bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the Inhibitor-Resistant SHV β-Lactamase SHV-107 in a Clinical Klebsiella pneumoniae Strain Coproducing GES-7 Enzyme
Authors: Manageiro Vera , Ferreira Eugénia , Cougnoux Antony , Albuquerque Luís , Caniça Manuela , Bonnet Richard 
Published: November 2011

ABSTRACT

The clinical
Klebsiella pneumoniae
INSRA6884 strain exhibited nonsusceptibility to all penicillins tested (MICs of 64 to >2,048 μg/ml). The MICs of penicillins were weakly reduced by clavulanate (from 2,048 to 512 μg/ml), and tazobactam restored piperacillin susceptibility. Molecular characterization identified the genes
bla
GES-7
and a new β-lactamase gene,
bla
SHV-107
, which encoded an enzyme that differed from SHV-1 by the amino acid substitutions Leu35Gln and Thr235Ala. The SHV-107-producing
Escherichia coli
strain exhibited only a β-lactam resistance phenotype with respect to amoxicillin, ticarcillin, and amoxicillin-clavulanate combination. The kinetic parameters of the purified SHV-107 enzyme revealed a high affinity for penicillins. However, catalytic efficiency for these antibiotics was lower for SHV-107 than for SHV-1. No hydrolysis was detected against oxyimino-β-lactams. The 50% inhibitory concentration (IC
50
) for clavulanic acid was 9-fold higher for SHV-107 than for SHV-1, but the inhibitory effects of tazobactam were unchanged. Molecular dynamics simulation suggested that the Thr235Ala substitution affects the accommodation of clavulanate in the binding site and therefore its inhibitory activity.
The Class A β-Lactamase FTU-1 Is Native to Francisella tularensis
Authors: Antunes Nuno T. , Frase Hilary , Toth Marta , Vakulenko Sergei B. 
Published: November 2011

ABSTRACTThe class A β-lactamase FTU-1 produces resistance to penicillins and ceftazidime but not to any other β-lactam antibiotics tested. FTU-1 hydrolyzes penicillin antibiotics with catalytic efficiencies of 105to 106M−1s−1and cephalosporins and carbapenems with catalytic efficiencies of 102to 103M−1s−1, but the monobactam aztreonam and the cephamycin cefoxitin are not substrates for the enzyme. FTU-1 shares 21 to 34% amino acid sequence identity with other class A β-lactamases and harbors two cysteine residues conserved in all class A carbapenemases. FTU-1 is the first weak class A carbapenemase that is native toFrancisella tularensis.
Yersinia pestisacrAB-tolCin Antibiotic Resistance and Virulence
Authors: Lister Ida M. , Raftery Connor , Mecsas Joan , Levy Stuart B. 
Published: November 2011

ABSTRACTThe efflux pump AcrAB is important in the antibiotic resistance and virulence of several pathogenic bacteria. We report that deletion of theYersinia pestisAcrAB-TolC homolog leads to increased susceptibility to diverse substrates, including, though unlike inEscherichia coli, the aminoglycosides. Neither is theY. pestispump affected by the efflux pump inhibitor phenylalanine-arginine beta-naphthylamide. In mouse plague models, pump deletion does not have a significant effect on tissue colonization.
Micafungin Concentrations in the Plasma and Burn Eschar of Severely Burned Patients
Authors: Sasaki Junichi , Yamanouchi Satoshi , Kudo Daisuke , Endo Tomoyuki , Nomura Ryosuke , Takuma Kiyotsugu , Kushimoto Shigeki , Shinozawa Yotaro , Kishino Satoshi , Hori Shingo , Aikawa Naoki 
Published: November 2011

ABSTRACT

Micafungin concentrations in plasma and burn eschar after daily intravenous infusion (1 h) of micafungin (200 to 300 mg) were investigated for six patients with severe burns. Micafungin treatment was initiated more than 72 h after the burn injuries. The peak and trough levels in the plasma after the initial administration and repeated administrations for more than 4 days were comparable with or slightly lower than the reported values for healthy volunteers. Micafungin concentrations in the plasma and burn eschar were between 3.6 and >1,000 times higher than the reported MIC
90
s of micafungin against clinically important
Candida
and
Aspergillus
species.
Ertapenem Pharmacokinetics and Pharmacodynamics during Continuous Ambulatory Peritoneal Dialysis
Authors: Cardone Katie E. , Grabe Darren W. , Kulawy Robert W. , Daoui Rachid , Roglieri Joseph , Meola Shari , Drusano George L. , Lodise Thomas P. 
Published: November 2011

