bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Analysis of Antimicrobial Resistance Mechanisms inNeisseria gonorrhoeaeIsolates from Ontario, Canada
Authors: Allen Vanessa G. , Farrell David J. , Rebbapragada Anuradha , Tan Jingyuan , Tijet Nathalie , Perusini Stephen J. , Towns Lynn , Lo Stephen , Low Donald E. , Melano Roberto G. 
Published: November 2010

ABSTRACTSurveillance of gonococcal antimicrobial resistance and the molecular characterization of the mechanisms underlying these resistance phenotypes are essential in order to establish correct empirical therapies, as well as to describe the emergence of new mechanisms in local bacterial populations. To address these goals, 149 isolates were collected over a 1-month period (October-November 2008) at the Ontario Public Health Laboratory, Toronto, Canada, and susceptibility profiles (8 antibiotics) were examined. Mutations in previously identified targets or the presence of some enzymes related to resistance (r), nonsusceptibility (ns) (resistant plus intermediate categories), or reduced susceptibility (rs) to the antibiotics tested were also studied. A significant proportion of nonsusceptibility to penicillin (PEN) (89.2%), tetracycline (TET) (72.3%), ciprofloxacin (CIP) (29%), and macrolides (erythromycin [ERY] and azithromycin; 22.3%) was found in these strains. Multidrug resistance was observed in 18.8% of the collection. Although all the strains were susceptible to spectinomycin and extended-spectrum cephalosporins (ESC) (ceftriaxone and cefixime), 9.4% of them displayed reduced susceptibility to extended-spectrum cephalosporins. PBP 2 mosaic structures were found in all of these ESCrsisolates. Alterations in themtrRpromoter, MtrR repressor (TETr, PENns, ESCrs, and ERYns), porin PIB (TETrand PENns), and ribosomal protein S10 (TETr) and double mutations ingyrAandparCquinolone resistance-determining regions (QRDRs) (CIPr) were associated with and presumably responsible for the resistance phenotypes observed. This is the first description of ESCrsin Canada. The detection of this phenotype indicates a change in the epidemiology of this resistance and highlights the importance of continued surveillance to preserve the last antimicrobial options available.
Efficacy of Fosfomycin in Experimental Osteomyelitis Due to Methicillin-Resistant
Staphylococcus aureus
Authors: Poeppl W. , Tobudic S. , Lingscheid T. , Plasenzotti R. , Kozakowski N. , Georgopoulos A. , Burgmann H. 
Published: November 2010

ABSTRACT

The activity of fosfomycin was evaluated in an experimental methicillin-resistant
Staphylococcus aureus
(MRSA) osteomyelitis model. Eighteen rats were treated for 4 weeks with 150 mg of fosfomycin/kg of body weight intraperitoneally once daily or with saline placebo. After treatment, animals were euthanized and the infected tibiae were processed for quantitative bacterial culture. Bone cultures were positive for methicillin-resistant
S. aureus
in all 9 (100%) untreated controls and in 2 of 9 (22.2%) fosfomycin-treated rats. Thus, fosfomycin treatment was significantly more efficacious than placebo. No development of resistance was observed after the 4-week treatment period.
Antibacterial Action of Polyphosphate on
Porphyromonas gingivalis
Authors: Moon Ji-Hoi , Park Jae-Hong , Lee Jin-Yong 
Published: November 2010

ABSTRACT

Polyphosphate [poly(P)] has antibacterial activity against various Gram-positive bacteria. In contrast, Gram-negative bacteria are generally resistant to poly(P). Here, we describe the antibacterial characterization of poly(P) against a Gram-negative periodontopathogen,
Porphyromonas gingivalis
. The MICs of pyrophosphate (Na
4
P
2
O
7
) and all poly(P) (Na

