bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased Susceptibility to Ciprofloxacin amongShigellaIsolates in the United States, 2006 to 2009
Authors: Folster Jason P. , Pecic Gary , Bowen Anna , Rickert Regan , Carattoli Alessandra , Whichard Jean M. 
Published: January 2011

ABSTRACTWe characterized 20Shigellaisolates with decreased susceptibility to fluoroquinolones. Most patients (80%) from whom a travel history was obtained reported travel to South or Southeast Asia. Mutations within the quinolone resistance determining regions ofgyrAandparCand plasmid-mediated resistance determinants (qnrB,qnrS, andaac(6′)-Ib-cr) were identified. The rise in antimicrobial resistance amongShigellaisolates may necessitate the increased use of extended-spectrum cephalosporins or macrolides in some patients.
Temperature-Dependent Modulation of
Porphyromonas gingivalis
Lipid A Structure and Interaction with the Innate Host Defenses
Authors: Curtis Michael A. , Percival Rimondia S. , Devine Deirdre , Darveau Richard P. , Coats Stephen R. , Rangarajan Minnie , Tarelli Edward , Marsh Philip D. 
Published: January 2011

ABSTRACT

Lipid A structure is a critical determinant of the interaction between pathogens and the innate immune system. Previously, we demonstrated the presence of non- and monophosphorylated tetra-acylated lipid A structures in the outer membrane of
Porphyromonas gingivalis
, an agent of human periodontal disease. These modifications to lipid A structure lead to evasion and suppression of innate defenses mediated by Toll-like receptor 4 (TLR4) and cationic antimicrobial peptides. In this investigation, we examined the influence of growth temperature on
P. gingivalis
lipid A structure and recognition by TLR4 as an example of an environmental influence which is known to vary between healthy and diseased sites in the periodontium. We demonstrate that
P. gingivalis
grown at a normal body temperature produces mainly nonphosphorylated and monophosphorylated tetra-acylated lipid A structures, whereas bacteria grown at 39°C and 41°C intended to mimic increasing levels of inflammation, producing increasing proportions of monophosphorylated, penta-acylated lipid A. The temperature-dependent alteration in lipid A renders the bacterium significantly more potent for activating TLR4 and more susceptible to killing by β-defensins 2 and 3. This is the first report of a lipid A remodeling system linked to temperature shifts associated with a deregulated inflammatory response. Temperature elevation at sites of inflammation in the periodontium may be a significant environmental regulator of the lipid A modification systems of
P. gingivalis
, which will influence the interaction of this organism with the innate host defense.
Global Identification of Multiple Substrates forPlasmodium falciparumSUB1, an Essential Malarial Processing Protease
Authors: Silmon de Monerri Natalie C. , Flynn Helen R. , Campos Marta G. , Hackett Fiona , Koussis Konstantinos , Withers-Martinez Chrislaine , Skehel J. Mark , Blackman Michael J. 
Published: January 2011

ABSTRACTThe protozoan pathogen responsible for the most severe form of human malaria,Plasmodium falciparum, replicates asexually in erythrocytes within a membrane-bound parasitophorous vacuole (PV). Following each round of intracellular growth, the PV membrane (PVM) and host cell membrane rupture to release infectious merozoites in a protease-dependent process called egress. Previous work has shown that, just prior to egress, an essential, subtilisin-like parasite protease called PfSUB1 is discharged into the PV lumen, where it directly cleaves a number of important merozoite surface and PV proteins. These include the essential merozoite surface protein complex MSP1/6/7 and members of a family of papain-like putative proteases called SERA (serine-rich antigen) that are implicated in egress. To determine whether PfSUB1 has additional, previously unrecognized substrates, we have performed a bioinformatic and proteomic analysis of the entire late asexual blood stage proteome of the parasite. Our results demonstrate that PfSUB1 is responsible for the proteolytic processing of a range of merozoite, PV, and PVM proteins, including the rhoptry protein RAP1 (rhoptry-associated protein 1) and the merozoite surface protein MSRP2 (MSP7-related protein-2). Our findings imply multiple roles for PfSUB1 in the parasite life cycle, further supporting the case for considering the protease as a potential new antimalarial drug target.
Branching Network of Proteinaceous Filaments within the Parasitophorous Vacuole of
Encephalitozoon cuniculi
and
Encephalitozoon hellem
Authors: Ghosh Kaya , Nieves Eddie , Keeling Patrick , Pombert Jean-Francois , Henrich Philipp P. , Cali Ann , Weiss Louis M. 
Published: January 2011

