bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid and Reliable Detection of Antimicrobial Peptide Penetration into Gram-Negative Bacteria Based on Fluorescence Quenching
Authors: Benincasa Monica , Pacor Sabrina , Gennaro Renato , Scocchi Marco 
Published: May 2009

ABSTRACT

In this paper, we describe a rapid flow cytometry method to identify antimicrobial peptides that are internalized into bacterial cells and differentiate them from those that are membrane active. The method was applied to fluorescently labeled Bac7
1-35
and polymyxin B, whose mechanisms of action are, respectively, based on cell penetration and on membrane binding and permeabilization. Identification of peptides with the former mechanism is of considerable interest for the intracellular delivery of membrane-impermeant drugs.
Aggregatibacter actinomycetemcomitansCytolethal Distending Toxin Induces Apoptosis in Nonproliferating Macrophages by a Phosphatase-Independent Mechanism
Authors: Rabin Shira D. P. , Flitton Jared G. , Demuth Donald R. 
Published: May 2009

ABSTRACTAggregatibacter actinomycetemcomitansstrains that express cytolethal distending toxin (Cdt) are associated with localized aggressive periodontitis. However, the in vivo targets of Cdt in the human oral cavity have not been firmly established. Here, we demonstrate thatA. actinomycetemcomitansCdt kills proliferating and nonproliferating U937 monocytic cells at a comparable specific activity, approximately 1.5-fold lower than that against the Cdt-hypersensitive Jurkat T-cell line. Cdt functioned both as a DNase and a phosphatidylinositol 3-phosphate (PIP3) phosphatase, and these activities were distinguished by site-specific mutagenesis of the active site residues of CdtB. Using these mutants, we determined that the DNase activity of CdtB is required for cell cycle arrest and caspase-dependent induction of apoptosis in proliferating U937 cells. In contrast, Cdt holotoxin induced apoptosis by a mechanism independent of caspase- and apoptosis-inducing factor in nonproliferating U937 cells. Furthermore, apoptosis of nonproliferating U937 cells was unaffected by the Cdt mutant possessing reduced phosphatase activity or by the addition of a specific PIP3phosphatase inhibitor, suggesting that the induction of apoptosis is independent of phosphatase activity. These results indicate that Cdt intoxication of proliferating and nonproliferating U937 cells occurs by distinct mechanisms and suggest that macrophages may also be potential in vivo targets of Cdt.
Screening of
Streptococcus pneumoniae
ABC Transporter Mutants Demonstrates that LivJHMGF, a Branched-Chain Amino Acid ABC Transporter, Is Necessary for Disease Pathogenesis
Authors: Basavanna Shilpa , Khandavilli Suneeta , Yuste Jose , Cohen Jonathan M. , Hosie Arthur H. F. , Webb Alexander J. , Thomas Gavin H. , Brown Jeremy S. 
Published: May 2009

ABSTRACT

Bacterial ABC transporters are an important class of transmembrane transporters that have a wide variety of substrates and are important for the virulence of several bacterial pathogens, including
Streptococcus pneumoniae
. However, many
S. pneumoniae
ABC transporters have yet to be investigated for their role in virulence. Using insertional duplication mutagenesis mutants, we investigated the effects on virulence and in vitro growth of disruption of 9
S. pneumoniae
ABC transporters. Several were partially attenuated in virulence compared to the wild-type parental strain in mouse models of infection. For one ABC transporter, required for full virulence and termed LivJHMGF due to its similarity to branched-chain amino acid (BCAA) transporters, a deletion mutant (Δ
livHMGF
) was constructed to investigate its phenotype in more detail. When tested by competitive infection, the Δ
livHMGF
strain had reduced virulence in models of both pneumonia and septicemia but was fully virulent when tested using noncompetitive experiments. The Δ
livHMGF
strain had no detectable growth defect in defined or complete laboratory media. Recombinant LivJ, the substrate binding component of the LivJHMGF, was shown by both radioactive binding experiments and tryptophan fluorescence spectroscopy to specifically bind to leucine, isoleucine, and valine, confirming that the LivJHMGF substrates are BCAAs. These data demonstrate a previously unsuspected role for BCAA transport during infection for
S. pneumoniae
and provide more evidence that functioning ABC transporters are required for the full virulence of bacterial pathogens.
Endogenous Tumor Suppression Mediated by PTEN Involves Survivin Gene Silencing
Authors: Guha Minakshi , Plescia Janet , Leav Irwin , Li Jing , Languino Lucia R. , Altieri Dario C. 
Published: May 2009

