bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imidazolium Salts as Small-Molecule Urinary Bladder Exfoliants in a Murine Model
Authors: Wagers Patrick O. , Tiemann Kristin M. , Shelton Kerri L. , Kofron William G. , Panzner Matthew J. , Wooley Karen L. , Youngs Wiley J. , Hunstad David A. 
Published: June 2015

ABSTRACT

We present a novel family of small-molecule urinary bladder exfoliants that are expected to be of great value in preclinical studies of urologic conditions and have improved potential for translation compared with prior agents. There is broad urologic interest in the therapeutic potential of such exfoliating agents. The primary agent used in preclinical models, the cationic peptide protamine sulfate (PS), has limited translational potential due to concerns including systemic adverse reactions and bladder tissue injury. Intravesical application of a safe, systemically nontoxic exfoliant would have potential utility in the eradication of
Escherichia coli
and other uropathogens that reside in the bladder epithelium following cystitis, as well as in chronic bladder pain and bladder cancer. Here, we introduce a family of imidazolium salts with potent and focused exfoliating activity on the bladder epithelium. Synthesis and purification were straightforward and scalable, and the compounds exhibited prolonged stability in lyophilized form. Most members of the compound family were cytotoxic to cultured uroepithelial cells, with >10-fold differences in potency across the series. Upon topical (intravesical) administration of selected compounds to the murine bladder, complete epithelial exfoliation was achieved with physiologically relevant imidazolium concentrations and brief contact times. The exfoliative activity of these compounds was markedly improved in comparison to PS, as assessed by microscopy, immunofluorescence, and immunoblotting for uroplakins. Bladder uroepithelium regenerated within days to yield a histologically normal appearance, and no toxicity was observed. Finally, the chemical scaffold offers an opportunity for inclusion of antimicrobials or conjugation with chemotherapeutic or other moieties.
In Vitro
Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole
Authors: Niece Krista L. , Boyd Natalie K. , Akers Kevin S. 
Published: June 2015

ABSTRACT

Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 μg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%;
P
< 0.001) and individual HLMs (86% versus 76%;
P
< 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections.
Role of CD4+Foxp3+Regulatory T Cells in Protection Induced by a Live Attenuated, Replicating Type I Vaccine Strain of Toxoplasma gondii
Authors: Akbar Haroon , Dimier-Poisson Isabelle , Moiré Nathalie 
Published: June 2015

ABSTRACTVaccination with the live attenuatedToxoplasma gondiiMic1.3KO strain induced long-lasting immunity against challenge withToxoplasma gondiitype I and type II strains. The involvement of regulatory T cells (Tregs) in the protection mechanism was investigated. Intraperitoneal injection of Mic1.3KO induced a weak and transient influx of CD4+Foxp3+T regulatory cells followed by recruitment/expansion of CD4+Foxp3−CD25+effector cells and control of the parasite at the site of infection. The local and systemic cytokine responses associated with this recruitment of Tregs were of the TH1/Treg-like type. In contrast, injection of RH, the wild-type strain from which the vaccinal strain is derived, induced a low CD4+Foxp3+cell influx and uncontrolled multiplication of the parasites at this local site, followed by death of the mice. The associated local and systemic cytokine responses were of the TH1/TH17-like type. In addition,in vivoTreg induction in RH-infected mice with interleukin-2 (IL-2)/anti-IL-2 complexes induced control of the parasite and a TH1/Treg cytokine response similar to the response after Mic1.3KO vaccination. These results suggest that Tregs may contribute to the protective response after vaccination with Mic1.3KO.
Structural Characterization of the Fla2 Flagellum of Rhodobacter sphaeroides
Authors: de la Mora Javier , Uchida Kaoru , del Campo Ana Martínez , Camarena Laura , Aizawa Shin-Ichi , Dreyfus Georges 
Published: June 2015

ABSTRACT

Rhodobacter sphaeroides
is a free-living alphaproteobacterium that contains two clusters of functional flagellar genes in its genome: one acquired by horizontal gene transfer (fla1) and one that is endogenous (fla2). We have shown that the Fla2 system is normally quiescent and under certain conditions produces polar flagella, while the Fla1 system is always active and produces a single flagellum at a nonpolar position. In this work we purified and characterized the structure and analyzed the composition of the Fla2 flagellum. The number of polar filaments per cell is 4.6 on average. By comparison with the Fla1 flagellum, the prominent features of the ultra structure of the Fla2 HBB are the absence of an H ring, thick and long hooks, and a smoother zone at the hook-filament junction. The Fla2 helical filaments have a pitch of 2.64 μm and a diameter of 1.4 μm, which are smaller than those of the Fla1 filaments. Fla2 filaments undergo polymorphic transitions
in vitro
and showed two polymorphs: curly (right-handed) and coiled. However,
in vivo
in free-swimming cells, we observed only a bundle of filaments, which should probably be left-handed. Together, our results indicate that Fla2 cell produces multiple right-handed polar flagella, which are not conventional but exceptional.