ABSTRACT

The microsporidia are a diverse phylum of obligate intracellular parasites that infect all major animal groups and have been recognized as emerging human pathogens for which few chemotherapeutic options currently exist. These organisms infect every tissue and organ system, causing significant pathology, especially in immune-compromised populations. The microsporidian spore employs a unique infection strategy in which its contents are delivered into a host cell via the polar tube, an organelle that lies coiled within the resting spore but erupts with a force sufficient to pierce the plasma membrane of its host cell. Using biochemical and molecular approaches, we have previously identified components of the polar tube and spore wall of the Encephalitozoonidae. In this study, we employed a shotgun proteomic strategy to identify novel structural components of these organelles in
Encephalitozoon cuniculi
. As a result, a new component of the
E. cuniculi
developing spore wall was identified. Surprisingly, using the same approach, a heretofore undescribed filamentous network within the lumen of the parasitophorous vacuole was discovered. This network was also present in the parasitophorous vacuole of
Encephalitozoon hellem
. Thus, in addition to further elucidating the molecular composition of seminal organelles and revealing novel diagnostic and therapeutic targets, proteomic analysis-driven approaches exploring the spore may also uncover unknown facets of microsporidian biology.
Phase I Dose-Escalation Study of the Pan-HER Inhibitor, PF299804, in Patients with Advanced Malignant Solid Tumors
Authors: Jänne Pasi A. , Boss David S. , Camidge D. Ross , Britten Carolyn D. , Engelman Jeffrey A. , Garon Edward B. , Guo Feng , Wong Steven , Liang Jane , Letrent Stephen , Millham Robert , Taylor Ian , Eckhardt S. Gail , Schellens Jan H.M. 
Published: January 2011

Abstract
Purpose: PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.
Experimental Design: PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non–small cell lung cancer (NSCLC) patients.
Results: 121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non–small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.
Conclusions: The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients. Clin Cancer Res; 17(5); 1131–9. ©2011 AACR.
Gefitinib or Placebo in Combination with Tamoxifen in Patients with Hormone Receptor–Positive Metastatic Breast Cancer: A Randomized Phase II Study
Authors: Osborne C. Kent , Neven Patrick , Dirix Luc Y. , Mackey John R. , Robert Jean , Underhill Craig , Schiff Rachel , Gutierrez Carolina , Migliaccio Ilenia , Anagnostou Valsamo K. , Rimm David L. , Magill Patrick , Sellers Mark 
Published: January 2011

AbstractPurpose: Increased growth factor signaling may contribute to tamoxifen resistance. This randomized phase II trial assessed tamoxifen plus placebo or the epidermal growth factor receptor inhibitor gefitinib in estrogen receptor (ER)–positive metastatic breast cancer.Experimental Design: Patients with newly metastatic disease or recurred after adjuvant tamoxifen (stratum 1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (stratum 2), were eligible. Primary variables were progression-free survival (PFS; stratum 1) and clinical benefit rate (CBR; stratum 2). A 5% or more improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor.Results: In stratum 1 (n = 206), the PFS HR (gefitinib:placebo) was 0.84 (95% CI, 0.59–1.18; median PFS 10.9 versus 8.8 months). In the stratum 1 endocrine therapy–naïve subset (n = 158) the HR was 0.78 (95% CI, 0.52–1.15), and the prior endocrine-treated subgroup (n = 48) 1.47 (95% CI, 0.63–3.45). In stratum 1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In stratum 2 (n = 84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in stratum 1 there was greater benefit with gefitinib in patients who were ER-negative or had lower levels of ER protein.Conclusions: In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy. In stratum 2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients. Clin Cancer Res; 17(5); 1147–59. ©2011 AACR.
Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models
Authors: Tan Nguyen , Malek Mehnaz , Zha Jiping , Yue Peng , Kassees Robert , Berry Leanne , Fairbrother Wayne J. , Sampath Deepak , Belmont Lisa D. 
Published: January 2011