n

+ 2
P

n

O
3

n

+ 1
;
n
= 3 to 75) tested for the bacterium by the agar dilution method were 0.24% and 0.06%, respectively. Orthophosphate (Na
2
HPO
4
) failed to inhibit bacterial growth. Poly-P75 was chosen for further study. In liquid medium, 0.03% poly-P75 was bactericidal against
P. gingivalis
irrespective of the growth phase and inoculum size, ranging from 10
5
to10
9
cells/ml. UV-visible spectra of the pigments from
P. gingivalis
grown on blood agar with or without poly-P75 showed that poly-P75 reduced the formation of μ-oxo bisheme by the bacterium. Poly-P75 increased hemin accumulation on the
P. gingivalis
surface and decreased energy-driven uptake of hemin by the bacterium. The expression of the genes encoding hemagglutinins, gingipains, hemin uptake loci, chromosome replication, and energy production was downregulated, while that of the genes related to iron storage and oxidative stress was upregulated by poly-P75. The transmission electron microscope showed morphologically atypical cells with electron-dense granules and condensed nucleoid in the cytoplasm. Collectively, poly(P) is bactericidal against
P. gingivalis
, in which hemin/heme utilization is disturbed and oxidative stress is increased by poly(P).
Interaction of W-Substituted Analogs of Cyclo-RRRWFW with Bacterial Lipopolysaccharides: the Role of the Aromatic Cluster in Antimicrobial Activity
Authors: Bagheri Mojtaba , Keller Sandro , Dathe Margitta 
Published: November 2010

ABSTRACTThe activity of cyclo-RRRWFW (c-WFW) againstEscherichia colihas been shown to be modulated by the aromatic motif and the lipopolysaccharides (LPS) in the bacterial outer membrane. To identify interaction sites and to elucidate the mode of c-WFW action, peptides were synthesized by the replacement of tryptophan (W) with analogs having altered hydrophobicity, dipole and quadrupole moments, hydrogen-bonding ability, amphipathicity, and ring size. The peptide activity againstBacillus subtilisand erythrocytes increased with increasing hydrophobicity, whereas the effect onE. colirevealed a more complex pattern. Although they had no effect on theE. coliinner membrane even at concentrations higher than the MIC, peptides permeabilized the outer membrane according to their antimicrobial activity pattern, suggesting a major role of LPS in peptide transport across the wall. For isothermal titration calorimetry (ITC) studies of peptide-lipid bilayer interaction, we used POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-choline), either alone or in mixtures with 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG), to mimic the charge properties of eukaryotic and bacterial membranes, respectively, as well as in mixtures with lipid A, rough LPS, and smooth LPS as models of the outer membrane ofE. coli. Peptide accumulation was determined by both electrostatic and hydrophobic interactions. The susceptibility of the lipid systems followed the order of POPC-smooth LPS >> POPC-rough LPS > POPC-lipid A = POPC-POPG > POPC. Low peptide hydrophobicity and enhanced flexibility reduced binding. The influence of the other properties on the free energy of partitioning was low, but an enhanced hydrogen-bonding ability and dipole moment resulted in remarkable variations in the contribution of enthalpy and entropy. In the presence of rough and smooth LPS, the binding-modulating role of these parameters decreased. The highly differentiated activity pattern againstE. coliwas poorly reflected in peptide binding to LPS-containing membranes. However, stronger partitioning into POPC-smooth LPS than into POPC-rough LPS uncovered a significant role of O-antigen and outer core oligosaccharides in peptide transport and the permeabilization of the outer membrane and the anti-E. coliactivity of the cyclic peptides.
Immunization with a ZmpB-Based Protein Vaccine Could Protect against Pneumococcal Diseases in Mice
Authors: Gong Yi , Xu Wenchun , Cui Yali , Zhang Xuemei , Yao Run , Li Dairong , Wang Hong , He Yujuan , Cao Ju , Yin Yibing 
Published: November 2010

