Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging

Targeted delivery represents a promising approach for the development of safer and more effective therapeutics for oncology applications. Although macromolecules accumulate nonspecifically in tumors through the enhanced permeability and retention (EPR) effect, previous studies using nanoparticles to deliver chemotherapeutics or siRNA demonstrated that attachment of cell-specific targeting ligands to the surface of nanoparticles leads to enhanced potency relative to nontargeted formulations. Here, we use positron emission tomography (PET) and bioluminescent imaging to quantify the in vivo biodistribution and function of nanoparticles formed with cyclodextrin-containing polycations and siRNA. Conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to the 5' end of the siRNA molecules allows labeling with 64Cu for PET imaging. Bioluminescent imaging of mice bearing luciferase-expressing Neuro2A s.c. tumors before and after PET imaging enables correlation of functional efficacy with biodistribution data. Although both nontargeted and transferrin-targeted siRNA nanoparticles exhibit similar biodistribution and tumor localization by PET, transferrin-targeted siRNA nanoparticles reduce tumor luciferase activity by {approx}50% relative to nontargeted siRNA nanoparticles 1 d after injection. Compartmental modeling is used to show that the primary advantage of targeted nanoparticles is associated with processes involved in cellular uptake in tumor cells rather than overall tumor localization. Optimization of internalization may therefore be key for the development of effective nanoparticle-based targeted therapeutics

Foodborne hepatitis A outbreak associated with bakery products in northern Germany, 2012

In October 2012, a hepatitis A (HA) outbreak with 83 laboratory-confirmed cases occurred in Lower Saxony. We defined primary outbreak cases as people with laboratory-confirmed HA and symptom onset between 8 October and 12 November 2012, residing in or visiting the affected districts. Secondary outbreak cases were persons with symptom onset after 12 November 2012 and close contact with primary cases. We identified 77 primary and six secondary cases. We enrolled 50 primary cases and 52 controls matched for age and sex, and found that 82% of cases and 60% of controls had consumed products from a particular bakery (OR=3.09; 95% CI: 1.15–8.68). Cases were more likely to have eaten sweet pastries (OR=5.74; 95% CI: 1.46–22.42). Viral isolates from five selected cases and three positively tested surfaces in the bakery had identical nucleotide sequences. One additional identical isolate derived from a salesperson of the bakery suffering from a chronic disease that required immunosuppressive treatment. Epidemiological and laboratory findings suggested that the salesperson contaminated products while packing and selling. Future risk assessment should determine whether food handlers with chronic diseases under immunosuppressive treatment could be more at risk of contaminating food and might benefit from HAV immunisation

FDG-PET/CT Imaging Predicts Histopathologic Treatment Responses after Neoadjuvant Therapy in Adult Primary Bone Sarcomas

Purpose. The aim of this study was to prospectively evaluate whether FDG-PET allows an accurate assessment of histopathologic response to neoadjuvant treatment in adult patients with primary bone sarcomas. Methods. Twelve consecutive patients with resectable, primary high grade bone sarcomas were enrolled prospectively. FDG-PET/CT imaging was performed prior to the initiation and after completion of neoadjuvant treatment. Imaging findings were correlated with histopathologic response. Results. Histopathologic responders showed significantly more pronounced decreases in tumor FDG-SUVmax from baseline to late follow up than non-responders (64 ± 19% versus 29 ± 30 %, resp.; P = .03). Using a 60% decrease in tumor FDG-uptake as a threshold for metabolic response correctly classified 3 of 4 histopathologic responders and 7 of 8 histopathologic non-responders as metabolic responders and non-responders, respectively (sensitivity, 75%; specificity, 88%). Conclusion. These results suggest that changes in FDG-SUVmax at the end of neoadjuvant treatment can identify histopathologic responders and non-responders in adult primary bone sarcoma patients

Precise Prediction for M_W in the MSSM

We present the currently most accurate evaluation of the W boson mass, M_W, in the Minimal Supersymmetric Standard Model (MSSM). The full complex phase dependence at the one-loop level, all available MSSM two-loop corrections as well as the full Standard Model result have been included. We analyse the impact of the different sectors of the MSSM at the one-loop level with a particular emphasis on the effect of the complex phases. We discuss the prediction for M_W based on all known higher-order contributions in representative MSSM scenarios. Furthermore we obtain an estimate of the remaining theoretical uncertainty from unknown higher-order corrections.Comment: 38 pages, 25 figures. Minor corrections, additional reference

Equity as a Prerequisite for Stability of Cooperation on Global Public Good Provision

Analysing cooperative provision of a global public good such as climate protection, we explore the relationship between equitable burden sharing on the one hand and core stability on the other. To assess the size of the burden which a public good contribution entails for a country, we make use of a specific measure based on Moulin (Econometrica 55:963-977, 1987). In particular, we show that a Pareto optimal allocation which is not in the core can always be blocked by a group of countries with the highest Moulin sacrifices. In this sense, it is the 'overburdening' and thus 'unfair' treatment of some countries that provides the reason for core instability. By contrast, a Pareto optimal allocation is in the core if the public good contributions are fairly equally distributed according to their Moulin sacrifices. The potential implications of our theoretical analysis for global climate policy are also discussed