Abstract
Endogenous tumor suppression provides a barrier against oncogenesis, but the molecular requirements of this process are not well understood. Here, we show that the dual specificity phosphatase PTEN, a gene almost universally altered in human tumors, silences the expression of survivin, an essential regulator of cell division and apoptosis in cancer. This pathway is independent of p53, involves active repression of survivin gene transcription, and is mediated by direct occupancy of the survivin promoter by FOXO1 and FOXO3a factors. Conditional deletion of PTEN in the mouse prostate causes deregulated induction of survivin before full-blown transformation in vivo, whereas expression of survivin and PTEN is inversely correlated in cancer patients. Therefore, silencing the survivin gene is an essential requirement of endogenous PTEN tumor suppression. [Cancer Res 2009;69(12):4954–8]
DNMT3B Expression Might Contribute to CpG Island Methylator Phenotype in Colorectal Cancer
Authors: Nosho Katsuhiko , Shima Kaori , Irahara Natsumi , Kure Shoko , Baba Yoshifumi , Kirkner Gregory J. , Chen Li , Gokhale Sumita , Hazra Aditi , Spiegelman Donna , Giovannucci Edward L. , Jaenisch Rudolf , Fuchs Charles S. , Ogino Shuji 
Published: May 2009

Abstract
Purpose: DNA methyltransferase-3B (DNMT3B) plays an important role in de novo CpG island methylation. Dnmt3b can induce colon tumor in mice with methylation in specific CpG islands. We hypothesized that cellular DNMT3B level might influence the occurrence of widespread CpG island methylation (i.e., the CpG island methylator phenotype, CIMP) in colon cancer.
Experimental Design: Utilizing 765 colorectal cancers in two cohort studies, we detected DNMT3B expression in 116 (15%) tumors by immunohistochemistry. We assessed microsatellite instability, quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) by Pyrosequencing, eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by real-time PCR (MethyLight).
Results: Tumoral DNMT3B overexpression was significantly associated with CIMP-high [≥6/8 methylated CIMP-specific promoters; odds ratio (OR), 3.34; 95% confidence interval, 2.11-5.29; P &lt; 0.0001]. The relations between DNMT3B and methylation in 16 individual CpG islands varied substantially (OR, 0.80-2.96), suggesting variable locus-to-locus specificities of DNMT3B activity. DNMT3B expression was not significantly related with LINE-1 hypomethylation. In multivariate logistic regression, the significant relation between DNMT3B and CIMP-high persisted (OR, 2.39; 95% confidence interval, 1.11-5.14; P = 0.026) after adjusting for clinical and other molecular features, including p53, β-catenin, LINE-1, microsatellite instability, KRAS, PIK3CA, and BRAF. DNMT3B expression was unrelated with patient outcome, survival, or prognosis.
Conclusions: Tumoral DNMT3B overexpression is associated with CIMP-high in colorectal cancer. Our data support a possible role of DNMT3B in nonrandom de novo CpG island methylation leading to colorectal cancer.
Nitric Oxide Synthase Inhibition Enhances the Tumor Vascular-Damaging Effects of Combretastatin A-4 3-O-Phosphate at Clinically Relevant Doses
Authors: Tozer Gillian M. , Prise Vivien E. , Lewis Gemma , Xie Shaoping , Wilson Ian , Hill Sally A. 
Published: May 2009