ABSTRACT

Zinc metalloprotease B (ZmpB) is present in all isolated pneumococcal strains and contributes to the pathogenesis of pneumococcal infection. In this study, recombinant ZmpB was cloned and expressed in
Escherichia coli
. The expression of ZmpB by different pneumococcal strains was detectable by Western blotting with antisera raised to recombinant ZmpB. Flow cytometry analysis demonstrated that anti-ZmpB polyclonal antibodies could bind to the cell surface of the pneumococcal strains analyzed. Both recombinant ZmpB protein and anti-ZmpB polyclonal antibodies significantly inhibited the adhesion of
Streptococcus pneumoniae
D39 to A549 cells. In mouse models, mucosal immunization with recombinant ZmpB could significantly reduce pneumococcal lung colonization caused by
S. pneumoniae
serotypes 19F and 14 and significantly increase mice survival times following invasive pneumococcal challenge with different pneumococcal strains, including serotypes 2, 3, 6B, and 14. Furthermore, intraperitoneal immunization with recombinant ZmpB in combination with the recombinant pneumolysin mutant (DeltaA146 Ply) and heat shock protein 40 (DnaJ) could enhance the protection against pneumococcal infection compared to protection provided by single-protein antigens. Passive immunization with hyperimmune antisera against these three antigens also demonstrated that the combination of three hyperimmune antisera could provide better protection than single antisera. Taken together, our results suggest that ZmpB is a good candidate pneumococcal vaccine antigen.
Rushing, distraction, walking on contaminated floors and risk of slipping in limited-service restaurants: a case–crossover study
Authors: Verma Santosh K , Lombardi David A , Chang Wen Ruey , Courtney Theodore K , Huang Yueng-Hsiang , Brennan Melanye J , Mittleman Murray A , Ware James H , Perry Melissa J 
Published: November 2010

ObjectivesThis nested case–crossover study examined the association between rushing, distraction and walking on a contaminated floor and the rate of slipping, and whether the effects varied according to weekly hours worked, job tenure and use of slip-resistant shoes.MethodsAt baseline, workers from 30 limited-service restaurants in the USA reported average work hours, average weekly duration of exposure to each transient risk factor and job tenure at the current location. Use of slip-resistant shoes was determined. During the following 12 weeks, participants reported weekly their slip experience and exposures to the three transient exposures at the time of slipping. The case–crossover design was used to estimate the rate ratios using the Mantel–Haenszel estimator for person-time data.ResultsAmong 396 participants providing baseline information, 210 reported one or more slips with a total of 989 slips. Rate of slipping was 2.9 times higher when rushing as compared to working at a normal pace (95% CI 2.5 to 3.3). Rate of slipping was also significantly increased by distraction (rate ratio (RR) 1.7, 95% CI 1.5 to 2.0) and walking on a contaminated floor (RR 14.6, 95% CI 12.6 to 17.0). Use of slip-resistant shoes decreased the effects of rushing and walking on a contaminated floor. Rate ratios for all three transient factors decreased monotonically as job tenure increased.ConclusionThe results suggest the importance of these transient risk factors, particularly floor contamination, on rate of slipping in limited-service restaurant workers. Stable characteristics, such as slip-resistant shoes, reduced the effects of transient exposures.
Workplace smoking policies and their association with male employees' smoking behaviours: a cross-sectional survey in one company in China
Authors: Gao JiaNing , Zheng PinPin , Gao JunLing , Chapman Simon , Fu Hua 
Published: November 2010

ObjectivesThe present work sought to evaluate different worksite smoking control policies and their associations with employees' smoking behaviours and attitudes among Chinese male workers.MethodsThis was a cross-sectional survey with a self-administered standardised questionnaire, conducted among seven production workplaces of one multinational company in Shanghai in 2008. In total, 1043 male workers were involved. Current smoking prevalence, daily cigarette consumption, quitting intention and their potential association with workplace smoking control policies (smoke free or restricted smoking) were measured.ResultsCurrent smoking prevalence in workplaces where smoke-free policies had been imposed for 3 years was 55.5%, about 18% lower than in workplaces that only restricted smoking. Smokers in smoke-free workplaces also smoked 3.4 cigarettes less per day, made more quit attempts, were more confident of successfully quitting and more willing to accept a company sponsored cessation programme. Those patterns declined or were not found among the workplaces where smoking control policies had been imposed for 10 years. Smoker quitting intentions were not associated with workplace smoking policies regardless of the duration of the policies imposed.ConclusionsA smoke-free workplace policy was found to have a significant association with lower smoking prevalence and daily cigarette consumption, but not with employee quitting intentions. Restrictive smoking policies had no impact on employee smoking behaviours. The impact of workplace smoking control policies may vary over time.
ON THE HERMAN–KLUK SEMICLASSICAL APPROXIMATION
Authors: ROBERT DIDIER 
Published: November 2010

