Gd(III) chelate is currently used as positive magnetic resonance imaging (MRI) contrast agent in clinical diagnosis, but generally induces the risk of nephrogenic systemic fibrosis (NSF) due to the dissociated Gd(3+) from Gd(III) chelates. To develop a novel positive MRI contrast agent with low toxicity and high sensitivity, ultrasmall MnO nanoparticles were PEGylated via catechol-Mn chelation and conjugated with cRGD as active targeting function to tumor. Particularly, the MnO nanoparticles with a size of ca. 5nm were modified by α,β-poly(aspartic acid)-based graft polymer containing PEG and DOPA moieties and, meanwhile, conjugated with cRGD to produce the contrast agent with a size of ca. 100nm and a longitudinal relaxivity (r1) of 10.2mM(-1)S(-1). Such nanoscaled contrast agent integrated passive- and active-targeting function to tumor, and its efficient accumulation behavior in tumor was verified by in vivo distribution study. At the same time, the PEG moiety played a role of hydrophilic coating to improve the biocompatibility and stability under storing and physiological conditions, and especially might guarantee enough circulation time in blood. Moreover, in vivo MRI revealed a good and long-term effect of enhancing MRI signal for as-fabricated contrast agent while cell viability assay proved its acceptable cytotoxicity for MRI application. On the whole, the as-fabricated PEGylated and cRGD-functionalized contrast agent based on ultrasmall MnO nanoparticles showed a great potential to the T1-weighted MRI diagnosis of tumor.
Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

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Develop a minimal mechanistic model based on in vitro-in vivo extrapolation (IVIVE) principles to predict extent of passive tubular reabsorption. Assess the ability of the model developed to predict extent of passive tubular reabsorption (Freab) and renal excretion clearance (CLR) from in vitro permeability data and tubular physiological parameters.
Model system parameters were informed by physiological data collated following extensive literature analysis. A database of clinical CLR was collated for 157 drugs. A subset of 45 drugs was selected for model validation; for those, Caco-2 permeability (Papp) data were measured under pH6.5-7.4 gradient conditions and used to predict Freab and subsequently CLR. An empirical calibration approach was proposed to account for the effect of inter-assay/laboratory variation in Papp on the IVIVE of Freab.
The 5-compartmental model accounted for regional differences in tubular surface area and flow rates and successfully predicted the extent of tubular reabsorption of 45 drugs for which filtration and reabsorption were contributing to renal excretion. Subsequently, predicted CLR was within 3-fold of the observed values for 87% of drugs in this dataset, with an overall gmfe of 1.96. Consideration of the empirical calibration method improved overall prediction of CLR (gmfe=1.73 for 34 drugs in the internal validation dataset), in particular for basic drugs and drugs with low extent of tubular reabsorption.
The novel 5-compartment model represents an important addition to the IVIVE toolbox for physiologically-based prediction of renal tubular reabsorption and CLR. Physiological basis of the model proposed allows its application in future mechanistic kidney models in preclinical species and human.
Copyright © 2015. Published by Elsevier B.V.

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Genome-wide association studies have identified a single-nucleotide polymorphism (SNP) to be associated with an increased risk of breast cancer. The biology of one of the susceptibility locus C6ORF-ESR1 and whether it also contributes to progression of established disease has not yet been ascertained. We examined the association of rs2046210 and its six linkage disequilibrium SNPs with clinicopathological characteristics, prognosis, and gene expression levels of ESR1 and the C6ORFs (C6ORF97:CCDC170, C6ORF211, C6ORF96:RMND1) in 344 breast cancer tissue samples and 253 corresponding samples of adjacent normal tissue. Tumor genotypes with homozygous risk alleles were more frequent than normal tissues. The tumor genotypes of rs2046210 and rs6929137 with homozygous risk alleles showed worse relapse-free survival (RFS, P=0.038 and P=0.031, respectively), whereas no notable associations were observed with either clinicopathological characteristics or expression of the peripheral genes. Higher C6ORF97 expression correlated with ER negativity (P<0.0001), highly proliferative characteristics (P=0.0005 for Ki67, P<0.0001 for nuclear grade) and worse RFS in the ER+/HER2- cohort (P=0.013), whereas the other two C6ORFs showed the inverse associations. Furthermore, C6ORF97 showed significant worse prognostic values especially in luminal B subtype in the publically available data sets. rs2046210 and the upstream gene C6ORF97 might have substantial roles not only in carcinogenesis but also in progression toward a more aggressive phenotype in breast cancer patients, which suggests that functional studies of this locus are imperative.

