bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of Target Gene Mutations and Efflux to Decreased Susceptibility of
Salmonella enterica
Serovar Typhimurium to Fluoroquinolones and Other Antimicrobials
Authors: Chen Sheng , Cui Shenghui , McDermott Patrick F. , Zhao Shaohua , White David G. , Paulsen Ian , Meng Jianghong 
Published: January 2007

ABSTRACT

The mechanisms involved in fluoroquinolone resistance in
Salmonella enterica
include target alterations and overexpression of efflux pumps. The present study evaluated the role of known and putative multidrug resistance efflux pumps and mutations in topoisomerase genes among laboratory-selected and naturally occurring fluoroquinolone-resistant
Salmonella enterica
serovar Typhimurium strains. Strains with ciprofloxacin MICs of 0.25, 4, 32, and 256 μg/ml were derived in vitro using serovar Typhimurium S21. These mutants also showed decreased susceptibility or resistance to many nonfluoroquinolone antimicrobials, including tetracycline, chloramphenicol, and several β-lactams. The expression of efflux pump genes
acrA
,
acrB
,
acrE
,
acrF
,
emrB
,
emrD
, and
mdlB
were substantially increased (≥2-fold) among the fluoroquinolone-resistant mutants. Increased expression was also observed, but to a lesser extent, with three other putative efflux pumps:
mdtB
(
yegN
),
mdtC
(
yegO
), and
emrA
among mutants with ciprofloxacin MICs of ≥32 μg/ml. Deletion of
acrAB
or
tolC
in S21 and its fluoroquinolone-resistant mutants resulted in increased susceptibility to fluoroquinolones and other tested antimicrobials. In naturally occurring fluoroquinolone-resistant serovar Typhimurium strains, deletion of
acrAB
or
tolC
increased fluoroquinolone susceptibility 4-fold, whereas replacement of
gyrA
double mutations (S83F D87N) with wild-type
gyrA
increased susceptibility >500-fold. These results indicate that a combination of topoisomerase gene mutations, as well as enhanced antimicrobial efflux, plays a critical role in the development of fluoroquinolone resistance in both laboratory-derived and naturally occurring quinolone-resistant serovar Typhimurium strains.
Overexpression and Initial Characterization of the Chromosomal Aminoglycoside 3′-
O
-Phosphotransferase APH(3′)-IIb from
Pseudomonas aeruginosa
Authors: Hainrichson Mariana , Yaniv Orit , Cherniavsky Marina , Nudelman Igor , Shallom-Shezifi Dalia , Yaron Sima , Baasov Timor 
Published: January 2007

ABSTRACT

The chromosomal gene
aph(3
′
)-IIb
, encoding an aminoglycoside 3′-phosphotransferase in
Pseudomonas aeruginosa
, was cloned and overexpressed in
Escherichia coli
. The APH(3′)-IIb enzyme was purified as a monomer in a two-step procedure and was shown to phosphorylate its substrates at the C-3′-OH position, with
k
cat
/

K
m

values of 0.4 × 10
4
to 36 × 10
4
M
−1
s
−1
.
Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma
Authors: Stutchbury Tamantha K. , Al-ejeh Fares , Stillfried Gillian E. , Croucher David R. , Andrews John , Irving David , Links Matthew , Ranson Marie 
Published: January 2007

Abstract
Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by 213Bi-labeled plasminogen activator inhibitor type 2 (α-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of α-PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human α-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg α-PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/kg/d × 5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d × 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of α-PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies. [Mol Cancer Ther 2007;6(1):203–11]
A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas
Authors: Siddiqui Farzan , Li Chuan-Yuan , LaRue Susan M. , Poulson Jean M. , Avery Paul R. , Pruitt Amy F. , Zhang Xiuwu , Ullrich Robert L. , Thrall Donald E. , Dewhirst Mark W. , Hauck Marlene L. 
Published: January 2007