Abstract
Purpose: To explore the potential of navitoclax in combination with taxane-based chemotherapy in the treatment of non–small cell lung cancer (NSCLC) by defining mechanism of synergy and identifying correlative biomarkers.
Experimental Design: We treated a panel of NSCLC lines with a dose matrix of paclitaxel and navitoclax (formerly ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w (1), and evaluated synergy. We next used time-lapse microscopy to explore mechanism of synergy. Finally, we developed an immunohistochemical assay and assessed prevalence of Bcl-xL in NSCLC tumor tissues.
Results: All cell lines exhibit greater than additive response to the combination of navitoclax and a taxane. These results were extended to mouse xenograft tumor models, in which the combination is more efficacious than either single-agent docetaxel or navitoclax. Addition of navitoclax to paclitaxel decreases the time from mitotic entry to cell death and changes cell fate from mitotic slippage to death during mitotic arrest. The relative levels of Bcl-xL and Mcl-1 correlate with the extent of synergy, suggesting that cancers with elevated levels of Bcl-xL will be relatively resistant to taxane-based therapy but could benefit from the addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit relatively high Bcl-xL levels.
Conclusions: The addition of navitoclax to taxane-based chemotherapy in NSCLC has the potential to increase efficacy, particularly in patients whose tumors express high levels of Bcl-xL. Clin Cancer Res; 17(6); 1394–404. ©2011 AACR.
Digital Transcript Profile Analysis with aRNA-LongSAGE Validates FERMT1 As a Potential Novel Prognostic Marker for Colon Cancer
Authors: Fan Junwei , Yan Dongwang , Teng Mujian , Tang Huamei , Zhou Chongzhi , Wang Xiaoliang , Li Dawei , Qiu Guoqiang , Peng Zhihai 
Published: January 2011

AbstractPurpose: To use gene transcript profiling to identify cancer-associated gene expression.Experimental Design: Methods included (i) marker discovery using laser capture microdissection (LCM)-assisted specimen preparation and antisense RNA-long serial analysis of gene expression (aRNA-LongSAGE) on matched colon cancer and uninvolved colon tissue specimens (n = 5). Candidate tumor-associated genes were selected by combining the LongSAGE libraries reported herein with our previous colon cancer LCM-microarray transcript profiling data; (ii) marker selection and validation by quantitative real-time PCR (n = 15) and immunohistochemistry (n = 31); and (iii) independent validation on multiple tissue microarray (n = 203).Results: Among 30 upregulated and 73 downregulated genes, upregulation of fermitin family member 1 (FERMT1), adenosylhomocysteinase (AHCY), secernin 1 (SCRN1), and SAC3 domain-containing protein 1 (SAC3D1) expression and downregulation of IgJ and MALL expression in colon cancer were confirmed by quantitative PCR. FERMT1 and AHCY protein expression was also upregulated in colon cancer compared with uninvolved colon mucosa, and FERMT1 expression showed upregulation in colon adenoma. Patients with moderate/strong tumor FERMT1 protein expression (n = 122) showed significantly poorer overall survival (OS; P = 0.011) and disease-free survival (DFS; P = 0.005) than patients with negative/weak tumor FERMT1 protein expression (n = 81). Multivariate Cox regression analysis showed that FERMT1 protein expression was also an independent prognostic factor for OS (P = 0.018) and DFS (P = 0.009). In addition, upregulated FERMT1 protein expression appeared to have some specificity among alimentary tract tumors.Conclusions: FERMT1 is a novel prognostic factor for colon carcinoma. Clin Cancer Res; 17(9); 2908–18. ©2011 AACR.
Incidence and Predictors of Early and Late Mortality After Transcatheter Aortic Valve Implantation in 663 Patients With Severe Aortic Stenosis
Authors: Tamburino Corrado , Capodanno Davide , Ramondo Angelo , Petronio Anna Sonia , Ettori Federica , Santoro Gennaro , Klugmann Silvio , Bedogni Francesco , Maisano Francesco , Marzocchi Antonio , Poli Arnaldo , Antoniucci David , Napodano Massimo , De Carlo Marco , Fiorina Claudia , Ussia Gian Paolo 
Published: January 2011

Background—
There is a lack of information on the incidence and predictors of early mortality at 30 days and late mortality between 30 days and 1 year after transcatheter aortic valve implantation (TAVI) with the self-expanding CoreValve Revalving prosthesis.

