bluuebunny/crossref_metadata_2025_split huggingface dataset:
Verification of patient‐specific dose distributions in proton therapy using a commercial two‐dimensional ion chamber array
Authors: Arjomandy Bijan , Sahoo Narayan , Ciangaru George , Zhu Ronald , Song Xiaofei , Gillin Michael 
Published: November 2010

Purpose:The purpose of this study was to determine whether a two‐dimensional (2D) ion chamber array detector quickly and accurately measures patient‐specific dose distributions in treatment with passively scattered and spot scanning proton beams.Methods:The 2D ion chamber array detector MatriXX was used to measure the dose distributions in plastic water phantom from passively scattered and spot scanning proton beam fields planned for patient treatment. Planar dose distributions were measured using MatriXX, and the distributions were compared to those calculated using a treatment‐planning system. The dose distributions generated by the treatment‐planning system and a film dosimetry system were similarly compared.Results:For passively scattered proton beams, the gamma index for the dose‐distribution comparison for treatment fields for three patients with prostate cancer and for one patient with lung cancer was less than 1.0 for 99% and 100% of pixels for a 3% dose tolerance and 3 mm distance‐to‐dose agreement, respectively. For spot scanning beams, the mean (± standard deviation) percentages of pixels with gamma indices meeting the passing criteria were and for MatriXX and film dosimetry, respectively, for 20 fields used to treat patients with prostate cancer.Conclusions:Unlike film dosimetry, MatriXX provides not only 2D dose‐distribution information but also absolute dosimetry in fractions of minutes with acceptable accuracy. The results of this study indicate that MatriXX can be used to verify patient‐field specific dose distributions in proton therapy.
Selective‐diffusion regularization for enhancement of microcalcifications in digital breast tomosynthesis reconstruction
Authors: Lu Yao , Chan Heang‐Ping , Wei Jun , Hadjiiski Lubomir M. 
Published: November 2010

Purpose:Digital breast tomosynthesis (DBT) has been shown to improve mass detection. Detection of microcalcifications is more challenging because of the large breast volume to be searched for subtle signals. The simultaneous algebraic reconstruction technique (SART) was found to provide good image quality for DBT, but the image noise is amplified with an increasing number of iterations. In this study, the authors developed a selective‐diffusion (SD) method for noise regularization with SART to improve the contrast‐to‐noise ratio (CNR) of microcalcifications in the DBT slices for human or machine detection.Methods:The SD method regularizes SART reconstruction during updating with each projection view. Potential microcalcifications are differentiated from the noisy background by estimating the local gradient information. Different degrees of regularization are applied to the signal or noise classes, such that the microcalcifications will be enhanced while the noise is suppressed. The new SD method was compared to several current methods, including the quadratic Laplacian (QL) method, the total variation (TV) method, and the nonconvex total‐variation (TpV) method for noise regularization with SART. A GE GEN2 prototype DBT system with a stationary digital detector was used for the acquisition of DBT scans at 21 angles in 3° increments over a ±30° range. The reconstruction image quality without regularization and that with the different regularization methods were compared using the DBT scans of an American College of Radiology phantom and a human subject. The CNR and the full width at half maximum (FWHM) of the line profiles of microcalcifications within the in‐focus DBT slices were used as image quality measures.Results:For the comparison of large microcalcifications in the DBT data of the subject, the SD method resulted in comparable CNR to the nonconvex TpV method. Both of them performed better than the other two methods. For subtle microcalcifications, the SD method was superior to other methods in terms of CNR. In both the subject and phantom DBT data, for large microcalcifications, the FWHM of the SD method was comparable to that without regularization, which was wider than that of the TV type methods. For subtle microcalcifications, the SD method had comparable FWHM values to the TV type methods. All three regularization methods were superior to the QL method in terms of FWHM.Conclusions:The SART regularized by the selective‐diffusion method enhanced the CNR and preserved the sharpness of microcalcifications. In comparison with three existing regularization methods, the selective‐diffusion regularization was superior to the other methods for subtle microcalcifications.
Activities of NXL104 Combinations with Ceftazidime and Aztreonam against Carbapenemase-Producing
Enterobacteriaceae
Authors: Livermore David M. , Mushtaq Shazad , Warner Marina , Zhang Jiancheng , Maharjan Sunil , Doumith Michel , Woodford Neil 
Published: November 2010