ABSTRACT

Scant data exist for the pharmacokinetics (PK) of ertapenem in patients on continuous ambulatory peritoneal dialysis (CAPD). The goals of this study were to characterize the PK profile of ertapenem during CAPD, determine the extent of ertapenem penetration into the peritoneal cavity, and quantify the probability of the target attainment (PTA) profile in the serum and peritoneal cavity. A single-dose PK study was conducted in seven patients on CAPD. Population PK modeling and Monte Carlo simulation determined the probability that ertapenem at 500 mg intravenously (i.v.) every 24 h (q24h) would achieve concentrations in excess of the MIC for 40% of the dosing interval (40%
T
>MIC, where
T
is time) in the serum and peritoneal cavity. Monte Carlo simulation was also used to calculate the peritoneal cavity/serum mean and median penetration ratios by estimating the area under the concentration-time curve in the peritoneal cavity and serum (AUC
Peritoneal
and AUC
Serum
, respectively) from zero to infinity after a single simulated dose. The population mean (± standard deviation [SD]) values for the apparent volume in the central compartment, clearance, and apparent volume in the peritoneal cavity were 2.78 (0.62) liters, 0.24 (0.07) liters/hr, and 5.81 (2.05) liters, respectively. The mean (SD) AUC
Peritoneal
/AUC
Serum
ratio was 1.039 (0.861), and the median penetration ratio was 0.801 (interquartile range, 0.486 to 1.317). In both the serum and peritoneal cavity, ertapenem at 500 mg i.v. q24h was very likely (>90%) to achieve the pharmacodynamic target for MICs of ≤2 mg/liter. The simulations suggest that 500 mg of ertapenem i.v. q24h is very likely to achieve the exposure target associated with clinical efficacy in both the serum and peritoneal cavity against the range of MIC values deemed susceptible by the Clinical and Laboratory Standards Institute.
Characterization of the Inhibition Mechanism of HIV-1 Nucleocapsid Protein Chaperone Activities by Methylated Oligoribonucleotides
Authors: Avilov Sergiy V. , Boudier Christian , Gottikh Marina , Darlix Jean-Luc , Mély Yves 
Published: November 2011

ABSTRACT
Since currently available therapies against HIV/AIDS still show important drawbacks, the development of novel anti-HIV treatments is a key issue. We recently characterized methylated oligoribonucleotides (mONs) that extensively inhibit HIV-1 replication in primary T cells at nanomolar concentrations. The mONs were shown to target both HIV-1 reverse transcriptase (RT) and the nucleocapsid protein (NC), which is an essential partner of RT during viral DNA synthesis. To further understand the mechanism of such mONs, we studied by isothermal titration calorimetry and fluorescence-based techniques their NC binding properties and ability to inhibit the nucleic acid chaperone properties of NC. Notably, we investigated the ability of mONs to inhibit the NC-induced destabilization of the HIV-1 cTAR (complementary DNA sequence to TAR [transactivation response element]) stem-loop and the NC-promoted cTAR annealing to its complementary sequence, required at the early stage of HIV-1 viral DNA synthesis. Moreover, we compared the activity of the mONs to that of a number of modified and nonmodified oligonucleotides. Results show that the mONs inhibit NC by a competitive mechanism whereby the mONs tightly bind the NC peptide, mainly through nonelectrostatic interactions with the hydrophobic platform at the top of the NC zinc fingers. Taken together, these results favor the notion that the mONs impair the process of the RT-directed viral DNA synthesis by sequestering NC molecules, thus preventing the chaperoning of viral DNA synthesis by NC. These findings contribute to the understanding of the molecular basis for NC inhibition by mONs, which could be used for the rational design of antiretroviral compounds targeting HIV-1 NC protein.
Evaluation of Once-Daily Vancomycin against Methicillin-Resistant Staphylococcus aureus in a Hollow-Fiber Infection Model
Authors: Nicasio Anthony M. , Bulitta Jürgen B. , Lodise Thomas P. , D'Hondt Rebecca E. , Kulawy Robert , Louie Arnold , Drusano George L. 
Published: November 2011

ABSTRACT

For methicillin-resistant
Staphylococcus aureus
(MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in an
in vitro
hollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 μg/ml) using an inoculum of ∼10
6
CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 μg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.
The Repeat-In-Toxin Family Member TosA Mediates Adherence of Uropathogenic Escherichia coli and Survival during Bacteremia
Authors: Vigil Patrick D. , Wiles Travis J. , Engstrom Michael D. , Prasov Lev , Mulvey Matthew A. , Mobley Harry L. T. 
Published: November 2011