Methods and Results—
A total of 663 consecutive patients (mean age 81.0±7.3 years) underwent TAVI with the third generation 18-Fr CoreValve device in 14 centers. Procedural success and intraprocedural mortality were 98% and 0.9%, respectively. The cumulative incidences of mortality were 5.4% at 30 days, 12.2% at 6 months, and 15.0% at 1 year. The incidence density of mortality was 12.3 per 100 person-year of observation. Clinical and hemodynamic benefits observed acutely after TAVI were sustained at 1 year. Paravalvular leakages were trace to mild in the majority of cases. Conversion to open heart surgery (odds ratio [OR] 38.68), cardiac tamponade (OR 10.97), major access site complications (OR 8.47), left ventricular ejection fraction <40% (OR 3.51), prior balloon valvuloplasty (OR 2.87), and diabetes mellitus (OR 2.66) were independent predictors of mortality at 30 days, whereas prior stroke (hazard ratio [HR] 5.47), postprocedural paravalvular leak ≥2+ (HR 3.79), prior acute pulmonary edema (HR 2.70), and chronic kidney disease (HR 2.53) were independent predictors of mortality between 30 days and 1 year.

Conclusions—
Benefit of TAVI with the CoreValve Revalving System is maintained over time up to 1 year, with acceptable mortality rates at various time points. Although procedural complications are strongly associated with early mortality at 30 days, comorbidities and postprocedural paravalvular aortic regurgitation ≥2+ mainly impact late outcomes between 30 days and 1 year.
Deregulation of microRNA-503 Contributes to Diabetes Mellitus–Induced Impairment of Endothelial Function and Reparative Angiogenesis After Limb Ischemia
Authors: Caporali Andrea , Meloni Marco , Völlenkle Christine , Bonci Desiree , Sala-Newby Graciela B. , Addis Roberta , Spinetti Gaia , Losa Sergio , Masson Rachel , Baker Andrew H. , Agami Reuven , le Sage Carlos , Condorelli Gianluigi , Madeddu Paolo , Martelli Fabio , Emanueli Costanza 
Published: January 2011

Background—
Diabetes mellitus impairs endothelial cell (EC) function and postischemic reparative neovascularization by molecular mechanisms that are not fully understood. microRNAs negatively regulate the expression of target genes mainly by interaction in their 3′ untranslated region.

Methods and Results—

We found that microRNA-503 (miR-503) expression in ECs is upregulated in culture conditions mimicking diabetes mellitus (high D-glucose) and ischemia-associated starvation (low growth factors). Under normal culture conditions, lentivirus-mediated miR-503–forced expression inhibited EC proliferation, migration, and network formation on Matrigel (comparisons versus
lentivirus.GFP
control). Conversely, blocking miR-503 activity by either adenovirus-mediated transfer of a miR-503 decoy (
Ad.decoymiR-503
) or by antimiR-503 (antisense oligonucleotide) improved the functional capacities of ECs cultured under high D-glucose/low growth factors. We identified CCNE1 and cdc25A as direct miR-503 targets which are downregulated by high glucose/low growth factors in ECs. Next, we obtained evidence that miR-503 expression is increased in ischemic limb muscles of streptozotocin-diabetic mice and in ECs enriched from these muscles. Moreover,
Ad.decoymiR-503
delivery to the ischemic adductor of diabetic mice corrected diabetes mellitus–induced impairment of postischemic angiogenesis and blood flow recovery. We finally investigated miR-503 and target gene expression in muscular specimens from the amputated ischemic legs of diabetic patients. As controls, calf biopsies of nondiabetic and nonischemic patients undergoing saphenous vein stripping were used. In diabetic muscles, miR-503 expression was remarkably higher, and it inversely correlated with cdc25 protein expression. Plasma miR-503 levels were also elevated in the diabetic individuals.

Conclusions—
Our data suggest miR-503 as a possible therapeutic target in diabetic patients with critical limb ischemia.
Heart Rate Response During Exercise and Pregnancy Outcome in Women With Congenital Heart Disease
Authors: Lui George K. , Silversides Candice K. , Khairy Paul , Fernandes Sue M. , Valente Anne Marie , Nickolaus Michelle J. , Earing Michael G. , Aboulhosn Jamil A. , Rosenbaum Marlon S. , Cook Stephen , Kay Joseph D. , Jin Zhezhen , Gersony Deborah R. ,   for the Alliance for Adult Research in Congenital Cardiology (AARCC)
Published: January 2011

Background—
Cardiopulmonary exercise testing is often used to evaluate exercise capacity in adults with congenital heart disease including women who are considering pregnancy. The relationship between cardiopulmonary exercise testing parameters and pregnancy outcome has not been defined.