Abstract
Purpose: The therapeutic potential of combining the prototype tumor vascular-disrupting agent combretastatin A-4 3-O-phosphate (CA-4-P) with systemic nitric oxide synthase (NOS) inhibition was investigated preclinically.
Experimental Design: Vascular response (uptake of 125I-labeled iodoantipyrine; laser Doppler flowmetry) and tumor response (histologic necrosis; cytotoxicity and growth delay) were determined.
Results: Inducible NOS selective inhibitors had no effect on blood flow in the P22 rat sarcoma. In contrast, the non–isoform-specific NOS inhibitor Nω-nitro- l-arginine (l-NNA; 1 and 10 mg/kg i.v. or chronic 0.1 or 0.3 mg/mL in drinking water) decreased the P22 blood flow rate selectively down to 36% of control at 1 hour but did not induce tumor necrosis at 24 hours. CA-4-P, at clinically relevant doses, decreased the P22 blood flow rate down to 6% of control at 1 hour for 3 mg/kg but with no necrosis induction. However, l-NNA administration enhanced both CA-4-P–induced tumor vascular resistance at 1 hour (chronic l-NNA administration) and necrosis at 24 hours, with 45% or 80% necrosis for 3 and 10 mg/kg CA-4-P, respectively. Bolus l-NNA given 3 hours after CA-4-P was the most effective cytotoxic schedule in the CaNT mouse mammary carcinoma, implicating a particular enhancement by l-NNA of the downstream consequences of CA-4-P treatment. Repeated dosing of l-NNA with CA-4-P produced enhanced growth delay over either treatment alone in P22, CaNT, and spontaneous T138 mouse mammary tumors, which represented a true therapeutic enhancement.
Conclusions: The combination of NOS inhibition with CA-4-P is a promising approach for targeting tumor vasculature, with relevance for similar vascular-disrupting agents in development.
Sagopilone Inhibits Breast Cancer Bone Metastasis and Bone Destruction Due to Simultaneous Inhibition of Both Tumor Growth and Bone Resorption
Authors: Strube Anne , Hoffmann Jens , Stepina Elizaveta , Hauff Peter , Klar Ulrich , Käkönen Sanna-Maria 
Published: May 2009

Abstract
Purpose: Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a “vicious cycle” of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo, and here we report its activity in the MDA-MB-231(SA) breast cancer bone metastasis mouse model.
Experimental Design: The potency of sagopilone was determined in treatment models simulating the adjuvant (preventive) and metastatic (therapeutic) settings in the clinic.
Results: We showed that sagopilone inhibited tumor burden and bone destruction, in addition to reducing tumor-induced cachexia and paraplegia. The reduction in osteolytic lesions, tumor growth in bone, and weight loss was statistically significant in the preventive model compared with the vehicle group. In the therapeutic model, sagopilone treatment significantly lowered the number of activated osteoclasts and significantly reduced the osteolytic lesion area, bone volume loss, and bone resorption compared with vehicle treatment while simultaneously inhibiting tumor burden. An in vitro assay confirmed that sagopilone inhibited osteoclast activation without cytotoxic effects, whereas paclitaxel resulted in lower inhibition and high levels of cytotoxicity.
Conclusions: Sagopilone seems to inhibit the vicious cycle at both the tumor growth and bone resorption stages, suggesting the possibility for substantial benefit in the treatment of patients with breast cancer at risk from bone metastases or with bone lesions already present. Phase II clinical trials with sagopilone in patients with breast cancer are ongoing.
FOXA1 Is a Potential Oncogene in Anaplastic Thyroid Carcinoma
Authors: Nucera Carmelo , Eeckhoute Jerome , Finn Stephen , Carroll Jason S. , Ligon Azra H. , Priolo Carmen , Fadda Guido , Toner Mary , Sheils Orla , Attard Marco , Pontecorvi Alfredo , Nose Vânia , Loda Massimo , Brown Myles 
Published: May 2009