For a subquadratic symbol H on ℝd× ℝd= T*(ℝd), the quantum propagator of the time dependent Schrödinger equation [Formula: see text] is a Semiclassical Fourier-Integral Operator when Ĥ = H(x, ℏDx) (ℏ-Weyl quantization of H). Its Schwartz kernel is described by a quadratic phase and an amplitude. At every time t, when ℏ is small, it is "essentially supported" in a neighborhood of the graph of the classical flow generated by H, with a full uniform asymptotic expansion in ℏ for the amplitude.In this paper, our goal is to revisit this well-known and fundamental result with emphasis on the flexibility for the choice of a quadratic complex phase function and on global L2estimates when ℏ is small and time t is large. One of the simplest choice of the phase is known in chemical physics as Herman–Kluk formula. Moreover, we prove that the semiclassical expansion for the propagator is valid for [Formula: see text] where δ > 0 is a stability parameter for the classical system.
Tradeoffs and Average-Case Equilibria in Selfish Routing
Authors: Hoefer Martin , Souza Alexander 
Published: November 2010

We study Nash equilibria in a selfish routing game on
m
parallel links with transmission speeds. Each player seeks to communicate a message by choosing one of the links, and each player desires to minimize his experienced transmission time (latency). For evaluating the social cost of Nash equilibria, we consider the price of anarchy, which is the largest ratio of the cost of any Nash equilibrium compared to the optimum solution. Similarly, we consider the price of stability, which is the smallest ratio. The main purpose of this article is to quantify the influence of three parameters upon the prices of the game: the total traffic in the network; restrictions of the players in terms of link choice; and fluctuations in message lengths.

Our main interest is to bound the sum of all player latencies, which we refer to as
collective latency
. For this cost, the prices of anarchy and stability are
Θ
(
n
/
t
), where
n
is the number of players and
t
the sum of message lengths (total traffic); that is, Nash equilibria approximate the optimum solution up to a constant factor if the traffic is high. If each player is restricted to choose from a subset of links, these link restrictions can cause a degradation in performance of order Θ(\sqrt{
m
}). The prices of anarchy and stability increase to Θ(
n
\sqrt{
m
}/
t
).

We capture fluctuations in message lengths through a stochastic model, in which we valuate Nash equilibria in terms of their expected price of anarchy. The expected price is Θ(
n
/\mathbb{E}[
T
]), where \mathbb{E}[
T
] is the expected traffic. The stochastic model resembles the deterministic one, even for the efficiency loss of order Θ(\sqrt{
m
}) for link restrictions.

For the social cost function maximum latency, the (expected) price of anarchy is 1 +
m
2
/
t
. In this case, Nash equilibria are almost optimal solutions for congested networks. Similar results hold when the cost function is a polynomial of the link loads.
CaM Kinase Kinase β-Mediated Activation of the Growth Regulatory Kinase AMPK Is Required for Androgen-Dependent Migration of Prostate Cancer Cells
Authors: Frigo Daniel E. , Howe Matthew K. , Wittmann Bryan M. , Brunner Abigail M. , Cushman Ian , Wang Qianben , Brown Myles , Means Anthony R. , McDonnell Donald P. 
Published: November 2010

Abstract
While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1–2 years. Although hormone-refractory disease is unresponsive to androgen-deprivation, androgen receptor (AR)-regulated signaling pathways remain active and are necessary for cancer progression. Thus, both AR itself and the processes downstream of the receptor remain viable targets for therapeutic intervention. Microarray analysis of multiple clinical cohorts showed that the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is both highly expressed in the prostate and further elevated in prostate cancers. Using cellular models of prostate cancer, we have determined that androgens (a) directly increase the expression of a CaMKKβ splice variant and (b) increase functional CaMKKβ protein levels as determined by the phosphorylation of both CaMKI and AMP-activated protein kinase (AMPK), two of CaMKKβ's primary substrates. Importantly, inhibition of the CaMKKβ-AMPK, but not CaMKI, signaling axis in prostate cancer cells by pharmacological inhibitors or siRNA-mediated knockdown blocks androgen-mediated migration and invasion. Conversely, overexpression of CaMKKβ alone leads to both increased AMPK phosphorylation and cell migration. Given the key roles of CaMKKβ and AMPK in the biology of prostate cancer cells, we propose that these enzymes are potential therapeutic targets in prostate cancer. Cancer Res; 71(2); 528–37. ©2010 AACR.
Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia
Authors: O'Hare Thomas , Deininger Michael W.N. , Eide Christopher A. , Clackson Tim , Druker Brian J. 
Published: November 2010

