bluuebunny/crossref_metadata_2025_split huggingface dataset:
Penetration of Moxifloxacin into Bone Evaluated by Monte Carlo Simulation
Authors: Landersdorfer Cornelia B. , Kinzig Martina , Hennig Friedrich F. , Bulitta Jürgen B. , Holzgrabe Ulrike , Drusano George L. , Sörgel Fritz , Gusinde Johannes 
Published: February 2009

ABSTRACT

Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into many tissues, including bone. Penetration of moxifloxacin into bone has not yet been studied using compartmental modeling techniques. Therefore, we determined the rate and extent of bone penetration by moxifloxacin and evaluated its pharmacodynamic profile in bone via Monte Carlo simulation. Twenty-four patients (10 males, 14 females) undergoing total hip replacement received 400 mg moxifloxacin orally 2 to 7 h prior to surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen by a cryogenic mill, including an internal standard. Drug concentrations were analyzed by high-performance liquid chromatography. We used ADAPT II (results reported), NONMEM, and WinBUGS for pharmacokinetic analysis. Monte Carlo simulation was performed to reverse engineer the necessary area under the free concentration-time curve
f
AUC
SERUM
/MIC in serum and total AUC
BONE
/MIC in bone for a successful clinical or microbiological outcome. The median (10% to 90% percentile for between-subject variability) of the AUC in bone divided by the AUC in serum (AUC
BONE
/AUC
SERUM
) was 80% (51 to 126%) for cortical bone and 78% (42 to 144%) for cancellous bone. Equilibration between serum and bone was rapid. Moxifloxacin achieved robust (≥90%) probabilities of target attainment (PTAs) in serum, cortical bone, and cancellous bone up to MICs of ≤0.375 mg/liter based on the targets
f
AUC
SERUM
/MIC ≥ 40 and AUC
BONE
/MIC ≥ 33. Moxifloxacin showed high bone concentrations and a rapid equilibrium between bone and serum. The favorable PTAs compared to the 90%-inhibitory MIC of
Staphylococcus aureus
warrant future clinical trials on the effectiveness of moxifloxacin in the treatment of bone infections.
Experimental Bacteriophage Therapy Increases Survival of
Galleria mellonella
Larvae Infected with Clinically Relevant Strains of the
Burkholderia cepacia
Complex
Authors: Seed Kimberley D. , Dennis Jonathan J. 
Published: February 2009

ABSTRACT

The
Burkholderia cepacia
complex (BCC) is a group of bacterial pathogens that are highly antibiotic resistant and associated with debilitating respiratory infections. Although bacteriophages of the BCC have been isolated and characterized, no studies have yet examined phage therapy against the BCC in vivo. In a caterpillar infection model, we show that BCC phage therapy is an alternative treatment possibility and is highly effective under specific conditions.
Apricitabine Does Not Select Additional Drug Resistance Mutations in Tissue Culture in Human Immunodeficiency Virus Type 1 Variants Containing K65R, M184V, or M184V plus Thymidine Analogue Mutations
Authors: Oliveira Maureen , Moisi Daniela , Spira Bonnie , Cox Susan , Brenner Bluma G. , Wainberg Mark A. 
Published: February 2009

ABSTRACTHuman immunodeficiency virus type 1 containing the reverse transcriptase mutation M184V or K65R or mutations M41L, M184V, and T215Y did not accumulate additional resistance mutations in the reverse transcriptase when increasing amounts of apricitabine drug pressure were applied. The original mutations were maintained by the presence of apricitabine but were lost when cultured without drug pressure.
A Redox Basis for Metronidazole Resistance in
Helicobacter pylori
Authors: Kaakoush N. O. , Asencio C. , Mégraud F. , Mendz G. L. 
Published: February 2009