AbstractInterleukin-12 (IL-12), a proinflammatory cytokine, shows anticancer properties. Systemically administered IL-12 causes dose-dependent toxicity. To achieve localized intratumoral gene expression, an adenoviral gene therapy vector with IL-12 controlled by a heat-inducible promoter (heat shock promoter 70B) was developed and tested in a phase I clinical trial in cats with spontaneously arising soft tissue sarcoma. A feasibility study was done in 16 cats with soft tissue sarcoma using murine IL-12 and/or enhanced green fluorescent protein adenoviral vectors under cytomegalovirus or heat shock promoter 70 control. Subsequently, we conducted a phase I clinical trial using an adenoviral feline IL-12 construct in 13 cats with soft tissue sarcoma. The soft tissue sarcomas were irradiated (48 Gy/16 fractions) followed by intratumoral injection of adenovirus. Twenty-four hours postinjection, tumors were heated (41°C, 60 min). Tumor expression of feline IL-12 and IFN-γ was determined. Cats were monitored for systemic toxicity. For the murine IL-12 construct, an association was noted between viral dose and murine IL-12 levels within tumor, whereas serum levels were minimal. Mild toxicity was noted at 1011 plaque-forming units (pfu). With the feline IL-12 construct, high levels of feline IL-12 mRNA were detected in tumor biopsies with low or absent IFN-γ mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-γ mRNA in tumor. It is possible to localize gene expression and limit systemic toxicity of IL-12 using the hyperthermia-induced gene therapy approach. The maximum tolerated dose of the feline IL-12 adenoviral vector was 1010 pfu/tumor as dose-limiting toxicities were noted at the 4 × 1010 pfu dose. [Mol Cancer Ther 2007;6(1):380–9]
The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein
Authors: Brändlein Stephanie , Rauschert Nicole , Rasche Leo , Dreykluft Angela , Hensel Frank , Conzelmann Ernst , Müller-Hermelink Hans-Konrad , Vollmers H. Peter 
Published: January 2007

AbstractLipids are essential for normal and malignant cells during growth and differentiation. The turnover is strictly regulated because an uncontrolled uptake and accumulation is cytotoxic and can lead to lipoapoptosis: lipoptosis. The human monoclonal antibody SAM-6 binds to a cell surface receptor on malignant cells and to oxidized low-density lipoprotein (LDL). SAM-6 induces an excess of intracellular lipids, by overfeeding malignant cells with oxidized LDL, via a receptor-mediated endocytosis. The treated cells overaccumulate depots of cholesteryl esters and triglycerides. This lipid overaccumulation is tumor specific; nonmalignant cells neither bind the antibody nor harvest lipids after incubation. Because for both forms of apoptosis, the death domain dependent (“extrinsic”) and independent (“intrinsic”), the activation of proteases is crucial, we also investigated this pathway in more detail. It was found that shortly after internalization of antibody/oxidized LDL/receptor complex and formation of lipid depots, cytochrome c is released by mitochondria. Followed by this, initiator caspase-8 and caspase-9 and effector caspase-3 and caspase-6 are activated. The mechanism of mitochondrial trigger (e.g., by free fatty acids) is under investigation. However, the present data indicate that the SAM-6 antibody induces an intrinsic-like form of apoptosis by overfeeding malignant cells with lipoproteins. [Mol Cancer Ther 2007;6(1):326–33]
Eupalmerin acetate, a novel anticancer agent from Caribbean gorgonian octocorals, induces apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway
Authors: Iwamaru Arifumi , Iwado Eiji , Kondo Seiji , Newman Robert A. , Vera Burnilda , Rodríguez Abimael D. , Kondo Yasuko 
Published: January 2007