IMPORTANCE
R. sphaeroides
possesses two functional sets of flagellar genes. The fla1 genes are normally expressed in the laboratory and were acquired by horizontal transfer. The fla2 genes are endogenous and are expressed in a Fla1
−
mutant grown phototrophically and in the absence of organic acids. The Fla1 system produces a single lateral or subpolar flagellum, and the Fla2 system produces multiple polar flagella. The two kinds of flagella are never expressed simultaneously, and both are used for swimming in liquid media. The two sets of genes are certainly ready for responding to specific environmental conditions. The characterization of the Fla2 system will help us to understand its role in the physiology of this microorganism.
Is social deprivation an independent predictor of outcomes following cardiac surgery? An analysis of 240 221 patients from a national registry
Authors: Barnard James , Grant Stuart W , Hickey Graeme L , Bridgewater Ben 
Published: June 2015

ObjectivesSocial deprivation impacts on healthcare outcomes but is not included in the majority of cardiac surgery risk prediction models. The objective was to investigate geographical variations in social deprivation of patients undergoing cardiac surgery and identify whether social deprivation is an independent predictor of outcomes.MethodsNational Adult Cardiac Surgery Audit data for coronary artery bypass graft (CABG), or valve surgery performed in England between April 2003 and March 2013, were analysed. Base hospitals in England were divided into geographical regions. Social deprivation was measured by quintile groups of the index of multiple deprivation (IMD) score with the first quintile group (Q1) being the least, and the last quintile group (Q5) the most deprived group. In-hospital mortality and midterm survival were analysed using mixed effects logistic, and stratified Cox proportional hazards regression models respectively.Results240 221 operations were analysed. There was substantial regional variation in social deprivation with the proportion of patients in IMD Q5 ranging from 34.5% in the North East to 6.5% in the East of England. Following adjustment for preoperative risk factors, patients undergoing all cardiac surgery in IMD Q5 were found to have an increased risk of in-hospital mortality relative to IMD Q1 (OR=1.13; 95%CI 1.03 to 1.24), as were patients undergoing isolated CABG (OR=1.19; 95%CI 1.03 to 1.37). For midterm survival, patients in IMD Q5 had an increased hazard in all groups (HRs ranged between 1.10 (valve+CABG) and 1.26 (isolated CABG)). For isolated CABG, the median postoperative length of stay was 6 and 7 days, respectively, for IMD Q1–Q4 and Q5.ConclusionsSignificant regional variation exists in the social deprivation of patients undergoing cardiac surgery in England. Social deprivation is associated with an increased risk of in-hospital mortality and reduced midterm survival. These findings have implications for health service provision, risk prediction models and analyses of surgical outcomes.
Yersinia pseudotuberculosis infection in an adult Boer goat
Authors: Helmer C , Eibach R , Kleinschmidt S , Ganter M 
Published: June 2015

This case report describes a Yersinia pseudotuberculosis infection in an adult, female single pet goat kept on a dairy cattle farm. The doe showed the habitus of a chronically ill animal, with poor body condition and chronic diarrhoea, when presented at the clinic. The animal displayed a grave manifestation of the disease with severe enteritis and typhlocolitis, lymphadenitis and some up to 10 cm in diameter pyogranulomatous inflammation in the liver, spleen, pancreas, omasum and the intestinal lymph nodes. All other causative agents that might explain the described signs were ruled out (Corynebacterium pseudotuberculosis, Mycobacterium avium subspecies paratuberculosis, tuberculosis, tumorous alterations, foreign bodies, caprine arthritis encephalitis). Goats seem to be vulnerable for yersiniosis, but in contrast to this case report, in most cases, Yersinia enterocolitica, and not Y. pseudotuberculosis, can be proved as infectious cause of yersiniosis.
Deciding Determinism with Fairness for Simple Transducer Networks
Authors: Ameloot Tom J. 
Published: June 2015