ABSTRACT

Metronidazole resistance in
Helicobacter pylori
has been attributed to mutations in
rdxA
or
frxA
. Insufficient data correlating RdxA and/or FrxA with the resistant phenotype, and the emergence of resistant strains with no mutations in either
rdxA
or
frxA
, indicated that the molecular basis of
H. pylori
resistance to metronidazole required further characterization. The
rdxA
and
frxA
genes of four matched pairs of metronidazole-susceptible and -resistant strains were sequenced. The resistant strains had mutations in either
rdxA
,
frxA
, neither gene, or both genes. The reduction rates of five substrates suggested that metabolic differences between susceptible and resistant strains cannot be explained only by mutations in
rdxA
and/or
frxA
. A more global approach to understanding the resistance phenotype was taken by employing two-dimensional gel electrophoresis combined with tandem mass spectrometry analyses to identify proteins differentially expressed by the matched pair of strains with no mutations in
rdxA
or
frxA
. Proteins involved in the oxireduction of ferredoxin were downregulated in the resistant strain. Other redox enzymes, such as thioredoxin reductase, alkyl hydroperoxide reductase, and superoxide dismutase, showed a pI change in the resistant strain. The data suggested that metronidazole resistance involved more complex metabolic changes than specific gene mutations, and they provided evidence of a role for the intracellular redox potential in the development of resistance.
Activity Profile In Vitro of Micafungin against Spanish Clinical Isolates of Common and Emerging Species of Yeasts and Molds
Authors: Cuenca-Estrella Manuel , Gomez-Lopez Alicia , Mellado Emilia , Monzon Araceli , Buitrago Maria J. , Rodriguez-Tudela Juan L. 
Published: February 2009

ABSTRACT

A collection of 2,278 isolates belonging to 86 different fungal species was tested with micafungin and eight other drugs using the EUCAST procedures. Micafungin was active against species of
Candida
and
Aspergillus
(even azole-resistant species) as well as
Penicillium
spp.,
Scedosporium apiospermum
, and
Acremonium
spp. It was inactive for species of
Basidiomycota
and
Mucorales
and for multiresistant species such as those of
Fusarium
.
Frequency and Domain Specificity of Toxin-Neutralizing Paratopes in the Human Antibody Response to Anthrax Vaccine Adsorbed
Authors: Reason Donald , Liberato Justine , Sun Jinying , Keitel Wendy , Zhou Jianhui 
Published: February 2009

ABSTRACT

Protective antigen (PA) is the cell surface recognition unit of the binary anthrax toxin system and the primary immunogenic component in both the current and proposed “next-generation” anthrax vaccines. Several studies utilizing animal models have indicated that PA-specific antibodies, acquired by either active or passive immunization, are sufficient to protect against infection with
Bacillus anthracis
. To investigate the human antibody response to anthrax immunization, we have established a large panel of human PA-specific monoclonal antibodies derived from multiple individuals vaccinated with the currently approved anthrax vaccine BioThrax. We have determined that although these antibodies bind PA in standard binding assays such as enzyme-linked immunosorbent assay, Western blotting, capture assays, and dot blots, less than 25% are capable of neutralizing lethal toxin (LT) in vitro. Nonneutralizing antibodies also fail to neutralize toxin when present in combination with other nonneutralizing paratopes. Although neutralizing antibodies recognize determinants throughout the PA monomer, they are significantly less common among those paratopes that bind to the immunodominant amino-terminal portion of the molecule. These findings demonstrate that PA binding alone is not sufficient to neutralize LT and suggest that for an antibody to effectively block PA-mediated toxicity, it must bind to PA such that one of the requisite toxin functions is disrupted. A vaccine design strategy that directed a higher percentage of the antibody response toward neutralizing epitopes may result in a more efficacious vaccine for the prevention of anthrax infection.
Interleukin-18-Related Genes Are Induced during the Contraction Phase but Do Not Play Major Roles in Regulating the Dynamics or Function of the T-Cell Response toListeria monocytogenesInfection
Authors: Haring Jodie S. , Harty John T. 
Published: February 2009

