The main goal of this research was to study the interactions of a fully characterized set of silver nanomaterials (Ag ENMs) with cells in vitro, according to the standards of Good Laboratory Practices (GLP), to assure the quality of nanotoxicology research. We were interested in whether Ag ENMs synthesized by the same method, with the same size distribution, shape and specific surface area, but with different charges and surface compositions could give different biological responses.
A range of methods and toxicity endpoints were applied to study the impacts of interaction of the Ag ENMs with TK6 cells. As tests of viability, relative growth activity and trypan blue exclusion were applied. Genotoxicity was evaluated by the alkaline comet assay for detection of strand breaks and oxidized purines. The mutagenic potential of Ag ENMs was investigated with the in vitro HPRT gene mutation test on V79-4 cells according to the OECD protocol. Ag ENM agglomeration, dissolution as well as uptake and distribution within the cells were investigated as crucial aspects of Ag ENM toxicity. Ag ENM stabilizers were included in addition to positive and negative controls.
Different cytotoxic effects were observed including membrane damage, cell cycle arrest and cell death. Ag ENMs also induced various kinds of DNA damage including strand breaks and DNA oxidation, and caused gene mutation. We found that positive Ag ENMs had greater impact on cyto- and genotoxicity than did Ag ENMs with neutral or negative charge, assumed to be related to their greater uptake into cells and to their presence in the nucleus and mitochondria, implying that Ag ENMs might induce toxicity by both direct and indirect mechanisms.
We showed that Ag ENMs could be cytotoxic, genotoxic and mutagenic. Our experiments with the HPRT gene mutation assay demonstrated that surface chemical composition plays a significant role in Ag ENM toxicity.

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In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

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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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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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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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