bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics
Authors: Djoko Karrera Y. , Goytia Maira M. , Donnelly Paul S. , Schembri Mark A. , Shafer William M. , McEwan Alastair G. 
Published: August 2015

ABSTRACT

There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using
Neisseria gonorrhoeae
showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in
Escherichia coli
was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of
N. gonorrhoeae
, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen.
Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 3. Tobramycin
Authors: Marchand Sandrine , Grégoire Nicolas , Brillault Julien , Lamarche Isabelle , Gobin Patrice , Couet William 
Published: August 2015

ABSTRACT

The aim of this study was to determine the biopharmaceutical characteristics of tobramycin (TOB) after nebulization in rats. TOB was administered by intravenous (i.v.) bolus or intratracheal nebulization (3 mg · kg
−1
), and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. The ratio of the TOB concentration in ELF to the plasma area under the curve (AUC) was more than 200 times as high after NEB as after i.v. bolus administration, indicating that TOB nebulization offers a biopharmaceutical advantage over i.v. administration.
Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm
Authors: Nazik Hasan , Penner John C. , Ferreira Jose A. , Haagensen Janus A. J. , Cohen Kevin , Spormann Alfred M. , Martinez Marife , Chen Vicky , Hsu Joe L. , Clemons Karl V. , Stevens David A. 
Published: August 2015

ABSTRACT

Iron acquisition is crucial for the growth of
Aspergillus fumigatus
.
A. fumigatus
biofilm formation occurs
in vitro
and
in vivo
and is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl
3
, or FeCl
3
alone. A preformed biofilm was exposed to DFP with or without FeCl
3
. The DFP and DFS MIC
50
against planktonic
A. fumigatus
was 1,250 μM, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of ≤2,500 μM. By XTT testing, DFM concentrations of <1,250 μM had no effect, whereas 2,500 μM increased biofilms forming in
A. fumigatus
or preformed biofilms (
P
< 0.01). DFP at 156 to 2,500 μM inhibited biofilm formation (
P
< 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 μM DFP plus any concentration of FeCl
3
was lower than that in the controls (
P
< 0.05 to 0.001). FeCl
3
at ≥625 μM reversed the DFP inhibitory effect (
P
< 0.05 to 0.01), but the reversal was incomplete compared to the controls (
P
< 0.05 to 0.01). For preformed biofilms, DFP in the range of ≥625 to 1,250 μM was inhibitory compared to the controls (
P
< 0.01 to 0.001). FeCl
3
at ≥625 μM overcame inhibition by 625 μM DFP (
P
< 0.001). FeCl
3
alone at ≥156 μM stimulated biofilm formation (
P
< 0.05 to 0.001). Preformed
A. fumigatus
biofilm increased with 2,500 μM FeCl
3
only (
P
< 0.05). In a strain survey, various susceptibilities of biofilms of
A. fumigatus
clinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation may be a potential therapy for
A. fumigatus
, but we show here that chelators must be chosen carefully. Individual isolate susceptibility assessments may be needed.
Comparative Genomics Provides Insight into the Diversity of the Attaching and Effacing Escherichia coli Virulence Plasmids
Authors: Hazen Tracy H. , Kaper James B. , Nataro James P. , Rasko David A. 
Published: August 2015

ABSTRACT

Attaching and effacing
Escherichia coli
(AEEC) strains are a genomically diverse group of diarrheagenic
E. coli
strains that are characterized by the presence of the locus of enterocyte effacement (LEE) genomic island, which encodes a type III secretion system that is essential to virulence. AEEC strains can be further classified as either enterohemorrhagic
E. coli
(EHEC), typical enteropathogenic
E. coli
(EPEC), or atypical EPEC, depending on the presence or absence of the Shiga toxin genes or bundle-forming pilus (BFP) genes. Recent AEEC genomic studies have focused on the diversity of the core genome, and less is known regarding the genetic diversity and relatedness of AEEC plasmids. Comparative genomic analyses in this study demonstrated genetic similarity among AEEC plasmid genes involved in plasmid replication conjugative transfer and maintenance, while the remainder of the plasmids had sequence variability. Investigation of the EPEC adherence factor (EAF) plasmids, which carry the BFP genes, demonstrated significant plasmid diversity even among isolates within the same phylogenomic lineage, suggesting that these EAF-like plasmids have undergone genetic modifications or have been lost and acquired multiple times. Global transcriptional analyses of the EPEC prototype isolate E2348/69 and two EAF plasmid mutants of this isolate demonstrated that the plasmid genes influence the expression of a number of chromosomal genes in addition to the LEE. This suggests that the genetic diversity of the EAF plasmids could contribute to differences in the global virulence regulons of EPEC isolates.
Opposite and Coordinated Rotation of Amphitrichous Flagella Governs Oriented Swimming and Reversals in a Magnetotactic Spirillum
Authors: Murat Dorothée , Hérisse Marion , Espinosa Leon , Bossa Alicia , Alberto François , Wu Long-Fei 
Published: August 2015