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Despite the ever-changing breast surgeon’s technical role, the surgeon forms an indispensible link between imaging, diagnostics, pathology, and the medical oncologist. Biomarkers of prognosis, prediction of response, and resistance to treatments, including imaging, tissue and circulating markers apply to the primary diagnostic and treatment settings as well as scenarios which include disease recurrence, both in the early and advanced settings. Whether it is via the diagnostic clinic referred by the primary care physician or via a breast screening service, primary early breast cancer is referred for initial treatment and/or diagnosis and currently remains the domain of the surgical oncologist. The surgeon is privileged by this unique "window of opportunity" to consider the biological aspects of the diagnosis and guide the patient appropriately toward initial therapy, only one of which is primary surgery. Options of neoadjuvant endocrine, cytotoxic, or targeted therapy as either standard of care or else in the clinical trial context should be considered to optimize treatment in all patients.
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

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Inhaled corticosteroid/long-acting β2-agonist combinations (ICS/LABA) have emerged as first line therapies for chronic obstructive pulmonary disease (COPD) patients with exacerbation history. No randomized clinical trial has compared exacerbation rates among COPD patients receiving budesonide/formoterol combination (BFC) and fluticasone/salmeterol combination (FSC) to date, and only limited comparative data are available. This study compared the real-world effectiveness of approved BFC and FSC treatments among matched cohorts of COPD patients in a large US managed care setting.
COPD patients (≥40 years) naive to ICS/LABA who initiated BFC or FSC treatments between 03/01/2009-03/31/2012 were identified in a geographically diverse US managed care database and followed for 12 months; index date was defined as first prescription fill date. Patients with a cancer diagnosis or chronic (≥180 days) oral corticosteroid (OCS) use within 12 months prior to index were excluded. Patients were matched 1-to-1 on demographic and pre-initiation clinical characteristics using propensity scores from a random forest model. The primary efficacy outcome was COPD exacerbation rate, and secondary efficacy outcomes included exacerbation rates by event type and healthcare resource utilization. Pneumonia objectives included rates of any diagnosis of pneumonia and pneumonia-related healthcare resource utilization.
Matching of the identified 3,788 BFC and 6,439 FSC patients resulted in 3,697 patients in each group. Matched patients were well balanced on age (mean=64 years), gender (BFC: 52% female; FSC: 54%), prior COPD-related medication use, healthcare utilization, and comorbid conditions. During follow-up, no significant difference was seen between BFC and FSC patients for number of COPD-related exacerbations overall (rate ratio [RR]=1.02, 95% CI=[0.96,1.09], p=0.56) or by event type: COPD-related hospitalizations (RR=0.96), COPD-related ED visits (RR=1.11), and COPD-related office/outpatient visits with OCS and/or antibiotic use (RR=1.01). The proportion of patients diagnosed with pneumonia during the post-index period was similar for patients in each group (BFC =17.3%, FSC =19.0%, odds ratio=0.92 [0.81,1.04], p=0.19), and no difference was detected for pneumonia-related healthcare utilization by place of service.
This study demonstrated no difference in COPD-related exacerbations or pneumonia events between BFC and FSC treatment groups for patients new to ICS/LABA treatment in a real-world setting.
ClinicalTrials.gov identifier NCT01921127 .

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