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

Lower Bound-oriented Parameter Calculation for AN Coding

The hardware as well as software communities have recently experienced a shift towards mitigating bit flips issues in software, rather than completely mitigating only in hardware. For this software error mitigation, arithmetic error coding schemes like AN coding are increasingly applied because arithmetic operations can be directly executed without decoding and bit flip detection is provided in an end-to-end fashion. In this case, each encoded data word is computed by multiplying the original data word with a constant integer value A. To reliably detect b bit flips in each code word, the value A has to be well-chosen, so that a minimum Hamming distance of b + 1 can be guaranteed. However, the value A depends on the data word length as well as on the desired minimum Hamming distance. Up to now, a very expensive brute force approach for computation of the value for A is applied. To tackle that in a more efficient way, we present a lower bound-oriented approach for this calculation in this paper

Compression-Aware In-Memory Query Processing: Vision, System Design and Beyond

In-memory database systems have to keep base data as well as intermediate results generated during query processing in main memory. In addition, the effort to access intermediate results is equivalent to the effort to access the base data. Therefore, the optimization of intermediate results is interesting and has a high impact on the performance of the query execution. For this domain, we propose the continuous use of lightweight compression methods for intermediate results and have the aim of developing a balanced query processing approach based on compressed intermediate results. To minimize the overall query execution time, it is important to find a balance between the reduced transfer times and the increased computational effort. This paper provides an overview and presents a system design for our vision. Our system design addresses the challenge of integrating a large and evolving corpus of lightweight data compression algorithms in an in-memory column store. In detail, we present our model-driven approach and describe ongoing research topics to realize our compression-aware query processing vision

From a Comprehensive Experimental Survey to a Cost-based Selection Strategy for Lightweight Integer Compression Algorithms

Lightweight integer compression algorithms are frequently applied in in-memory database systems to tackle the growing gap between processor speed and main memory bandwidth. In recent years, the vectorization of basic techniques such as delta coding and null suppression has considerably enlarged the corpus of available algorithms. As a result, today there is a large number of algorithms to choose from, while different algorithms are tailored to different data characteristics. However, a comparative evaluation of these algorithms with different data and hardware characteristics has never been sufficiently conducted in the literature. To close this gap, we conducted an exhaustive experimental survey by evaluating several state-of-the-art lightweight integer compression algorithms as well as cascades of basic techniques. We systematically investigated the influence of data as well as hardware properties on the performance and the compression rates. The evaluated algorithms are based on publicly available implementations as well as our own vectorized reimplementations. We summarize our experimental findings leading to several new insights and to the conclusion that there is no single-best algorithm. Moreover, in this article, we also introduce and evaluate a novel cost model for the selection of a suitable lightweight integer compression algorithm for a given dataset

Capturing Smart Contract Design with DCR Graphs

Smart contracts manage blockchain assets. While smart contracts embody business processes, their platforms are not process-aware. Mainstream smart contract programming languages such as Solidity do not have explicit notions of roles, action dependencies, and time. Instead, these concepts are implemented in program code. This makes it very hard to design and analyze smart contracts. We argue that DCR graphs are a suitable formalization tool for smart contracts because they explicitly and visually capture these features. We utilize this expressiveness to show that many common high-level design patterns in smart-contract applications can be naturally modeled this way. Applying these patterns shows that DCR graphs facilitate the development and analysis of correct and reliable smart contracts by providing a clear and easy-to-understand specification

Monocular visual acuity of persons 4-74 years, United States, 1971-1972

Visual acuity levels with usual correction, if any, as determined in the opthalmology examination before dilation by race, geographic region, family income, and other selected demographic variables.[Jean Roberts and Jacqueline Ludford].Includes bibliographical references.197730168

National unterschiedliche Produktionsbedingungen als Schranke einer gewerkschaftlichen Internationalisierung: Zur Kritik des syndikalistischen Internationalismus