ABSTRACT

Combinations of NXL104 with ceftazidime and aztreonam were tested against carbapenem-resistant members of the
Enterobacteriaceae
. Ceftazidime-NXL104 was active against strains with the OXA-48 enzyme or with combinations of impermeability and an extended-spectrum β-lactamase (ESBL) or AmpC enzyme and also against most
Klebsiella
spp. with the KPC enzyme, but metallo-β-lactamase producers were resistant. Aztreonam-NXL104 was active against all carbapenemase producers at 4 and 4 μg/ml, including those with metallo-β-lactamases.
In Vitro
Activity of Ceftaroline against a Broad Spectrum of Recent Clinical Anaerobic Isolates
Authors: Snydman David R. , Jacobus Nilda V. , McDermott Laura A. 
Published: November 2010

ABSTRACT

The
in vitro
activity of ceftaroline was compared with those of ceftriaxone, clindamycin, imipenem, metronidazole, moxifloxacin, tigecycline, and vancomycin against 514 clinical anaerobic isolates using Clinical and Laboratory Standards Institute (CLSI) standard methodology. Ceftaroline demonstrated good to excellent activity against Gram-positive anaerobic pathogens and limited activity against Gram-negative pathogens, particularly
Bacteroides fragilis
group isolates.
Genetic Predisposition Favors the Acquisition of Stable Artemisinin Resistance in Malaria Parasites
Authors: Beez Dorothee , Sanchez Cecilia P. , Stein Wilfred D. , Lanzer Michael 
Published: November 2010

ABSTRACTThe emergence of artemisinin-resistantPlasmodium falciparummalaria jeopardizes efforts to control this infectious disease. To identify factors contributing to reduced artemisinin susceptibility, we have employed a classical genetic approach by analyzing artemisinin responses in the F1 progeny of a genetic cross. Our data show that reduced artemisinin susceptibility is a multifactorial trait, withpfmdr1and two additional loci (on chromosomes 12 and 13) contributing to it. We further show that the different artemisinin susceptibilities of the progeny strains affect their responses to selection with increasing concentrations of artemisinin. Stable, high-levelin vitroartemisinin resistance rapidly arose in those parasites that were the least artemisinin susceptible among the F1 progeny, whereas progeny that were highly artemisinin susceptible did not acquire stable artemisinin resistance. These data suggest that genetic predisposition favors the acquisition of high-level artemisinin resistance.In vitro-induced artemisinin resistance did not result in cross-resistance to artesunate or artemether, suggesting that resistance to one derivative does not necessarily render the entire drug class ineffective.
Novel Insights into the Mode of Inhibition of Class A SHV-1 β-Lactamases Revealed by Boronic Acid Transition State Inhibitors
Authors: Ke Wei , Sampson Jared M. , Ori Claudia , Prati Fabio , Drawz Sarah M. , Bethel Christopher R. , Bonomo Robert A. , van den Akker Focco 
Published: November 2010