ABSTRACTProinflammatory cytokines, such as gamma interferon (IFN-γ), impact aspects of T-cell responses after infection, including expansion, contraction, and memory formation. Interleukin-18 (IL-18) functions as a proinflammatory cytokine by stimulating the production of IFN-γ from multiple cell types and accentuating the development of Th1 CD4 T-cell responses. Focused microarray analyses revealed upregulation of IL-18 and IL-18 receptor genes in CD8 T cells during the contraction phase. Based on these findings we investigated if and how signaling through the IL-18 receptor influences the development and kinetics of antigen (Ag)-specific CD8 and CD4 T-cell responses following infection. IL-18Rα−/−and IL-18−/−mice developed frequencies and total numbers of Ag-specific CD8 T cells afterListeria monocytogenesinfection that were similar to those of wild-type C57BL/6 mice. The kinetics of expansion, contraction, and memory CD8 T-cell maintenance were also similar. When IL-18Rα deficiency was isolated to Ag-specific CD8 T cells, the kinetics of the expansion and contraction phases were also normal. These basic findings were confirmed by examining the response to vaccinia virus infection. In contrast, the expansion of Ag-specific CD4 T cells was slightly curtailed by the absence of IL-18Rα; however, contraction and the maintenance of memory were not altered. Importantly, both memory Ag-specific CD8 and CD4 T cells generated in the absence of IL-18Rα expanded appropriately after secondary antigen exposure and were protective, indicating that signaling through the IL-18 receptor is not required for normal T-cell response kinetics and survival of immunized mice challenged with a lethalL. monocytogenesinfection.
Hfq, a Novel Pleiotropic Regulator of Virulence-Associated Genes in
Francisella tularensis
Authors: Meibom Karin L. , Forslund Anna-Lena , Kuoppa Kerstin , Alkhuder Khaled , Dubail Iharilalao , Dupuis Marion , Forsberg Åke , Charbit Alain 
Published: February 2009

ABSTRACT

Francisella tularensis
is a highly infectious pathogen that infects animals and humans, causing tularemia. The ability to replicate within macrophages is central for virulence and relies on expression of genes located in the
Francisella
pathogenicity island (FPI), as well as expression of other genes. Regulation of FPI-encoded virulence gene expression in
F. tularensis
involves at least four regulatory proteins and is not fully understood. Here we studied the RNA-binding protein Hfq in
F. tularensis
and particularly the role that it plays as a global regulator of gene expression in stress tolerance and pathogenesis. We demonstrate that Hfq promotes resistance to several cellular stresses (including osmotic and membrane stresses). Furthermore, we show that Hfq is important for the ability of the
F. tularensis
vaccine strain LVS to induce disease and persist in organs of infected mice. We also demonstrate that Hfq is important for stress tolerance and full virulence in a virulent clinical isolate of
F. tularensis
, FSC200. Finally, microarray analyses revealed that Hfq regulates expression of numerous genes, including genes located in the FPI. Strikingly, Hfq negatively regulates only one of two divergently expressed putative operons in the FPI, in contrast to the other known regulators, which regulate the entire FPI. Hfq thus appears to be a new pleiotropic regulator of virulence in
F. tularensis
, acting mostly as a repressor, in contrast to the other regulators identified so far. Moreover, the results obtained suggest a novel regulatory mechanism for a subset of FPI genes.
Novel Microtubule Polymerization Inhibitor with Potent Antiproliferative and Antitumor Activity
Authors: Arora Sonia , Wang Xin I. , Keenan Susan M. , Andaya Christina , Zhang Qiang , Peng Youyi , Welsh William J. 
Published: February 2009

Abstract
Microtubule-stabilizing and microtubule-destabilizing agents are commonly used as anticancer agents. Although highly effective, success with these agents has been limited due to their relative insolubility, cumbersome synthesis/purification, toxic side effects, and development of multidrug resistance. Hence, the identification of improved agents that circumvent one or more of these problems is warranted. We recently described the rational design of a series of triazole-based compounds as antimitotic agents. Members of this N-substituted 1,2,4-triazole family of compounds exhibit potent tubulin polymerization inhibition and broad spectrum cellular cytotoxicity. Here, we extensively characterize the in vitro and in vivo effects of our lead compound from the series 1-methyl-5-(3-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-4-yl)-1H-indole, designated T115. We show that T115 competes with colchicine for its binding pocket in tubulin, produces robust inhibition of tubulin polymerization, and disrupts the microtubule network system inside the cells. In addition, T115 arrests human cancer cells in the G2-M phase of cell cycling, a hallmark of microtubule destabilizing drugs. T115 also inhibits cell viability of several cancer cell lines, including multidrug-resistant cell lines, in the low nanomolar range. No cytotoxicity was observed by T115 against normal human skin fibroblasts cell lines, and acute toxicity studies in normal nontumor-bearing mice indicated that T115 is well-tolerated in vivo (maximum total tolerated dose, 400 mg/kg). In a mouse xenograft model using human colorectal (HT-29) and prostate (PC3) cancer cells, T115 significantly inhibited tumor growth when administered i.p. Taken together, our results suggest that T115 is a potential drug candidate for cancer chemotherapy. [Cancer Res 2009;69(5):1910–5]
The β-Catenin Axis Integrates Multiple Signals Downstream from RET/Papillary Thyroid Carcinoma Leading to Cell Proliferation
Authors: Castellone Maria Domenica , De Falco Valentina , Rao Deva Magendra , Bellelli Roberto , Muthu Magesh , Basolo Fulvio , Fusco Alfredo , Gutkind J. Silvio , Santoro Massimo 
Published: February 2009