Abstract
The marine ecosystem is a vast but largely untapped resource for potential naturally based medicines. We tested 15 compounds derived from organisms found in the Caribbean Sea (14 gorgonian octocoral–derived compounds and one sponge-derived compound) for their anticancer effects on human malignant glioma U87-MG and U373-MG cells. Eupalmerin acetate (EPA) was chosen as the lead compound based on its longer-term stability and greater cytotoxicity than those of the other compounds we tested in these cell types. EPA induced G2-M cell cycle arrest and apoptosis via the mitochondrial pathway; it translocated Bax from the cytoplasm to the mitochondria and dissipated the mitochondrial transmembrane potential in both cell types. EPA was found to increase phosphorylated c-Jun NH2-terminal kinase (JNK) by &gt;50% in both U87-MG and U373-MG cells. A specific JNK inhibitor, SP600125, inhibited EPA-induced apoptosis, confirming the involvement of the JNK pathway in EPA-induced apoptotic cell death. Furthermore, 7 days of daily intratumoral injections of EPA significantly suppressed the growth of s.c. malignant glioma xenografts (P &lt; 0.01, on day 19). These results indicate that EPA is therapeutically effective against malignant glioma cells in vitro and in vivo and that it, or a similar marine-based compound, may hold promise as a clinical anticancer agent. [Mol Cancer Ther 2007;6(1):184–92]
MRP8/ABCC11 directly confers resistance to 5-fluorouracil
Authors: Oguri Tetsuya , Bessho Yuji , Achiwa Hiroyuki , Ozasa Hiroaki , Maeno Ken , Maeda Hiroyoshi , Sato Shigeki , Ueda Ryuzo 
Published: January 2007

Abstract
Multidrug-resistance–associated protein, MRP8/ABCC11 (ABCC11), is an efflux pump for nucleotide analogues and 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP). To test whether ABCC11 directly confers 5-fluorouracil (5-FU) resistance, we used the 5-FU–resistant subline PC-6/FU23-26 selected from PC-6 human small-cell lung cancer cells by 5-FU and found that it increases the resistance by ∼25-fold. The intracellular FdUMP accumulation was reduced in PC-6/FU23-26 cells concomitant with the overexpression of the ABCC11 gene. These findings suggest that ABCC11 confers 5-FU resistance in the sublines by enhancing the efflux for the active metabolite FdUMP. Previously, methotrexate also increased the efflux by ABCC11, and we found cross-resistance to methotrexate in PC-6/FU23-26 cells. To confirm our hypothesis, we examined whether decreasing the expression of ABCC11 in PC-6/FU23-26 cells by small interfering RNA altered the cytotoxicity to 5-FU and methotrexate and found that this enhanced 5-FU and methotrexate cytotoxicity in PC-6/FU23-26 cells. These data indicate that expression of the ABCC11 gene is induced by 5-FU, and that ABCC11 is directly involved in 5-FU resistance by the efflux transport of the active metabolite FdUMP. [Mol Cancer Ther 2007;6(1):122–7]
The JAMM motif of human deubiquitinase Poh1 is essential for cell viability
Authors: Gallery Melissa , Blank Jonathan L. , Lin Yinghui , Gutierrez Juan A. , Pulido Jacqueline C. , Rappoli David , Badola Sunita , Rolfe Mark , MacBeth Kyle J. 
Published: January 2007

AbstractPoh1 deubiquitinase activity is required for proteolytic processing of polyubiquitinated substrates by the 26S proteasome, linking deubiquitination to complete substrate degradation. Poh1 RNA interference (RNAi) in HeLa cells resulted in a reduction in cell viability and an increase in polyubiquitinated protein levels, supporting the link between Poh1 and the ubiquitin proteasome pathway. To more specifically test for any requirement of the zinc metalloproteinase motif of Poh1 to support cell viability and proteasome function, we developed a RNAi complementation strategy. Effects on cell viability and proteasome activity were assessed in cells with RNAi of endogenous Poh1 and induced expression of wild-type Poh1 or a mutant form of Poh1, in which two conserved histidines of the proposed catalytic site were replaced with alanines. We show that an intact zinc metalloproteinase motif is essential for cell viability and 26S proteasome function. As a required enzymatic component of the proteasome, Poh1 is an intriguing therapeutic drug target for cancer. [Mol Cancer Ther 2007;6(1):262–8]
Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells
Authors: Sarthy Aparna V. , Morgan-Lappe Susan E. , Zakula Dorothy , Vernetti Lawrence , Schurdak Mark , Packer Jeremy C.L. , Anderson Mark G. , Shirasawa Senji , Sasazuki Takehiko , Fesik Stephen W. 
Published: January 2007

