016041 (COMPARE).