Abstract
Purpose: FOXA1 is a mammalian endodermal transcription factor belonging to the human forkhead box gene family that plays a role in certain tumor types. Here, we investigated the potential role of FOXA1 in human thyroid carcinomas.
Experimental Design: We examined the level of FOXA1 expression and gene copy number by immunohistochemistry and fluorescence in situ hybridization, respectively, in a cohort of benign and malignant thyroid tumors. In addition, we examined the role of FOXA1 in the proliferation of an undifferentiated thyroid carcinoma cell line by short hairpin RNA-mediated silencing.
Results: We show that FOXA1 is overexpressed in human anaplastic thyroid carcinomas (ATC). In addition, we identify FOXA1 DNA copy number gain within the 14q21.1 locus in both an ATC cell line and human ATC cases. Silencing of FOXA1 in an ATC cell line causes G1 growth arrest and reduction of cell proliferation. Moreover, we observe a potential link between FOXA1 and the cell cycle machinery by identifying p27kip1 up-regulation on FOXA1 silencing.
Conclusions: FOXA1 is overexpressed in aggressive thyroid cancers and involved in cell cycle progression in an ATC cell line. Therefore, FOXA1 may be an important oncogene in thyroid tumorigenesis and a potential new therapeutic target for the treatment of anaplastic thyroid cancers.
Integrative Analysis of Cyclin Protein Levels Identifies Cyclin B1 as a Classifier and Predictor of Outcomes in Breast Cancer
Authors: Agarwal Roshan , Gonzalez-Angulo Ana-Maria , Myhre Simen , Carey Mark , Lee Ju-Seog , Overgaard Jens , Alsner Jan , Stemke-Hale Katherine , Lluch Ana , Neve Richard M. , Kuo Wen Lin , Sorlie Therese , Sahin Aysegul , Valero Vicente , Keyomarsi Khandan , Gray Joe W. , Borresen-Dale Anne-Lise , Mills Gordon B. , Hennessy Bryan T. 
Published: May 2009

Abstract
Purpose: We studied the expression levels of cyclins B1, D1, and E1 and the implications of cyclin overexpression for patient outcomes in distinct breast cancer subtypes defined by clinical variables and transcriptional profiling.
Experimental Design: The expression levels of cyclins B1, D1, and E1 were quantified in 779 breast tumors and 53 cell lines using reverse phase protein arrays and/or transcriptional profiling.
Results: Whereas cyclin E1 overexpression was a specific marker of triple-negative and basal-like tumors, cyclin B1 overexpression occurred in poor prognosis hormone receptor–positive, luminal B and basal-like breast cancers. Cyclin D1 overexpression occurred in luminal and normal-like cancers. Breast cancer subgroups defined by integrated expression of cyclins B1, D1, and E1 correlated significantly (P &lt; 0.000001) with tumor subtypes defined by transcriptional profiling and clinical criteria. Across three hormone receptor–positive data sets, cyclin B1 was the dominant cyclin associated with poor prognosis in univariate and multivariate analyses. Although CCNE1 was present in significantly higher copy numbers in basal-like versus other subtypes (ANOVA P &lt; 0.001), CCNB1 gene copy number did not show gain in breast cancer. Instead, cyclin B1 expression was increased in tumors with co-occurrence of TP53 mutations and MYC amplification, a combination that seems to characterize basal-like and luminal B tumors. CCNB1 gene expression was significantly correlated with PLK, CENPE, and AURKB gene expression.
Conclusion: Cyclins B1, D1, and E1 have distinct expressions in different breast cancer subtypes. Novel PLK, CENPE, and AURKB inhibitors should be assessed for therapeutic utility in poor prognosis cyclin B1–overexpressing breast cancers.
3,3′-Diindolylmethane Enhances the Efficacy of Butyrate in Colon Cancer Prevention through Down-Regulation of Survivin
Authors: Bhatnagar Namrata , Li Xia , Chen Yue , Zhou Xudong , Garrett Scott H. , Guo Bin 
Published: May 2009

Abstract
Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently showed that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor–induced apoptosis in colon cancers. Here, we show that APC mutation rendered colon cancer cells resistant to butyrate-induced apoptosis due to the failure of butyrate to down-regulate survivin in these cells. Another cancer-preventive agent, 3,3′-diindolylmethane (DIM), was identified to be able to down-regulate survivin in colon cancers expressing mutant APC. DIM inhibited survivin mRNA expression and promoted survivin protein degradation through inhibition of p34cdc2-cyclin B1–mediated survivin Thr34 phosphorylation. Pretreatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/butyrate combination treatment induced the expression of proapoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. Whereas overexpression of survivin blocked DIM/butyrate–induced apoptosis, knocking down of survivin by small interfering RNA increased butyrate-induced apoptosis in colon cancer cells. We further showed that DIM was able to down-regulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APCmin/+ mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer.
Synergistic Growth Inhibition of Squamous Cell Carcinoma of the Head and Neck by Erlotinib and Epigallocatechin-3-Gallate: The Role of p53-Dependent Inhibition of Nuclear Factor-κB
Authors: Amin A.R.M. Ruhul , Khuri Fadlo R. , Chen Zhuo (Georgia) , Shin Dong M. 
Published: May 2009