Methods and Results—

We conducted a multicenter retrospective observational study of women with congenital heart disease who had undergone cardiopulmonary exercise testing within 2 years of pregnancy or during the first trimester. Cardiopulmonary exercise testing variables included peak oxygen consumption and measures of chronotropic response: peak heart rate, percentage of maximum age predicted heart rate, heart rate reserve (peak heart rate−resting heart rate), and chronotropic index [(peak heart rate−resting heart rate)/(220−age−resting heart rate)]. We identified 89 pregnancies in 83 women. There were 4 spontaneous abortions and 1 termination. One or more adverse cardiac events occurred in 18%; congestive heart failure in 14%, and sustained arrhythmia in 7%. Peak heart rate (odds ratio [OR] 0.71; 95% confidence interval [CI] [0.53, 0.94];
P
=0.02), percentage of maximum age predicted heart rate (OR 0.93; 95% CI [0.88, 0.98];
P
=0.01), and chronotropic index (OR 0.65; 95% CI [0.47, 0.90];
P
=0.01) were associated with a cardiac event. Neonatal events occurred in 20%. Peak heart rate (OR 0.75; 95% CI [0.58, 0.98];
P
=0.04), percentage of maximum age predicted heart rate (OR 0.94; 95% CI [0.89, 0.99];
P
=0.02), heart rate reserve (OR 0.8; 95% CI [0.64, 0.99];
P
=0.04), and chronotropic index (OR 0.73; 95% CI [0.54, 0.98];
P
=0.04) correlated with a neonatal event. Peak oxygen consumption was not associated with an adverse pregnancy outcome.

Conclusions—
Abnormal chronotropic response correlates with adverse pregnancy outcomes in women with congenital heart disease and should be considered in refining risk stratification schemes.
Strut Coverage and Late Malapposition With Paclitaxel-Eluting Stents Compared With Bare Metal Stents in Acute Myocardial Infarction
Authors: Guagliumi Giulio , Costa Marco A. , Sirbu Vasile , Musumeci Giuseppe , Bezerra Hiram G. , Suzuki Nobuaki , Matiashvili Aleksandre , Lortkipanidze Nikoloz , Mihalcsik Laurian , Trivisonno Antonio , Valsecchi Orazio , Mintz Gary S. , Dressler Ovidiu , Parise Helen , Maehara Akiko , Cristea Ecaterina , Lansky Alexandra J. , Mehran Roxana , Stone Gregg W. 
Published: January 2011

Background—
The safety of drug-eluting stents in ST-segment elevation myocardial infarction (STEMI) continues to be debated. Pathological studies have demonstrated an association between uncovered struts and subsequent stent thrombosis. Optical coherence tomography can detect stent strut coverage in vivo on a micron-scale level. We therefore used optical coherence tomography to examine strut coverage in patients with STEMI treated with paclitaxel-eluting stents (PES) and bare metal stents (BMS).

Methods and Results—

In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients with STEMI were randomized 3:1 to PES or BMS implantation. In a formal substudy, optical coherence tomography at 13 months was performed in 118 consecutive randomized patients (89 PES, 29 BMS) in whom 188 stents were assessed (146 PES and 42 BMS). A total of 44 139 stent struts were analyzed by an independent core laboratory blinded to stent assignment. The primary prespecified end point, the percentage of uncovered stent struts per lesion at follow-up, was 1.1±2.5% in BMS lesions versus 5.7±7.0% in PES lesions (
P
<0.0001). Malapposed struts were observed in 0.1±0.2% of BMS lesions versus 0.9±2.1% of PES lesions (
P
=0.0003). Percentage net volume obstruction was 36.0±15.4% with BMS and 19.2±11.3% with PES (
P
<0.0001).

Conclusions—
In patients with STEMI undergoing primary percutaneous coronary intervention, implantation of PES as compared with BMS significantly reduces neointimal hyperplasia but results in higher rates of uncovered and malapposed stent struts as assessed by optical coherence tomography at 13-month follow-up. Further studies are required to determine the clinical significance of these findings.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00433966.