ABSTRACT

Uropathogenic
Escherichia coli
(UPEC) is responsible for the majority of uncomplicated urinary tract infections (UTI) and represents the most common bacterial infection in adults. UPEC utilizes a wide range of virulence factors to colonize the host, including the novel repeat-in-toxin (RTX) protein TosA, which is specifically expressed in the host urinary tract and contributes significantly to the virulence and survival of UPEC.
tosA
, found in strains within the B2 phylogenetic subgroup of
E. coli
, serves as a marker for strains that also contain a large number of well-characterized UPEC virulence factors. The presence of
tosA
in an
E. coli
isolate predicts successful colonization of the murine model of ascending UTI, regardless of the source of the isolate. Here, a detailed analysis of the function of
tosA
revealed that this gene is transcriptionally linked to genes encoding a conserved type 1 secretion system similar to other RTX family members. TosA localized to the cell surface and was found to mediate (i) adherence to host cells derived from the upper urinary tract and (ii) survival in disseminated infections and (iii) to enhance lethality during sepsis (as assessed in two different animal models of infection). An experimental vaccine, using purified TosA, protected vaccinated animals against urosepsis. From this work, it was concluded that TosA belongs to a novel group of RTX proteins that mediate adherence and host damage during UTI and urosepsis and could be a novel target for the development of therapeutics to treat ascending UTIs.
The Vsa Shield of Mycoplasma pulmonis Is Antiphagocytic
Authors: Shaw Brandon M. , Simmons Warren L. , Dybvig Kevin 
Published: November 2011

ABSTRACT

The infection of mice with
Mycoplasma pulmonis
is a model for studying chronic mycoplasmal respiratory disease. Many
in vivo
and
in vitro
studies have used the organism to gain a better understanding of host-pathogen interactions in chronic respiratory infection. The organism's Vsa proteins contain an extensive tandem repeat region. The length of the tandem repeat unit varies from as few as 11 amino acids to as many as 19. The number of tandem repeats can be as high as 60. The number of repeats varies at a high frequency due to slipped-strand mispairing events that occur during DNA replication. When the number of repeats is high, e.g., 40, the mycoplasma is resistant to lysis by complement but does not form a robust biofilm. When the number of repeats is low, e.g., 5, the mycoplasma is killed by complement when the cells are dispersed but has the capacity to form a biofilm that resists complement. Here, we examine the role of the Vsa proteins in the avoidance of phagocytosis and find that cells producing a protein with many tandem repeats are relatively resistant to killing by macrophages. These results may be pertinent to understanding the functions of similar proteins that have extensive repeat regions in other microbes.
A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults
Authors: Minassian Angela M , Rowland Rosalind , Beveridge Natalie E R , Poulton Ian D , Satti Iman , Harris Stephanie , Poyntz Hazel , Hamill Matthew , Griffiths Kristin , Sander Clare R , Ambrozak David R , Price David A , Hill Brenna J , Casazza Joseph P , Douek Daniel C , Koup Richard A , Roederer Mario , Winston Alan , Ross Jonathan , Sherrard Jackie , Rooney Guy , Williams Nicola , Lawrie Alison M , Fletcher Helen A , Pathan Ansar A , McShane Helen 
Published: November 2011

ObjectivesControl of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults.DesignThis was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis.ResultsMVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable.ConclusionMVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited.
Oral contraceptive use is associated with prostate cancer: an ecological study
Authors: Margel David , Fleshner Neil E 
Published: November 2011

BackgroundSeveral recent studies have suggested that oestrogen exposure may increase the risk of prostate cancer (PCa).ObjectivesTo examine associations between PCa incidence and mortality and population-based use of oral contraceptives (OCs). It was hypothesised that OC by-products may cause environmental contamination, leading to an increased low level oestrogen exposure and therefore higher PCa incidence and mortality.MethodsThe hypothesis was tested in an ecological study. Data from the International Agency for Research on Cancer were used to retrieve age-standardised rates of prostate cancer in 2007, and data from the United Nations World Contraceptive Use 2007 report were used to retrieve data on contraceptive use. A Pearson correlation and multivariable linear regression were used to associate the percentage of women using OCs, intrauterine devices, condoms or vaginal barriers to the age standardised prostate cancer incidence and mortality. These analyses were performed by individual nations and by continents worldwide.ResultsOC use was significantly associated with prostate cancer incidence and mortality in the individual nations worldwide (r=0.61 and r=0.53, respectively; p<0.05 for all). PCa incidence was also associated with OC use in Europe (r=0.545, p<0.05) and by continent (r=0.522, p<0.05). All other forms of contraceptives (ie, intra-uterine devices, condoms or vaginal barriers) were not correlated with prostate cancer incidence or mortality. On multivariable analysis the correlation with OC was independent of a nation's wealth.ConclusionA significant association between OCs and PCa has been shown. It is hypothesised that the OC effect may be mediated through environmental oestrogen levels; this novel concept is worth further investigation.
Integrative Genomic Analyses of Sporadic Clear Cell Renal Cell Carcinoma Define Disease Subtypes and Potential New Therapeutic Targets
Authors: Dondeti Vijay R. , Wubbenhorst Bradley , Lal Priti , Gordan John D. , D'Andrea Kurt , Attiyeh Edward F. , Simon M. Celeste , Nathanson Katherine L. 
Published: November 2011