Abstract
We have previously reported that the green tea polyphenol epigallocatechin-3-gallate (EGCG) and the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib had synergistic growth-inhibitory effects in cell culture and a nude mouse xenograft model of squamous cell carcinoma of the head and neck. However, the mechanism of their antitumor synergism is not fully understood. In the current study, we investigate the mechanism of their synergistic growth-inhibitory effects. The treatment of squamous cell carcinoma of the head and neck cell lines with erlotinib time-dependently increased the expression of cell cycle regulatory proteins p21 and p27 and apoptosis regulatory protein Bim. EGCG alone had very little or no effect on the expression of these proteins among the cell lines. However, simultaneous treatment with EGCG and erlotinib strongly inhibited erlotinib-induced expression of p21 and p27 without affecting the expression of Bim. Moreover, erlotinib increased the expression of p53 protein, the ablation of which by short hairpin RNA strongly inhibited EGCG- and erlotinib-mediated growth inhibition and the expression of p21, p27, and Bim. In addition, combined treatment with erlotinib and EGCG inhibited the protein level of p65 subunit of nuclear factor-κB and its transcriptional target Bcl-2, but failed to do so in cells with ablated p53. Taken together, our results, for the first time, suggest that erlotinib treatment activates p53, which plays a critical role in synergistic growth inhibition by erlotinib and EGCG via inhibiting nuclear factor-κB signaling pathway. Characterizing the underlying mechanisms of EGCG and erlotinib synergism will provide an important rationale for chemoprevention or treatment trials using this combination.
Connecting Prepaid Cards and Retail Loans: Innovative Practical Solution or Confusing Legal Combination? Implications of the EU Financial Services Law from an Estonian Perspective
Authors: Ulst Ingrid 
Published: May 2009

AbstractA prepaid card is a fairly new financial product that is part of the global innovations in financial services of the last 10 years. Some non-bank financing companies (e.g., SMS loan providers) have further advanced this product by linking prepaid cards to retail loans, which entails more developed transaction schemes and technical solutions. This combination is seen as a practical solution that broadens the customer base of loan providers and improves consumer convenience. However, from a legal point of view, practicality often entails complexity.This article seeks to address some of the major legal features and positions with regard to the prepaid card and its combination with a retail loan. In doing so, it will review the position of a prepaid card and the status of the issuer within the existing legal framework in Estonia. It also seeks to explain how the idea of linking prepaid cards with retail loans is being carried in practical terms through a complex network of agreements. We shall also discuss treating a prepaid card as an instrument of electronic money or some other form of payment, and examine the functions and licensing of an issuer. In anticipating potential discussion of the above topics from the perspective of a member state, this article compares the principles of EU law and the legal framework of Estonia. While we shall briefly deal with certain aspects of consumer protection, the focus of the article is on examining the relevant financial services legislation.
Diagnosis of the MJO Modulation of Tropical Cyclogenesis Using an Empirical Index
Authors: Camargo Suzana J. , Wheeler Matthew C. , Sobel Adam H. 
Published: May 2009

Abstract
The modulation of tropical cyclone activity by the Madden–Julian oscillation (MJO) is explored using an empirical genesis potential (GP) index. Composite anomalies of the genesis index associated with the different MJO phases are consistent with the composite anomalies in TC genesis frequency that occur in the same phases, indicating that the index captures the changes in the environment that are at least in part responsible for the genesis frequency changes. Of the four environmental variables that enter the genesis potential index, the midlevel relative humidity makes the largest contribution to the MJO composite GP anomalies. The second largest contribution comes from the low-level absolute vorticity, and only very minor contributions come from the vertical wind shear and potential intensity.
When basin-integrated MJO composite anomalies of the GP index are regressed against basin-integrated composite anomalies of TC genesis frequency, the results differ quantitatively from those obtained from the analogous calculation performed on the annual climatologies in the two quantities. The GP index captures the MJO modulation of TC genesis to a lesser degree than the climatological annual cycle of genesis (to which it was originally tuned). This may be due to weaknesses of the reanalysis or indicative of the importance of precursor disturbances, not well captured in the GP index computed from weekly data, to the intraseasonal TC genesis frequency fluctuations.