A distributed database system often operates in an asynchronous communication model where messages can be arbitrarily delayed. This communication model causes nondeterministic effects like unpredictable arrival orders of messages. Nonetheless, in general we want the distributed system to be deterministic; the system should produce the same output despite the nondeterministic effects on messages.
Previously, two interpretations of determinism have been proposed. The first says that all infinite fair computation traces produce the same output. The second interpretation is a confluence notion, saying that all finite computation traces can still be extended to produce the same output. A decidability result for the confluence notion was previously obtained for so-called simple transducer networks, a model from the field of declarative networking. In the current article, we also present a decidability result for simple transducer networks, but this time for the first interpretation of determinism, with infinite fair computation traces. We also compare the expressivity of simple transducer networks under both interpretations.
Interleukin-6 Prevents the Initiation but Enhances the Progression of Lung Cancer
Authors: Qu Zhaoxia , Sun Fan , Zhou Jingjiao , Li Liwen , Shapiro Steven D. , Xiao Gutian 
Published: June 2015

Abstract
Recent studies suggest that high expression of the proinflammatory cytokine IL6 is associated with poor survival of lung cancer patients. Accordingly, IL6 has been a target of great interest for lung cancer therapy. However, the role of IL6 in lung cancer has not been determined yet. Here, we demonstrate that IL6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared with wild-type mice, IL6-deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL6-deficient mice were significantly smaller. Notably, both the lung tumor–suppressing and –promoting functions of IL6 involve its ability in activating the transcription factor STAT3. IL6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages, and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator cyclin D1. These studies reveal a previously unexplored role of IL6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL6/STAT3-targeted therapies for this deadliest human cancer. Cancer Res; 75(16); 3209–15. ©2015 AACR.
Tackling Crizotinib Resistance: The Pathway from Drug Discovery to the Pediatric Clinic
Authors: Tucker Elizabeth R. , Danielson Laura S. , Innocenti Paolo , Chesler Louis 
Published: June 2015

Abstract
Neuroblastoma is a childhood malignancy that has not yet benefitted from the rapid progress in the development of small-molecule therapeutics for cancer. An opportunity to take advantage of pharmaceutical innovation in this area arose when the identification of ALK fusion proteins in non–small cell lung cancer (NSCLC) occurred in parallel to the discovery of point mutations of ALK in neuroblastomas. ALK is now known to be a marker of poor outcome in neuroblastoma, and therefore, urgent development of specific ALK inhibitors to treat this devastating disease is a necessity. However, the translation of small molecules from adult directly into pediatric practice has thus far been challenging, due to mutation-specific structural variances in the ALK kinase domain. We discuss how the most recent structural and biological characterizations of ALK are directing preclinical and clinical studies of ALK inhibitors for both NSCLC and neuroblastoma. Cancer Res; 75(14); 2770–4. ©2015 AACR.
Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo
Authors: Kimbrough Charles W. , Khanal Anil , Zeiderman Matthew , Khanal Bigya R. , Burton Neal C. , McMasters Kelly M. , Vickers Selwyn M. , Grizzle William E. , McNally Lacey R. 
Published: June 2015

Abstract
Background: pH-low insertion peptides (pHLIP) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer.
Methods: A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semiquantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model.
Results: In vitro, the V7-750 probe demonstrated significantly higher fluorescence at pH 6.6 compared with pH 7.4 (S2VP10, P = 0.0119; S2013, P = 0.0160), whereas no difference was observed with the K7-750 control (S2VP10, P = 0.8783; S2013, P = 0.921). In the in vivo S2VP10 model, V7-750 probe resulted in 782.5 MSOT a.u. signal compared with 5.3 MSOT a.u. in K7-750 control in tumor (P = 0.0001). Similarly, V7-750 probe signal was 578.3 MSOT a.u. in the S2013 model compared with K7-750 signal at 5.1 MSOT a.u. (P = 0.0005). There was minimal off-target accumulation of the V7-750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging.
Conclusions: Compared with pH-insensitive controls, V7-750 pH-sensitive probe specifically targets pancreatic adenocarcinoma and has minimal off-target accumulation. The noninvasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer. Clin Cancer Res; 21(20); 4576–85. ©2015 AACR.
See related commentary by Reshetnyak, p. 4502
Ablation of B7-H3 but Not B7-H4 Results in Highly Increased Tumor Burden in a Murine Model of Spontaneous Prostate Cancer
Authors: Kreymborg Katharina , Haak Stefan , Murali Rajmohan , Wei Joyce , Waitz Rebecca , Gasteiger Georg , Savage Peter A. , van den Brink Marcel R. M. , Allison James P. 
Published: June 2015