AbstractSporadic clear cell renal cell carcinoma (ccRCC), the most common type of adult kidney cancer, is often associated with genomic copy number aberrations on chromosomes 3p and 5q. Aberrations on chromosome 3p are associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), which activates the hypoxia-inducible factors HIF1α and HIF2α. In contrast, ccRCC genes on chromosome 5q remain to be defined. In this study, we conducted an integrated analysis of high-density copy number and gene expression data for 54 sporadic ccRCC tumors that identified the secreted glycoprotein STC2 (stanniocalcin 2) and the proteoglycan VCAN (versican) as potential 5q oncogenes in ccRCCs. In functional assays, STC2 and VCAN each promoted tumorigenesis by inhibiting cell death. Using the same approach, we also investigated the two VHL-deficient subtypes of ccRCC, which express both HIF1α and HIF2α (H1H2) or only HIF2α (H2). This analysis revealed a distinct pattern of genomic aberrations in each group, with the H1H2 group displaying, on average, a more aberrant genome than the H2 group. Together our findings provide a significant advance in understanding ccRCCs by offering a molecular definition of two subtypes with distinct characteristics as well as two potential chromosome 5q oncogenes, the overexpression of which is sufficient to promote tumorigenesis by limiting cell death. Cancer Res; 72(1); 112–21. ©2011 AACR.
Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1
Authors: Arnault Jean Philippe , Mateus Christine , Escudier Bernard , Tomasic Gorana , Wechsler Janine , Hollville Emilie , Soria Jean-Charles , Malka David , Sarasin Alain , Larcher Magalie , André Jocelyne , Kamsu-Kom Nyam , Boussemart Lise , Lacroix Ludovic , Spatz Alain , Eggermont Alexander M. , Druillennec Sabine , Vagner Stephan , Eychène Alain , Dumaz Nicolas , Robert Caroline 
Published: November 2011

Abstract
Purpose: The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.
Experimental Design: Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1, and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes.
Results: We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1, and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin.
Sorafenib induced BRAF–CRAF dimerization in cultured keratinocytes and activated CRAF with a dose-dependent effect on MAP-kinase pathway activation and on keratinocyte proliferation.
Conclusion: Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors. Clin Cancer Res; 18(1); 263–72. ©2011 AACR.
Vemurafenib and BRAF Inhibition: A New Class of Treatment for Metastatic Melanoma
Authors: Luke Jason J. , Hodi F. Stephen 
Published: November 2011

Abstract
The U.S. Food and Drug Administration recently approved vemurafenib for the treatment of BRAF valine in exon 15, at codon 600 (V600E) mutant metastatic melanoma. Vemurafenib is a competitive small-molecule serine–threonine kinase inhibitor that functions by binding to the ATP-binding domain of mutant BRAF. Compared with dacarbazine chemotherapy, vemurafenib significantly improved the 6-month overall survival of patients from 64% to 84% and exhibited a response rate of approximately 50%. Median progression-free survival was also significantly improved with vemurafenib as compared with dacarbazine (5.3 versus 1.6 months, respectively), and this was consistent among groups analyzed, including age, sex, geography, Eastern Cooperative Oncology Group status, disease stage, and serum lactate dehydrogenase. The success of targeting melanoma genomics has created a paradigm shift for future drug development. Currently, the elucidation of resistant mechanisms to vemurafenib therapy remains an important area of active investigation that will shape rational drug treatments for melanoma. The development of vemurafenib, the role of BRAF targeting, and the changing landscape of treatment for melanoma provide a new foundation for clinical investigation. Clin Cancer Res; 18(1); 9–14. ©2011 AACR.