Abstract
RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the β-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal–regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3β (GSK3β) phosphorylation, thereby reducing GSK3β-mediated NH2-terminal β-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with β-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)β-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3β complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP–responsive element binding protein (CREB) phosphorylation and promotes the formation of a β-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing β-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC–expressing cells. Silencing of β-catenin by small interfering RNA inhibits proliferation of RET/PTC–transformed PC Cl3 thyrocytes, whereas a constitutively active form of β-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on β-catenin to stimulate cell proliferation. [Cancer Res 2009;69(5):1867–76]
Overexpression of the Cellular DEK Protein Promotes Epithelial Transformation In vitro and In vivo
Authors: Wise-Draper Trisha M. , Mintz-Cole Rachael A. , Morris Teresa A. , Simpson David S. , Wikenheiser-Brokamp Kathryn A. , Currier Mark A. , Cripe Timothy P. , Grosveld Gerard C. , Wells Susanne I. 
Published: February 2009

Abstract
High levels of expression of the human DEK gene have been correlated with numerous human malignancies. Intracellular DEK functions have been described in vitro and include DNA supercoiling, DNA replication, RNA splicing, and transcription. We have shown that DEK also suppresses cellular senescence, apoptosis, and differentiation, thus promoting cell growth and survival in monolayer and organotypic epithelial raft models. Such functions are likely to contribute to cancer, but direct evidence to implicate DEK as an oncogene has remained elusive. Here, we show that in line with an early role in tumorigenesis, murine papilloma formation in a classical chemical carcinogenesis model was reduced in DEK knockout mice. Additionally, human papillomavirus E6/E7, hRas, and DEK cooperated in the transformation of keratinocytes in soft agar and xenograft establishment, thus also implicating DEK in tumor promotion at later stages. Finally, adenoviral DEK depletion via short hairpin RNA expression resulted in cell death in human tumor cells in vitro and in vivo, but did not significantly affect differentiated epithelial cells. Taken together, our data uncover oncogenic DEK activities as postulated from its frequent up-regulation in human malignancies, and suggest that the targeted suppression of DEK may become a strategic approach to the treatment of cancer. [Cancer Res 2009;69(5):1792–9]
Silencing of TMS1/ASC Promotes Resistance to Anoikis in Breast Epithelial Cells
Authors: Parsons Melissa J. , Patel Pritty , Brat Daniel J. , Colbert Laronna , Vertino Paula M. 
Published: February 2009

Abstract
Ductal carcinoma in situ (DCIS) is characterized by ductal epithelial cells that have filled the luminal space of the breast duct and survive despite loss of extracellular matrix contact. In normal epithelial cells, the loss of such contact triggers a form of apoptosis known as detachment-induced apoptosis or “anoikis.” TMS1/ASC is a bipartite adaptor molecule that participates in inflammatory and apoptotic signaling pathways. Epigenetic silencing of TMS1 has been observed in a significant proportion of human breast and other cancers, but the mechanism by which TMS1 silencing contributes to carcinogenesis is unknown. Here, we examined the role of TMS1 in anoikis. We found that TMS1 expression is induced in response to loss of substratum interactions in breast epithelial cells. siRNA-mediated knockdown of TMS1 leads to anoikis resistance, due in part to the persistent activation of extracellular signal-regulated kinase and an impaired ability to up-regulate the BH3-only protein Bim. We further show that the detachment-induced cleavage of procaspase-8, a newly described mediator of cellular adhesion, is significantly inhibited in the absence of TMS1. These data show a novel upstream role for TMS1 in the promotion of anoikis, and suggest that silencing of TMS1 may contribute to the pathogenesis of breast cancer by allowing epithelial cells to bypass cell death in the early stages of breast cancer development. This conclusion is supported by in vivo data showing that TMS1 is selectively down-regulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary DCIS lesions. [Cancer Res 2009;69(5):1706–11]
Sulforaphane Inhibits Prostate Carcinogenesis and Pulmonary Metastasis in TRAMP Mice in Association with Increased Cytotoxicity of Natural Killer Cells
Authors: Singh Shivendra V. , Warin Renaud , Xiao Dong , Powolny Anna A. , Stan Silvia D. , Arlotti Julie A. , Zeng Yan , Hahm Eun-Ryeong , Marynowski Stanley W. , Bommareddy Ajay , Desai Dhimant , Amin Shantu , Parise Robert A. , Beumer Jan H. , Chambers William H. 
Published: February 2009