ABSTRACT

Boronic acid transition state inhibitors (BATSIs) are potent class A and C β-lactamase inactivators and are of particular interest due to their reversible nature mimicking the transition state. Here, we present structural and kinetic data describing the inhibition of the SHV-1 β-lactamase, a clinically important enzyme found in
Klebsiella pneumoniae
, by BATSI compounds possessing the R1 side chains of ceftazidime and cefoperazone and designed variants of the latter, compounds 1 and 2. The ceftazidime and cefoperazone BATSI compounds inhibit the SHV-1 β-lactamase with micromolar affinity that is considerably weaker than their inhibition of other β-lactamases. The solved crystal structures of these two BATSIs in complex with SHV-1 reveal a possible reason for SHV-1's relative resistance to inhibition, as the BATSIs adopt a deacylation transition state conformation compared to the usual acylation transition state conformation when complexed to other β-lactamases. Active-site comparison suggests that these conformational differences might be attributed to a subtle shift of residue A237 in SHV-1. The ceftazidime BATSI structure revealed that the carboxyl-dimethyl moiety is positioned in SHV-1's carboxyl binding pocket. In contrast, the cefoperazone BATSI has its R1 group pointing away from the active site such that its phenol moiety moves residue Y105 from the active site via end-on stacking interactions. To work toward improving the affinity of the cefoperazone BATSI, we synthesized two variants in which either one or two extra carbons were added to the phenol linker. Both variants yielded improved affinity against SHV-1, possibly as a consequence of releasing the strain of its interaction with the unusual Y105 conformation.
Identification of Diverse OXA-40 Group Carbapenemases, Including a Novel Variant, OXA-160, fromAcinetobacter baumanniiin Pennsylvania
Authors: Tian Guo-Bao , Adams-Haduch Jennifer M. , Bogdanovich Tatiana , Pasculle Anthony W. , Quinn John P. , Wang Hong-Ning , Doi Yohei 
Published: November 2010

ABSTRACTThreeAcinetobacter baumanniiisolates that possess OXA-40 group carbapenemase genes were identified. They belonged to novel sequence types (ST122, ST123, and ST124) and harboredblaOXA-160,blaOXA-72, andblaOXA-40, respectively. OXA-160 is a novel variant of OXA-40 with a P227S substitution. An isogenicEscherichia coliclone producing OXA-160 was more susceptible to carbapenems than a clone producing OXA-40. The genetic environment ofblaOXA-160andblaOXA-40beyond the putative XerC/XerD recombination sites was distinct from the scaffold reported previously.
Cytomegalovirus UL97 Mutations Affecting Cyclopropavir and Ganciclovir Susceptibility
Authors: Chou Sunwen , Bowlin Terry L. 
Published: November 2010

ABSTRACT

Among the 7 most common UL97 mutations encountered in ganciclovir-resistant clinical cytomegalovirus isolates, the associated cyclopropavir cross-resistance varies from insignificant (L595S) to substantial (M460I and H520Q) as determined by recombinant phenotyping. Mutations M460I and H520Q were preferentially selected
in vitro
under cyclopropavir and conferred 12- to 20-fold increases in 50% effective concentration (EC
50
) values, while M460V, C592G, A594V, and C603W conferred 3- to 5-fold increases. Uncommon mutations M460T and C603R increased cyclopropavir EC
50
s by 8- to 10-fold.
Coevolution of TH1, TH2, and TH17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia
Authors: Murdock Benjamin J. , Shreiner Andrew B. , McDonald Roderick A. , Osterholzer John J. , White Eric S. , Toews Galen B. , Huffnagle Gary B. 
Published: November 2010

ABSTRACTAspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure toA. fumigatusconidia. C57BL/6 mice were challenged intranasally withA. fumigatusconidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% ofA. fumigatusconidia were cleared within 24 h after inoculation, and repeated exposure toA. fumigatusconidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (Treg) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continuedA. fumigatuschallenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure toA. fumigatusconidia induced T cell activation in the lungs and the codevelopment by four exposures of TH1, TH2, and TH17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or Tregnumbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure toA. fumigatusconidia.
Genome-Wide Identification ofStreptococcus pneumoniaeGenes Essential for Bacterial Replication during Experimental Meningitis
Authors: Molzen T. E. , Burghout P. , Bootsma H. J. , Brandt C. T. , van der Gaast-de Jongh Christa E. , Eleveld M. J. , Verbeek M. M. , Frimodt-Møller N. , Østergaard C. , Hermans P. W. M. 
Published: November 2010