ABSTRACT

Current knowledge regarding the mechanism that governs flagellar motor rotation in response to environmental stimuli stems mainly from the study of monotrichous and peritrichous bacteria. Little is known about how two polar flagella, one at each cell pole of the so-called amphitrichous bacterium, are coordinated to steer the swimming. Here we fluorescently labeled the flagella of
Magnetospirillum magneticum
AMB-1 cells and took advantage of the magnetically controllable swimming of this bacterium to investigate flagellar rotation in moving cells. We identified three motility behaviors (runs, tumbles, and reversals) and two characteristic fluorescence patterns likely corresponding to flagella rotating in opposite directions. Each AMB-1 locomotion mode was systematically associated with particular flagellar patterns at the poles which led us to conclude that, while cell runs are allowed by the asymmetrical rotation of flagellar motors, their symmetrical rotation triggers cell tumbling. Our observations point toward a precise coordination of the two flagellar motors which can be temporarily unsynchronized during tumbling.

IMPORTANCE
Motility is essential for bacteria to search for optimal niches and survive. Many bacteria use one or several flagella to explore their environment. The mechanism by which bipolarly flagellated cells coordinate flagellar rotation is poorly understood. We took advantage of the genetic amenability and magnetically controlled swimming of the spirillum-shaped magnetotactic bacterium
Magnetospirillum magneticum
AMB-1 to correlate cell motion with flagellar rotation. We found that asymmetric rotation of the flagella (counterclockwise at the lagging pole and clockwise at the leading pole) enables cell runs whereas symmetric rotation triggers cell tumbling. Taking into consideration similar observations in spirochetes, bacteria possessing bipolar ribbons of periplasmic flagella, we propose a conserved motility paradigm for spirillum-shaped bipolarly flagellated bacteria.
Protocol—the RAMESES II study: developing guidance and reporting standards for realist evaluation
Authors: Greenhalgh Trisha , Wong Geoff , Jagosh Justin , Greenhalgh Joanne , Manzano Ana , Westhorp Gill , Pawson Ray 
Published: August 2015

IntroductionRealist evaluation is an increasingly popular methodology in health services research. For realist evaluations (RE) this project aims to: develop quality and reporting standards and training materials; build capacity for undertaking and critically evaluating them; produce resources and training materials for lay participants, and those seeking to involve them.MethodsTo achieve our aims, we will: (1) Establish management and governance infrastructure; (2) Recruit an interdisciplinary Delphi panel of 35 participants with diverse relevant experience of RE; (3) Summarise current literature and expert opinion on best practice in RE; (4) Run an online Delphi panel to generate and refine items for quality and reporting standards; (5) Capture ‘real world’ experiences and challenges of RE—for example, by providing ongoing support to realist evaluations, hosting the RAMESES JISCmail list on realist research, and feeding problems and insights from these into the deliberations of the Delphi panel; (6) Produce quality and reporting standards; (7) Collate examples of the learning and training needs of researchers, students, reviewers and lay members in relation to RE; (8) Develop, deliver and evaluate training materials for RE and deliver training workshops; and (9) Develop and evaluate information and resources for patients and other lay participants in RE (eg, draft template information sheets and model consent forms) and; (10) Disseminate training materials and other resources.Planned outputs: (1) Quality and reporting standards and training materials for RE. (2) Methodological support for RE. (3) Increase in capacity to support and evaluate RE. (4) Accessible, plain-English resources for patients and the public participating in RE.DiscussionThe realist evaluation is a relatively new approach to evaluation and its overall place in the is not yet fully established. As with all primary research approaches, guidance on quality assurance and uniform reporting is an important step towards improving quality and consistency.
A Low-Power Variation-Aware Adaptive Write Scheme for Access-Transistor-Free Memristive Memory
Authors: Ghofrani Amirali , lastras-montaño Miguel-angel , Gaba Siddharth , Payvand Melika , Lu Wei , Theogarajan Luke , Cheng Kwang-Ting 
Published: August 2015

Recent advances in access-transistor-free memristive crossbars have demonstrated the potential of memristor arrays as high-density and ultra-low-power memory. However, with considerable variations in the write-time characteristics of individual memristors, conventional fixed-pulse write schemes cannot guarantee reliable completion of the write operations and waste significant amount of energy.
We propose an adaptive write scheme that adaptively adjusts the write pulses to address such variations in memristive arrays, resulting in 7×--11× average energy saving in our case studies. Our scheme embeds an online monitor to detect the completion of a write operation and takes into account the parasitic effect of line-shared devices in access-transistor-free crossbars. This feature also helps shorten the test time of memory march algorithms by eliminating the need of a verifying read right after a write, which is commonly employed in the test sequences of march algorithms.
Socially-Optimal Design of Service Exchange Platforms with Imperfect Monitoring
Authors: Xiao Yuanzhang , Schaar Mihaela Van Der 
Published: August 2015