AbstractTo identify cancer-specific targets, we have conducted a synthetic lethal screen using a small interfering RNA (siRNA) library targeting ∼4,000 individual genes for enhanced killing in the DLD-1 colon carcinoma cell line that expresses an activated copy of the K-Ras oncogene. We found that siRNAs targeting baculoviral inhibitor of apoptosis repeat-containing 5 (survivin) significantly reduced the survival of activated K-Ras-transformed cells compared with its normal isogenic counterpart in which the mutant K-Ras gene had been disrupted (DKS-8). In addition, survivin siRNA induced a transient G2-M arrest and marked polyploidy that was associated with increased caspase-3 activation in the activated K-Ras cells. These results indicate that tumors expressing the activated K-Ras oncogene may be particularly sensitive to inhibitors of the survivin protein. [Mol Cancer Ther 2007;6(1):269–76]
Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod
Authors: Choudhari Sweeta R. , Khan Muhammad A. , Harris Genesis , Picker Donald , Jacob Gary S. , Block Timothy , Shailubhai Kunwar 
Published: January 2007

Abstract
Atiprimod is a novel anticancer and antiangiogenic drug candidate which is currently being evaluated in patients with liver carcinoid and multiple myeloma. In this study, we report that atiprimod selectively inhibited proliferation and induced apoptosis in HCC cells that expressed either hepatitis B virus (HBV) or hepatitis C virus, through deactivation of protein kinase B (Akt) and signal transducers and activators of transcription 3 (STAT3) signaling. In HepG2 AD38 cells, which express HBV genome under the control of a tetracycline-off promoter, both Akt and STAT3 were constitutively activated in response to HBV expression. However, this constitutive activation was not sensitive to lamivudine, a drug that inhibits HBV replication without affecting its gene expression, suggesting that HBV replication per se might not be responsible for the activation. Interestingly, the electrophoretic mobility of p-STAT3 protein bands on immunoblot was slower when AD38 cells were cultured in the absence of tetracycline, suggesting a differential phosphorylation in response to HBV expression. In HCC cells, interleukin 6 stimulates the phosphorylation of STAT3 both at serine 727 and at tyrosine 705 positions. The interleukin 6–stimulated activation of STAT3 and Akt was inhibited not only by atiprimod but also by LY294002, a phosphoinositide-3-kinase–specific inhibitor, and by NS398, a cyclooxygenase-2–selective inhibitor. The combination of these compounds did not produce any additive effect, implying that the mechanisms by which HBV activates Akt and STAT3 might also involve phosphoinositide-3-kinase and cyclooxygenase-2. Collectively, these results suggest that atiprimod could be useful as a multifunctional drug candidate for the treatment of HCC in humans. [Mol Cancer Ther 2007;6(1):112–21]
Dynamics of Eddy-Driven Low-Frequency Dipole Modes. Part I: A Simple Model of North Atlantic Oscillations
Authors: Luo Dehai , Lupo Anthony R. , Wan Han 
Published: January 2007