Abstract
The costimulatory molecules B7-H3 and B7-H4 are overexpressed in a variety of human tumors and have been hypothesized as possible biomarkers and immunotherapeutic targets. Despite this potential, the predominating uncertainty about their functional implication in tumor–host interaction hampers their evaluation as a target for cancer therapy. By means of a highly physiologic, spontaneous tumor model in mice, we establish a causal link between B7-H3 and host tumor control and found B7-H4 to be redundant. Cancer Immunol Res; 3(8); 849–54. ©2015 AACR.
CHAPADA DOS GUIMARÃES: BORDA DA BACIA DO PARANÁ
Authors: Ross Jurandyr Luciano Sanches 
Published: June 2015

<p>A Chapada dos Guimarães corresponde a uma extensa superfície de relevo elevado e de topo aplanado posicionada na extremidade noroeste da bacia sedimentar do Paraná localizada no Estado de Mato Grosso-Brasil.As formas planas do topo, estão entre 600 e 800m de altitude com a superfície pouco inclinada de noroeste para sul e leste. Está esculpida sobre rochas sedimentares preferencialmente arenitos do período Devoniano e do Cretáceo. Suas bordas são escarpadas, sendo que as frentes de escarpas voltadas para a Depressão Cuiabana ultrapassam os 500m de gradiente topográfico. Nessa região a Chapada também apresenta nos topos formas de relevos ruiniformes esculpidos nos arenitos vermelhos e amarelos da Formação Ponta Grossa (Devoniano). A chapada é contornada por Depressões como a Cuiabana e a Interplanaltica de Paranatinga a noroeste e norte e também por Planaltos a noroeste e sul. Essas áreas são fortemente marcadas por feixes de falhas de direção NE-SW e que têm vinculações com as áreas de dobramentos do pré-Cambriano Superior denominado de Cinturão Orogenético Paraguai-Araguaia. A região passou a ter reativações tectônicas a partir do meso-cenozoico atuando nos processos de soerguimento generalizado com arqueamentos dômicos mais localizados como ocorre com o chamado “Arco de São Vicente”. A morfogênese da Chapada têm fortes relações com o tectonismo meso-cenozoico de um lado e de outro com os ativos processos denudacionais concomitantes, responsáveis pelo rebaixamento erosivo das depressões e da intensa dissecação do relevo dos planaltos do entorno da Chapada.A Chapada dos Guimarães, corresponde portanto a um segmento de relevo da borda noroeste da bacia do Paraná, que se manteve mais preservada dos processos de falhamentos e consequentemente das atividades erosivas meso-cenozoicas.</p>
Estimated Global, Regional, and National Disease Burdens Related to Sugar-Sweetened Beverage Consumption in 2010
Authors: Singh Gitanjali M. , Micha Renata , Khatibzadeh Shahab , Lim Stephen , Ezzati Majid , Mozaffarian Dariush 
Published: June 2015

Background—
Sugar-sweetened beverages (SSBs) are consumed globally and contribute to adiposity. However, the worldwide impact of SSBs on burdens of adiposity-related cardiovascular diseases (CVDs), cancers, and diabetes mellitus has not been assessed by nation, age, and sex.

Methods and Results—
We modeled global, regional, and national burdens of disease associated with SSB consumption by age/sex in 2010. Data on SSB consumption levels were pooled from national dietary surveys worldwide. The effects of SSB intake on body mass index and diabetes mellitus, and of elevated body mass index on CVD, diabetes mellitus, and cancers were derived from large prospective cohort pooling studies. Disease-specific mortality/morbidity data were obtained from Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We computed cause-specific population-attributable fractions for SSB consumption, which were multiplied by cause-specific mortality/morbidity to compute estimates of SSB-attributable death/disability. Analyses were done by country/age/sex; uncertainties of all input data were propagated into final estimates. Worldwide, the model estimated 184 000 (95% uncertainty interval, 161 000–208 000) deaths/y attributable to SSB consumption: 133 000 (126 000–139 000) from diabetes mellitus, 45 000 (26 000–61 000) from CVD, and 6450 (4300–8600) from cancers. Five percent of SSB-related deaths occurred in low-income, 70.9% in middle-income, and 24.1% in high-income countries. Proportional mortality attributable to SSBs ranged from <1% in Japanese >65 years if age to 30% in Mexicans <45 years of age. Among the 20 most populous countries, Mexico had largest absolute (405 deaths/million adults) and proportional (12.1%) deaths from SSBs. A total of 8.5 (2.8, 19.2) million disability-adjusted life years were related to SSB intake (4.5% of diabetes mellitus–related disability-adjusted life years).

Conclusions—
SSBs are a single, modifiable component of diet that can impact preventable death/disability in adults in high-, middle-, and low-income countries, indicating an urgent need for strong global prevention programs.