We study the design of service exchange platforms in which long-lived anonymous users exchange services with each other. The users are randomly and repeatedly matched into pairs of clients and servers, and each server can choose to provide high-quality or low-quality services to the client with whom it is matched. Since the users are anonymous and incur high costs (e.g., exert high effort) in providing high-quality services, it is crucial that the platform incentivizes users to provide high-quality services. Rating mechanisms have been shown to work effectively as incentive schemes in such platforms. A rating mechanism labels each user by a rating, which summarizes the user's past behaviors, recommends a desirable behavior to each server (e.g., provide higher-quality services for clients with higher ratings), and updates each server's rating based on the recommendation and its client's report on the service quality. Based on this recommendation, a low-rating user is less likely to obtain high-quality services, thereby providing users with incentives to obtain high ratings by providing high-quality services.
However, if monitoring or reporting is imperfect—clients do not perfectly assess the quality or the reports are lost—a user's rating may not be updated correctly. In the presence of such errors, existing rating mechanisms cannot achieve the social optimum. In this article, we propose the first rating mechanism that does achieve the social optimum, even in the presence of monitoring or reporting errors. On one hand, the socially-optimal rating mechanism needs to be complicated enough, because the optimal recommended behavior depends not only on the current rating distribution, but also (necessarily) on the history of past rating distributions in the platform. On the other hand, we prove that the social optimum can be achieved by “simple” rating mechanisms that use binary rating labels and a small set of (three) recommended behaviors. We provide design guidelines of socially-optimal rating mechanisms and a low-complexity online algorithm for the rating mechanism to determine the optimal recommended behavior.
Prognostic Value of MRS Metabolites in Postoperative Irradiated High Grade Gliomas
Authors: Tolia Maria , Verganelakis Dimitrios , Tsoukalas Nikolaos , Kyrgias George , Papathanasiou Matilda , Mosa Eftichia , Kokakis Ioannis , Kouvaris John R. , Pissakas George , Pistevou-Gombaki Kyriaki , Kelekis Nikolaos , Kouloulias Vasileios 
Published: August 2015

Purpose. We studied the prognostic significance of Magnetic Resonance Spectroscopy (MRS) in operated high grade gliomas.Materials and Methods. Twelve patients were treated with radiotherapy and Temozolomide. The MRS data were taken four weeks after operation (before radiotherapy) and every six months after the completion of RT. The N-acetyl aspartate, choline, creatine, and myo-inositol parameters were quantified, analyzed, and correlated to recurrence-free survival (RFS).Results. The median RFS was 26.06 months. RFS was significantly worse in elderly patients(P=0.001)along with the higher choline/creatine ratios at either baseline(P= 0.003)or six months post Radiotherapy(P=0.042). Median RFS was 23 months in high choline/creatine levels ≥2 at 6 months after radiotherapy and 11 months for those with <2 choline/creatine levels. There was a significant correlation of maximum difference of choline/creatine ratio with RFS (rho = 0.64,P=0.045).Conclusion. Age and choline/creatine ratio are strong independent prognostic factors in high grade gliomas.
Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages
Authors: Frankenberger Casey , Rabe Daniel , Bainer Russell , Sankarasharma Devipriya , Chada Kiran , Krausz Thomas , Gilad Yoav , Becker Lev , Rosner Marsha Rich 
Published: August 2015

Abstract
Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor-associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP+ tumors, relative to metastatic RKIP− tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP+ tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis-suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics. Cancer Res; 75(19); 4063–73. ©2015 AACR.
A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis
Authors: Remy Elisabeth , Rebouissou Sandra , Chaouiya Claudine , Zinovyev Andrei , Radvanyi François , Calzone Laurence 
Published: August 2015

Abstract
Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non–muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer. Cancer Res; 75(19); 4042–52. ©2015 AACR.
Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy
Authors: McBryan Jean , Fagan Ailís , McCartan Damian , Bane Fiona T. , Varešlija Damir , Cocchiglia Sinéad , Byrne Christopher , Bolger Jarlath , McIlroy Marie , Hudson Lance , Tibbitts Paul , Ó Gaora Peadar , Hill Arnold D. , Young Leonie S. 
Published: August 2015

Abstract
Purpose: Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting.
Experimental Design: Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine-resistant tumors in vivo was investigated in a xenograft model.
Results: The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumors were common to all patients. Larger divergence was observed between primary and liver tumors than between primary and nodal tumors, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions.
Conclusions: This novel global analysis highlights the influence of primary tumor biology in determining the transcriptomic profile of metastatic tumors, as well as the need for adaptations in cell–cell communications to facilitate successful tumor cell colonization of distant host organs. Clin Cancer Res; 21(23); 5371–9. ©2015 AACR.
CCR 20th Anniversary Commentary: A Genetic Mechanism of Imatinib Resistance in Gastrointestinal Stromal Tumor—Where Are We a Decade Later?
Authors: Antonescu Cristina R. , DeMatteo Ronald P. 
Published: August 2015

Abstract
In the June 1, 2005, issue of Clinical Cancer Research, Antonescu and colleagues defined second-site KIT mutations in gastrointestinal stromal tumor (GIST) as the leading mechanism of acquired resistance to imatinib. Secondary mutations were detectable mainly in KIT exon 11 mutant GISTs after prolonged initial clinical responses. These findings played a critical role in designing the next generation of tyrosine kinase inhibitors. Clin Cancer Res; 21(15); 3363–5. ©2015 AACR.
See related article by Antonescu et al., Clin Cancer Res 2005;11(11) June 1, 2005;4182–90