Die gewerkschaftliche Diskussion über multinationale Konzerne, die Anfang der Süer Jahre in den USA entstanden ist, und seit Mitte der 60er Jahre auch von den westeuropäischen Gewerkschaften aufgegriffen wird, hat - zumindest vorübergehend - zu einer euphorischen Beurteilung der Möglichkeiten einer gewerkschaftlichen Internationalisierung geführt. Einer solchen Euphorie liegt die Annahme zugrunde, daß durch den Prozeß der ,Internationalisierung des Kapitals' in Gestallt der multinationalen Konzerne erstmals in der Geschichte des Kapitalismus objektive Bedingungen für eine Überwindung der nationalen Fraktionierung der Gewerkschaftsbewegung gegeben seien. ,,Die objektiven Voraussetzungen sind gegeben: sie sind viel weiter ausgereift als die subjektiven Bedingungen .... Die Schwierigkeiten sind hauptsächlich bei den Gewerkschaften zu suchen ... " (1 ). Eine derartige Reduktion der Frage nach den Möglichkeiten und Grenzen einer internationalen Gewerkschaftspolitik auf ein bloßes „Nachlaufspiel" (2) der Gewerkschaften, in dem es für diese nur noch darum gehe, politisch-rechtlich nachzuholen, was durch die ökonomische Entwicklung bereits vollzogen sei, ist unserer Auffassung nach in mehrerer Hinsicht problematisch

Model-Driven Integration of Compression Algorithms in Column-Store Database Systems

Abstract. Modern database systems are very often in the position to store their entire data in main memory. Aside from increased main memory capacities, a further driver for in-memory database systems was the shift to a decomposition storage model in combination with lightweight data compression algorithms. Using both mentioned storage design concepts, large datasets can be held and processed in main memory with a low memory footprint. In recent years, a large corpus of lightweight data compression algorithms has been developed to efficiently support different data characteristics. In this paper, we present our novel model-driven concept to integrate this large and evolving corpus of lightweight data compression algorithms in column-store database systems. Core components of our concept are (i) a unified conceptual model for lightweight compression algorithms, (ii) specifying algorithms as platform-independent model instances, (iii) transforming model instances into low-level system code, and (iv) integrating low-level system code into a storage layer

MorphStore — In-Memory Query Processing based on Morphing Compressed Intermediates LIVE

In this demo, we present MorphStore, an in-memory column store with a novel compression-aware query processing concept. Basically, compression using lightweight integer compression algorithms already plays an important role in existing in-memory column stores, but mainly for base data. The continuous handling of compression from the base data to the intermediate results during query processing has already been discussed, but not investigated in detail since the computational effort for compression as well as decompression is often assumed to exceed the benefits of a reduced transfer cost between CPU and main memory. However, this argument increasingly loses its validity as we are going to show in our demo. Generally, our novel compression-aware query processing concept is characterized by the fact that we are able to speed up the query execution by morphing compressed intermediate results from one scheme to another scheme to dynamically adapt to the changing data characteristics during query processing. Our morphing decisions are made using a cost-based approach

Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this class of compounds, we report on 17 different ruthenium(II) complexes and four promising osmium(II) analogues with cinnamic acid derivatives as O,S bidentate ligands. The aim of this study was to determine the anticancer activity and the ability to evade platin resistance mechanisms for these compounds. (2) Methods: Structural characterizations and stability determinations have been carried out with standard techniques, including NMR spectroscopy and X-ray crystallography. All complexes and single ligands have been tested for cytotoxic activity on two ovarian cancer cell lines (A2780, SKOV3) and their cisplatin-resistant isogenic cell cultures, a lung carcinoma cell line (A549) as well as selected compounds on three non-cancerous cell cultures in vitro. FACS analyses and histone γH2AX staining were carried out for cell cycle distribution and cell death or DNA damage analyses, respectively. (3) Results: IC50 values show promising results, specifically a high cancer selective cytotoxicity and evasion of resistance mechanisms for Ru(II) and Os(II) compounds. Histone γH2AX foci and FACS experiments validated the high cytotoxicity but revealed diminished DNA damage-inducing activity and an absence of cell cycle disturbance thus pointing to another mode of action. (4) Conclusion: Ru(II) and Os(II) compounds with O,S-bidentate ligands show high cytotoxicity without strong effects on DNA damage and cell cycle, and this seems to be the basis to circumvent resistance mechanisms and for the high cancer cell specificity