Abstract
A simple theoretical model is proposed to clarify how synoptic-scale waves drive the life cycle of the North Atlantic Oscillation (NAO) with a period of nearly two weeks. This model is able to elucidate what determines the phase of the NAO and an analytical solution is presented to indicate a high similarity between the dynamical processes of the NAO and zonal index, which is not derived analytically in previous theoretical studies. It is suggested theoretically that the NAO is indeed a nonlinear initial-value problem, which is forced by both preexisting planetary-scale and synoptic-scale waves. The eddy forcing arising from the preexisting synoptic-scale waves is shown to be crucial for the growth and decay of the NAO, but the preexisting low-over-high (high-over-low) dipole planetary-scale wave must be required to match the preexisting positive-over-negative (negative-over-positive) dipole eddy forcing so as to excite a positive (negative) phase NAO event. The positive and negative feedbacks of the preexisting dipole eddy forcing depending upon the background westerly wind seem to dominate the life cycle of the NAO and its life period.
An important finding in the theoretical model is that negative-phase NAO events could be excited repeatedly after the first event has decayed, but for the positive phase downstream isolated dipole blocks could be produced after the first event has decayed. This is supported by observed cases of the NAO events presented in this paper. In addition, a statistical study of the relationship between the phase of the NAO and blocking activity over Europe in terms of the seasonal mean NAO index shows that blocking events over Europe are more frequent and long-lived for strong positive-phase NAO years, indicating that the positive-phase NAO favors the occurrence of European blocking events.
Linear and Nonlinear Signatures in the Planetary Wave Dynamics of an AGCM: Probability Density Functions
Authors: Berner Judith , Branstator Grant 
Published: January 2007

Abstract
To identify and quantify indications of linear and nonlinear planetary wave behavior and their impact on the distribution of atmospheric states, characteristics of a very long integration of an atmospheric general circulation model (GCM) in a four-dimensional phase space are examined. The phase space is defined by the leading four empirical orthogonal functions of 500-hPa geopotential heights.
First it is established that nonlinear tendencies similar to those reported in an earlier study of the phase space behavior in this GCM have the potential to lead to non-Gaussian features in the probability density function (PDF) of planetary waves. Then using objective measures it is demonstrated that the model’s distribution of states has distinctive non-Gaussian features. These features are characterized in various subspaces of dimension as high as four. A key feature is the presence of three radial ridges of enhanced probability emanating from the mode, which is shifted away from the climatological mean. There is no evidence of multiple maxima in the full PDF, but the radial ridges lead to three distinct modes in the distribution of circulation patterns.
It is demonstrated that these key aspects of non-Gaussianity are captured by a two-Gaussian mixture model fitted in four dimensions. The two circulation states at the centroids of the component Gaussians are very similar to those associated with two nonlinear features identified by Branstator and Berner in their analysis of the trajectories of the GCM. These two dynamical features are locally linear, so it is concluded that the behavior of planetary waves can be conceptualized as being approximately piecewise-linear, leading to a two-Gaussian mixture with three preferred patterns.
Impact of Atmosphere–Ocean Coupling on the Predictability of Monsoon Intraseasonal Oscillations*
Authors: Fu Xiouhua , Wang Bin , Waliser Duane E. , Tao Li 
Published: January 2007

Abstract
The impact of air–sea coupling on the predictability of monsoon intraseasonal oscillations (MISO) has been investigated with an atmosphere–ocean coupled model and its atmospheric component. From a 15-yr coupled control run, 20 MISO events are selected. A series of twin perturbation experiments have been conducted for all the selected events using both the coupled model and the atmosphere-only model. Two complementary measures are used to quantify the MISO predictability: (i) the ratio of signal-to-forecast error and (ii) the spatial anomaly correlation coefficient (ACC).
In the coupled model, the MISO predictability is generally higher over the Indian sector than that over the western Pacific with a maximum of 35 days in the eastern equatorial Indian Ocean. Air–sea coupling significantly improves the predictability in almost the entire Asian–western Pacific region. The mean predictability of the MISO-related rainfall over its active area (10°S–30°N, 60°–160°E) reaches about 24 days in the coupled model and is about 17 days in the atmosphere-only model. This result suggests that including an interactive ocean allows the MISO predictability of an atmosphere-only model to be extended by about a week. The extended predictability is primarily due to the coupled model capturing the two-way interactions between the MISO and underlying sea surface. The MISO forces a coherent intraseasonal SST response in underlying ocean that in return exerts an external control on the future evolutions of the MISO.
The break phase of the MISO is more predictable than the active phase in both the atmosphere-only model and the coupled model as revealed in the observations. Air–sea coupling appears to extend the MISO predictability uniformly regardless of the active or break phases.