Abstract
Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABLT315I. A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABLT315I. The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABLT315I mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABLT315I in the development pipeline. Clin Cancer Res; 17(2); 212–21. ©2010 AACR.
HGF Rescues Colorectal Cancer Cells from EGFR Inhibition via MET Activation
Authors: Liska David , Chen Chin-Tung , Bachleitner-Hofmann Thomas , Christensen James G. , Weiser Martin R. 
Published: November 2010

Abstract
Purpose: Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), is active in colorectal cancer (CRC). However, response rates range from only 10% to 20%. Here, we investigate hepatocyte growth factor (HGF)-dependent mesenchymal-epithelial transition factor (MET) activation as a mediator of cetuximab resistance through signal diversification in CRC cell lines.
Experimental Design: DiFi, GEO, and LIM1215 cells were treated with varying concentrations and combinations of EGF, HGF, cetuximab, and PHA-665752 (a highly specific MET kinase inhibitor). Biological end points included proliferation, cell cycle arrest, and apoptosis. Proliferation was measured using WST-1 assays and synergy investigated via isobolograms. Expression and signaling were examined using immunoblotting.
Results: EGFR and MET are coexpressed in these CRC cell lines, and dual receptor activation synergistically increased proliferation. Cetuximab inhibited cell growth by 60%–80% with an associated dephosphorylation of EGFR, MAPK, and/or AKT. Addition of HGF to cetuximab-treated cells phosphorylated MET, but not EGFR or ErbB3, restimulated the MAPK and AKT pathways, restored cell proliferation, and rescued cells from G1 arrest and apoptosis. Importantly, this effect could be abrogated by inhibiting MET activation with PHA-665752 or by downregulating MET expression with RNAi.
Conclusions: HGF-induced MET activation is a novel mechanism of cetuximab resistance in CRC. Inhibition of the HGF-MET pathway may improve response to EGFR inhibitors in CRC, and combination therapy should be further investigated. Clin Cancer Res; 17(3); 472–82. ©2010 AACR.
Myocardial Perfusion Scans
Authors: Berrington de Gonzalez Amy , Kim Kwang-Pyo , Smith-Bindman Rebecca , McAreavey Dorothea 
Published: November 2010

Background—
Myocardial perfusion scans contribute up to 20% of the estimated annual collective radiation dose to the US population. We estimated potential future cancer risk from these scans by age at exposure and current frequency of use in the United States.

Methods and Results—
Usage patterns were determined from national survey data, and radionuclide dosage was based on current guidelines. Cancer risk projection models were generated on the basis of the National Research Council Biological Effects of Ionizing Radiation VII report, under the assumption that risk has a linear relationship with radiation exposure even at low doses. The mean projected number of radiation-related incident cancers and 95% uncertainty intervals were estimated with the use of Monte Carlo simulations. Estimated risks for a scan performed at age 50 years ranged from 2 cancers per 10 000 scans (95% uncertainty interval, 1 to 5) for a positron emission tomography ammonia-13 test to 25 cancers per 10 000 scans (95% uncertainty interval, 9 to 58) for a dual-isotope (thallium-201 plus technetium-99m) scan. Risks were 50% lower at age 70 years but were similar for men and women. The combination of cancer risk estimates and data on frequency of use suggests that the 9.1 million myocardial perfusion scans performed annually in the United States could result in 7400 (95% uncertainty interval, 3300 to 13 700) additional future cancers.

Conclusions—
The lifetime cancer risk from a single myocardial perfusion scan is small and should be balanced against likely benefit and appropriateness of the test. The estimates depend on a number of assumptions, including life expectancy. They apply directly to asymptomatic individuals with life expectancies similar to those of the general population. For individuals with a symptomatic clinical profile, on whom such scans are typically performed, the risks will be lower because of shorter life expectancy.