ABSTRACTMeningitis is the most serious of invasive infections caused by the Gram-positive bacteriumStreptococcus pneumoniae. Vaccines protect only against a limited number of serotypes, and evolving bacterial resistance to antimicrobials impedes treatment. Further insight into the molecular pathogenesis of invasive pneumococcal disease is required in order to enable the development of new or adjunctive treatments and/or pneumococcal vaccines that are efficient across serotypes. We applied genomic array footprinting (GAF) in the search forS. pneumoniaegenes that are essential during experimental meningitis. A total of 6,000 independent TIGR4marinerT7transposon mutants distributed over four libraries were injected intracisternally into rabbits, and cerebrospinal fluid (CSF) was collected after 3, 9, and 15 h. Microarray analysis of mutant-specific probes from CSF samples and inocula identified 82 and 11 genes mutants of which had become attenuated or enriched, respectively, during infection. The results point to essential roles for capsular polysaccharides, nutrient uptake, and amino acid biosynthesis in bacterial replication during experimental meningitis. The GAF phenotype of a subset of identified targets was followed up by detailed studies of directed mutants in competitive and noncompetitive infection models of experimental rat meningitis. It appeared that adenylosuccinate synthetase, flavodoxin, and LivJ, the substrate binding protein of a branched-chain amino acid ABC transporter, are relevant as targets for future therapy and prevention of pneumococcal meningitis, since their mutants were attenuated in both models of infection as well as in competitive growth in human cerebrospinal fluidin vitro.
Older Adults Have a Low Capacity To Opsonize Pneumococci Due to Low IgM Antibody Response to Pneumococcal Vaccinations
Authors: Park Saeyoung , Nahm Moon H. 
Published: November 2010

ABSTRACTSince the 23-valent pneumococcal polysaccharide vaccine (PPV23) is less effective for older adults than for young adults, it is important to investigate the immunologic basis for the reduced efficacy of PPV23 among older adults. We determined the effectiveness of PPV23 among young (n= 55) and older (n= 44) adults by measuring the serum IgG, IgM, and IgA concentrations and opsonic capacities against serotypes 14, 18C, and 23F. While young and older adults showed no difference in levels of IgG antibodies against pneumococcal polysaccharide (PPS), older adults had lower IgA and IgM antibody levels than young adults for all three serotypes. In both age groups, anti-PPS IgA or IgM antibody levels were much lower than anti-PPS IgG antibody levels. Young adults showed higher opsonic capacities than older adults for serotypes 14 and 23F. In order to determine the effects of anti-PPS IgA or IgM antibodies on the functional difference between young and older adults, anti-PPS IgA or IgM antibodies were removed from immune sera by affinity chromatography. The difference in opsonic capacity between young and older adults disappeared for serotypes 14 and 23F (but not for serotype 18C) when IgM antibody was removed. However, there was no significant difference between the two age groups when IgA antibody was removed. In conclusion, even though anti-PPS IgG antibody levels are high compared with anti-PPS IgM antibody levels, the low levels of anti-PPS IgM antibody alone can explain the functional difference observed between young and older adults immunized with PPV23 with regard to some pneumococcal serotypes.
Porphyromonas gingivalis
Virulence in a
Drosophila melanogaster
Model
Authors: Igboin Christina O. , Moeschberger Melvin L. , Griffen Ann L. , Leys Eugene J. 
Published: November 2010

ABSTRACT

Porphyromonas gingivalis
has been implicated in the etiology of adult periodontitis. In this study, we examined the viability of
Drosophila melanogaster
as a new model for examining
P. gingivalis
-host interactions.
P. gingivalis
(W83) infection of
Drosophila
resulted in a systemic infection that killed in a dose-dependent manner. Differences in the virulence of several clinically prevalent
P. gingivalis
strains were observed in the
Drosophila
killing model, and the results correlated well with studies in mammalian infection models and human epidemiologic studies.
P. gingivalis
pathobiology in
Drosophila
did not result from uncontrolled growth of the bacterium in the
Drosophila
hemolymph (blood) or overt damage to
Drosophila
tissues.
P. gingivalis
killing of
Drosophila
was multifactorial, involving several bacterial factors that are also involved in virulence in mammals. The results from this study suggest that many aspects of
P. gingivalis
pathogenesis in mammals are conserved in
Drosophila
, and thus the
Drosophila
killing model should be useful for characterizing
P. gingivalis
-host interactions and, potentially, polymicrobe-host interactions.
Porphyromonas gingivalis-Host Interactions in aDrosophila melanogasterModel
Authors: Igboin Christina O. , Tordoff Kevin P. , Moeschberger Melvin L. , Griffen Ann L. , Leys Eugene J. 
Published: November 2010