Abstract
The present study shows that oral gavage of 6 μmol d,l-sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L isomer, thrice per week beginning at 6 weeks of age, significantly inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice without causing any side effects. The incidence of the prostatic intraepithelial neoplasia and well-differentiated (WD) carcinoma were ∼23% to 28% lower (P &lt; 0.05 compared with control by Mann-Whitney test) in the dorsolateral prostate (DLP) of SFN-treated mice compared with controls, which was not due to the suppression of T-antigen expression. The area occupied by the WD carcinoma was also ∼44% lower in the DLP of SFN-treated mice relative to that of control mice (P = 0.0011 by Mann Whitney test). Strikingly, the SFN-treated mice exhibited ∼50% and 63% decrease, respectively, in pulmonary metastasis incidence and multiplicity compared with control mice (P &lt; 0.05 by t test). The DLP from SFN-treated mice showed decreased cellular proliferation and increased apoptosis when compared with that from control mice. Additionally, SFN administration enhanced cytotoxicity of cocultures of natural killer (NK) cells and dendritic cells (DC) against TRAMP-C1 target cells, which correlated with infiltration of T cells in the neoplastic lesions and increased levels of interleukin-12 production by the DC. In conclusion, the results of the present study indicate that SFN administration inhibits prostate cancer progression and pulmonary metastasis in TRAMP mice by reducing cell proliferation and augmenting NK cell lytic activity. [Cancer Res 2009;69(5):2117–25]
Polymorphisms in the Vitamin D Receptor and Risk of Ovarian Cancer in Four Studies
Authors: Tworoger Shelley S. , Gate Margaret A. , Lee I-Min , Buring Julie E. , Titus-Ernstoff Linda , Cramer Daniel , Hankinson Susan E. 
Published: February 2009

Abstract
Prior studies have suggested that vitamin D may reduce ovarian cancer risk. Thus, we examined whether three single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene (Fok1, Bsm1, Cdx2) were associated with risk of epithelial ovarian cancer in a retrospective case-control study (New England Case-Control study, NECC) and a nested case-control study of three prospective cohort studies: the Nurses' Health Study (NHS), NHSII, and the Women's Health Study. Data from the cohort studies were combined and analyzed using conditional logistic regression and pooled with the results from the NECC, which were analyzed using unconditional logistic regression, using a random effects model. We obtained genotype data for 1,473 cases and 2,006 controls. We observed a significant positive association between the number of Fok1 f alleles and ovarian cancer risk in the pooled analysis (Ptrend = 0.03). The odds ratio (OR) for the ff versus FF genotype was 1.26 [95% confidence interval (CI) = 1.01–1.57]. Neither the Bsm1 (Ptrend = 0.96) or Cdx2 (Ptrend = 0.13) SNPs were significantly associated with ovarian cancer risk. Among the prospective studies, the risk of ovarian cancer by plasma vitamin D levels did not clearly vary by any of the genotypes. For example, among women with the Fok1 FF genotype, the OR comparing plasma 25-hydroxyvitamin D ≥32 ng/mL versus &lt;32 ng/mL was 0.66 (95% CI, 0.34–1.28), and among women with the Ff or ff genotype the OR was 0.71 (95% CI, 0.43–1.18). Our results of an association with the Fok1 VDR polymorphism further support a role of the vitamin D pathway in ovarian carcinogenesis. [Cancer Res 2009;69(5):1885–91]