ABSTRACTPorphyromonas gingivalisis a Gram-negative obligate anaerobe that has been implicated in the etiology of adult periodontitis. We recently introduced aDrosophila melanogasterkilling model for examination ofP. gingivalis-host interactions. In the current study, theDrosophilakilling model was used to characterize the host response toP. gingivalisinfection by identifying host components that play a role during infection.Drosophilaimmune response gene mutants were screened for altered susceptibility to killing byP. gingivalis. The Imd signaling pathway was shown to be important for the survival ofDrosophilainfected by nonencapsulatedP. gingivalisstrains but was dispensable for the survival ofDrosophilainfected by encapsulatedP. gingivalisstrains. TheP. gingivaliscapsule was shown to mediate resistance to killing byDrosophilaantimicrobial peptides (Imd pathway-regulated cecropinA and drosocin) and human beta-defensin 3.Drosophilathiol-ester protein II (Tep II) and Tep IV and the tumor necrosis factor (TNF) homolog Eiger were also involved in the immune response againstP. gingivalisinfection, while the scavenger receptors Eater and Croquemort played no roles in the response toP. gingivalisinfection. This study demonstrates that theDrosophilakilling model is a useful high-throughput model for characterizing the host response toP. gingivalisinfection and uncovering novel interactions between the bacterium and the host.
Burkholderia pseudomalleiProteins Presented by Monocyte-Derived Dendritic Cells Stimulate Human Memory T CellsIn Vitro
Authors: Tippayawat Patcharaporn , Pinsiri Maneerat , Rinchai Darawan , Riyapa Donporn , Romphruk Amornrat , Gan Yunn-Hwen , Houghton Raymond L. , Felgner Philip L. , Titball Richard W. , Stevens Mark P. , Galyov Edouard E. , Bancroft Gregory J. , Lertmemongkolchai Ganjana 
Published: November 2010

ABSTRACTMelioidosis is a severe infectious disease caused by the saprophytic facultative intracellular pathogenBurkholderia pseudomallei. The disease is endemic in Southeast Asia and Northern Australia, and no effective vaccine exists. To describe human cell-mediated immune responses toB. pseudomalleiand to identify candidate antigens for vaccine development, the ability of antigen-pulsed monocyte-derived dendritic cells (moDCs) to trigger autologous T-cell responses toB. pseudomalleiand its products was tested. moDCs were prepared from healthy individuals exposed or not exposed toB. pseudomallei, based on serological evidence. These were pulsed with heat-killedB. pseudomalleior purified antigens, including ABC transporters (LolC, OppA, and PotF), Bsa type III secreted proteins (BipD and BopE), tandem repeat sequence-containing proteins (Rp1 and Rp2), flagellin, and heat shock proteins (Hsp60 and Hsp70), prior to being mixed with autologous T-cell populations. After pulsing of cells with either heat-killedB. pseudomallei, LolC, or Rp2, coculturing the antigen-pulsed moDCs with T cells elicited gamma interferon production from CD4+T cells from seropositive donors at levels greater than those for seronegative donors. These antigens also induced granzyme B (cytotoxic) responses from CD8+T cells. Activation of antigen-specific CD4+T cells required direct contact with moDCs and was therefore not dependent on soluble mediators. Rp peptide epitopes recognized by T cells in healthy individuals were identified. Our study provides valuable novel data on the induction of human cell-mediated immune responses toB. pseudomalleiand its protein antigens that may be exploited in the rational development of vaccines to combat melioidosis.